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Entry
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- #188055 - THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE; THPH2
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- OMIM
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<p>
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<span class="h4">#188055</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/188055"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS188050"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#heterogeneity">Heterogeneity</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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<div><a href="https://clinicaltrials.gov/search?cond=THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1368/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/9393" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/factor-v-leiden-thrombophilia" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=188055[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111902" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/188055" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ICD10CM:</strong> D68.51<br />
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<strong>DO:</strong> 0111902<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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188055
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE; THPH2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ACTIVATED PROTEIN C RESISTANCE<br />
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APC RESISTANCE<br />
|
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THROMBOPHILIA DUE TO DEFICIENCY OF ACTIVATED PROTEIN C COFACTOR<br />
|
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PROC COFACTOR DEFICIENCY<br />
|
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PCCF DEFICIENCY<br />
|
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THROMBOPHILIA V
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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THROMBOPHILIA DUE TO FACTOR V LEIDEN, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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<tbody>
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<span class="mim-font">
|
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<a href="/geneMap/1/1404?start=-3&limit=10&highlight=1404">
|
|
1q24.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Thrombophilia, susceptibility to, due to factor V Leiden}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> 188055 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
F5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> 612309 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1404?start=-3&limit=10&highlight=1404">
|
|
1q24.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Thrombophilia 2 due to activated protein C resistance
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> 188055 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
F5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> 612309 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/188055" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS188050" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/188055" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/188055" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Venous thrombosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111293003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111293003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I82.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I82.90</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042487&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042487</a>, <a href="https://bioportal.bioontology.org/search?q=C0517555&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0517555</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004936</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004936</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> PRENATAL MANIFESTATIONS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Maternal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Increased risk for preeclampsia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674153&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674153</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Delivery </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Increased fetal loss <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674154&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674154</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Resistance to activated protein C <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600433&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600433</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012175</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012175</a>]</span><br /> -
|
|
Poor anticoagulant response to exogenous activated protein C as measured by the activated partial thromboplastin time (APTT) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674155&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674155</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Most cases are caused by the factor V Leiden mutation (R506Q, <a href="/entry/612309#0001">612309.0001</a>)<br /> -
|
|
Onset of symptoms usually in adulthood<br /> -
|
|
Thrombosis triggered by pregnancy, oral contraceptives, trauma, surgery<br /> -
|
|
Homozygotes have more severe disease with earlier onset of thrombosis<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the coagulation factor V gene (F5, <a href="/entry/612309#0001">612309.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Thrombophilia
|
|
- <a href="/phenotypicSeries/PS188050">PS188050</a>
|
|
- 17 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/157?start=-3&limit=10&highlight=157"> 1p36.22 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> {Thromboembolism, susceptibility to} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> 188050 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607093"> MTHFR </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607093"> 607093 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1404?start=-3&limit=10&highlight=1404"> 1q24.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> {Thrombophilia, susceptibility to, due to factor V Leiden} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> 188055 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> F5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> 612309 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1404?start=-3&limit=10&highlight=1404"> 1q24.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> Thrombophilia 2 due to activated protein C resistance </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188055"> 188055 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> F5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612309"> 612309 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1440?start=-3&limit=10&highlight=1440"> 1q25.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613118"> Thrombophilia 7 due to antithrombin III deficiency </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613118"> 613118 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107300"> SERPINC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107300"> 107300 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/623?start=-3&limit=10&highlight=623"> 2q14.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612304"> Thrombophilia 3 due to protein C deficiency, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612304"> 612304 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612283"> PROC </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612283"> 612283 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/623?start=-3&limit=10&highlight=623"> 2q14.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176860"> Thrombophilia 3 due to protein C deficiency, autosomal dominant </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176860"> 176860 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612283"> PROC </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612283"> 612283 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/481?start=-3&limit=10&highlight=481"> 3q11.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612336"> Thrombophilia 5 due to protein S deficiency, autosomal dominant </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612336"> 612336 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176880"> PROS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176880"> 176880 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/481?start=-3&limit=10&highlight=481"> 3q11.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614514"> Thrombophilia 5 due to protein S deficiency, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614514"> 614514 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176880"> PROS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176880"> 176880 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/938?start=-3&limit=10&highlight=938"> 3q27.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613116"> Thrombophilia 11 due to HRG deficiency </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613116"> 613116 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/142640"> HRG </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/142640"> 142640 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/35?start=-3&limit=10&highlight=35"> 6p25.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> {Venous thrombosis, protection against} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> 188050 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/134570"> F13A1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/134570"> 134570 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/171?start=-3&limit=10&highlight=171"> 8p12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612348"> ?Thrombophilia 9 due to decreased release of tissue plasminogen </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612348"> 612348 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612348"> THPH9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612348"> 612348 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/571?start=-3&limit=10&highlight=571"> 10q25.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> {Venous thromboembolism, susceptibility to} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> 188050 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603924"> HABP2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603924"> 603924 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/351?start=-3&limit=10&highlight=351"> 11p11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> Thrombophilia 1 due to thrombin defect </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188050"> 188050 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176930"> F2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176930"> 176930 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/20/145?start=-3&limit=10&highlight=145"> 20p11.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614486"> Thrombophilia 12 due to thrombomodulin defect </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614486"> 614486 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188040"> THBD </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188040"> 188040 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/22/67?start=-3&limit=10&highlight=67"> 22q11.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612356"> Thrombophilia 10 due to heparin cofactor II deficiency </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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<p>A number sign (#) is used with this entry because of evidence that the disorder is caused by heterozygous mutation in the gene that encodes factor V (F5; <a href="/entry/612309">612309</a>) on chromosome 1q24.</p>
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<p>Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; <a href="/entry/612283">612283</a>) and results in a tendency to thrombosis.</p><p>See also factor V deficiency (<a href="/entry/227400">227400</a>), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V.</p><p>The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; <a href="/entry/612309#0001">612309.0001</a>), named after the town in the Netherlands where <a href="#2" class="mim-tip-reference" title="Bertina, R. M., Koeleman, B. P. C., Koster, T., Rosendaal, F. R., Dirven, R. J., de Ronde, H., van der Velden, P. A., Reitsma, P. H. <strong>Mutation in blood coagulation factor V associated with resistance to activated protein C.</strong> Nature 369: 64-67, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164741</a>] [<a href="https://doi.org/10.1038/369064a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164741">Bertina et al. (1994)</a> discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8164741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Dahlback, B., Carlsson, M., Svensson, P. J. <strong>Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.</strong> Proc. Nat. Acad. Sci. 90: 1004-1008, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8430067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8430067</a>] [<a href="https://doi.org/10.1073/pnas.90.3.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8430067">Dahlback et al. (1993)</a> reported a family in which 5 individuals spanning 3 generations had adult-onset thromboembolic disease, most often deep venous thrombosis of the legs, inherited in an autosomal dominant pattern. Laboratory studies of patients' plasma demonstrated a poor anticoagulant response upon the addition of activated protein C (APC; <a href="/entry/612283">612283</a>), as measured by the lack of prolongation of clotting time in an activated partial thromboplastin time (aPTT) assay. In addition, 14 of 19 tested family members showed a similar defect in this assay. Known coagulation defects and serum autoantibodies or inhibitors to APC were excluded. Two additional unrelated patients with thrombophilia and inherited poor response to APC were identified using this novel assay. The thromboembolic events occurred during pregnancy or in the postpartum period in the 2 additional families. <a href="#11" class="mim-tip-reference" title="Dahlback, B., Carlsson, M., Svensson, P. J. <strong>Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.</strong> Proc. Nat. Acad. Sci. 90: 1004-1008, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8430067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8430067</a>] [<a href="https://doi.org/10.1073/pnas.90.3.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8430067">Dahlback et al. (1993)</a> concluded that these individuals were lacking a previously unrecognized cofactor for APC that was responsible for the subnormal APC effects in the degradation of factors Va and VIIIa (<a href="/entry/300841">300841</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8430067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Greengard, J. S., Eichinger, S., Griffin, J. H., Bauer, K. A. <strong>Variability of thrombosis among homozygous siblings with resistance to activated protein C due to an arg-to-gln mutation in the gene for factor V.</strong> New Eng. J. Med. 331: 1559-1562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7969326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7969326</a>] [<a href="https://doi.org/10.1056/NEJM199412083312305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7969326">Greengard et al. (1994)</a> reported variability of thrombosis in a family in which 4 sibs were homozygous for the R560Q mutation. The oldest son, who was homozygous, developed deep vein thrombosis (DVT) of the leg after an injury to that extremity at age 18 years. Two weeks later, during treatment with warfarin, he developed a DVT of the other leg. A clip was placed on the inferior vena cava and warfarin therapy was continued for 2 years. He later developed severe bilateral postphlebitic syndrome with chronic leg ulcers. Another son, who was heterozygous, developed a spontaneous DVT of the leg at age 23 years. The youngest son, who was homozygous, had a spontaneous pulmonary embolus confirmed by pulmonary angiography at the age of 16 years. This recurred 1 year later after the discontinuation of warfarin treatment. At the age of 24, he had a DVT of the right leg when he was not receiving warfarin; he was treated for 6 months. Four months after the discontinuation of treatment, he had a recurrent DVT in the right leg. The heterozygous mother developed a DVT of the left leg during her most recent pregnancy at the age of 37. Two daughters, aged 28 and 33 years, who were homozygous for the mutation, and the father, who was heterozygous, had not developed thrombosis. <a href="#21" class="mim-tip-reference" title="Greengard, J. S., Eichinger, S., Griffin, J. H., Bauer, K. A. <strong>Variability of thrombosis among homozygous siblings with resistance to activated protein C due to an arg-to-gln mutation in the gene for factor V.</strong> New Eng. J. Med. 331: 1559-1562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7969326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7969326</a>] [<a href="https://doi.org/10.1056/NEJM199412083312305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7969326">Greengard et al. (1994)</a> noted that the daughters had not been exposed to risk factors, such as major surgical procedures, the use of oral contraceptives, or pregnancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7969326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Zoller, B., Dahlback, B. <strong>Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis.</strong> Lancet 343: 1536-1538, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911873</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92940-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7911873">Zoller and Dahlback (1994)</a> studied a large kindred in which familial thrombophilia and APC resistance was inherited as an autosomal dominant trait, and all affected individuals had the R506Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7911873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 47 Swedish families with APC resistance and the R506Q mutation, <a href="#63" class="mim-tip-reference" title="Zoller, B., Svensson, P. J., He, X., Dahlback, B. <strong>Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.</strong> J. Clin. Invest. 94: 2521-2524, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7989612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7989612</a>] [<a href="https://doi.org/10.1172/JCI117623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7989612">Zoller et al. (1994)</a> observed that by age 33 years, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestations of venous thrombosis. In a majority of both heterozygous and homozygous individuals, thrombosis was associated with risk factors, most commonly pregnancy, oral contraceptives, trauma, and surgery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7989612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Pipe, S. W., Schmaier, A. H., Nichols, W. C., Ginsburg, D., Bozynski, M. E. A., Castle, V. P. <strong>Neonatal purpura fulminans in association with factor V R506Q mutation.</strong> J. Pediat. 128: 706-709, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8627449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8627449</a>] [<a href="https://doi.org/10.1016/s0022-3476(96)80142-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8627449">Pipe et al. (1996)</a> reported a patient with neonatal purpura fulminans associated with heterozygosity for the R506Q mutation. At 8 hours of age, the neonate had progressive purpuric skin lesions and later had evidence of microvascular hemorrhagic thrombosis in the brain. The infant was treated with fresh frozen plasma infusions and had complete resolution of the skin lesions and no apparent long-term complications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8627449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Simioni, P., Prandoni, P., Lensing, A. W. A., Scudeller, A., Sardella, C., Prins, M. H., Villalta, S., Dazzi, F., Girolami, A. <strong>The risk of recurrent venous thromboembolism in patients with an arg506-to-gln mutation in the gene for factor V (factor V Leiden).</strong> New Eng. J. Med. 336: 399-403, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9010145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9010145</a>] [<a href="https://doi.org/10.1056/NEJM199702063360602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9010145">Simioni et al. (1997)</a> found heterozygosity for factor V Leiden in 41 (16.3%) of 251 unselected patients with a first episode of symptomatic deep vein thrombosis diagnosed by venography. The cumulative incidence of recurrent venous thromboembolism after follow-up of up to 8 years was 39.7% among carriers of the mutation, as compared with 18.3% among patients without the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9010145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Jackson, R. T., Luplow, R. E., III. <strong>Adult purpura fulminans and digital necrosis associated with sepsis and the factor V mutation. (Letter)</strong> JAMA 280: 1829-1830, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9846775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9846775</a>] [<a href="https://doi.org/10.1001/jama.280.21.1829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9846775">Jackson and Luplow (1998)</a> described 2 adults with purpura fulminans related to sepsis who were found to be heterozygous for the factor V Leiden mutation. Each patient survived disseminated intravascular coagulation, shock, and digital necrosis, but eventually required digit amputations. The first patient was a 42-year-old man with Streptococcus pneumoniae. Acrocyanosis progressed to dry gangrene of all the fingers and toes; however, the skin of the forehead, ears, and nose recovered without scarring. The second patient was a 40-year-old woman with septicemia due to Bacteroides fragilis and Fusobacterium species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9846775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male neonate with inferior vena cava thrombosis, complicated by bilateral adrenal hemorrhage and left renal vein thrombosis <a href="#20" class="mim-tip-reference" title="Gorbe, E., Nagy, B., Varadi, V., Kiss, E., Mattyus, I., Rigo, J., Jr., Papp, Z. <strong>Mutation in the factor V gene associated with inferior vena cava thrombosis in newborns. (Letter)</strong> Clin. Genet. 55: 65-66, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10066036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10066036</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1999.550113.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10066036">Gorbe et al. (1999)</a> identified a homozygous factor V Leiden mutation. The infant improved with intravenous administration of dopamine-dobutamine and low doses of heparin. An associated persistent ductus arteriosus detected by echocardiography was ligated during hospitalization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10066036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a population-based cohort study of 9,253 Danish adults, <a href="#29" class="mim-tip-reference" title="Juul, K., Tybjaerg-Hansen, A., Schnohr, P., Nordestgaard, B. G. <strong>Factor V Leiden and the risk for venous thromboembolism in the adult Danish population.</strong> Ann. Intern. Med. 140: 330-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14996674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14996674</a>] [<a href="https://doi.org/10.7326/0003-4819-140-5-200403020-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14996674">Juul et al. (2004)</a> found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14996674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Role in Pregnancy Complications</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Brenner, B., Lanir, N., Thaler, I. <strong>HELLP syndrome associated with factor V R506Q mutation.</strong> Brit. J. Haemat. 92: 999-1001, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8616100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8616100</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1996.410947.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8616100">Brenner et al. (1996)</a> observed 2 patients with the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) who were heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see <a href="/entry/189800">189800</a>). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8616100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 122 pregnant women with preeclampsia or intrauterine growth retardation, <a href="#37" class="mim-tip-reference" title="Lindqvist, P. G., Svensson, P. J., Dahlback, B., Marsal, K. <strong>Factor V Q-506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss: a possible evolutionary selection mechanism.</strong> Thromb. Haemost. 79: 69-73, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9459326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9459326</a>]" pmid="9459326">Lindqvist et al. (1998)</a> found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. However, there was no difference between the 2 groups regarding preeclampsia or intrauterine growth retardation. <a href="#37" class="mim-tip-reference" title="Lindqvist, P. G., Svensson, P. J., Dahlback, B., Marsal, K. <strong>Factor V Q-506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss: a possible evolutionary selection mechanism.</strong> Thromb. Haemost. 79: 69-73, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9459326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9459326</a>]" pmid="9459326">Lindqvist et al. (1998)</a> speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9459326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Kupferminc, M. J., Eldor, A., Steinman, N., Many, A., Bar-Am, A., Jaffa, A., Fait, G., Lessing, J. B. <strong>Increased frequency of genetic thrombophilia in women with complications of pregnancy.</strong> New Eng. J. Med. 340: 9-12, 1999. Note: Erratum: New Eng. J. Med. 341: 384 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9878639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9878639</a>] [<a href="https://doi.org/10.1056/NEJM199901073400102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9878639">Kupferminc et al. (1999)</a> identified the factor V R506Q mutation in 22 of 110 women with obstetrical complications, including severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth, and in 7 of 110 women with normal pregnancies (p = 0.003). In 24 of the women with complications, as compared with 9 women without complications, homozygosity for the 677C-T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR; <a href="/entry/607093#0003">607093.0003</a>) was also found. Overall, 57 women with obstetrical complications had a thrombophilic mutation, as compared with 19 women with normal pregnancies (p less than 0.001). Anticardiolipin antibodies or deficiency of protein S, protein C, or antithrombin III were detected in an additional 14 women with complications, as compared with 1 woman with a normal pregnancy (p less than 0.001). <a href="#35" class="mim-tip-reference" title="Kupferminc, M. J., Eldor, A., Steinman, N., Many, A., Bar-Am, A., Jaffa, A., Fait, G., Lessing, J. B. <strong>Increased frequency of genetic thrombophilia in women with complications of pregnancy.</strong> New Eng. J. Med. 340: 9-12, 1999. Note: Erratum: New Eng. J. Med. 341: 384 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9878639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9878639</a>] [<a href="https://doi.org/10.1056/NEJM199901073400102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9878639">Kupferminc et al. (1999)</a> recommended that women with such obstetrical complications should be tested for genetic and acquired markers of thrombophilia because these complications tend to recur in subsequent pregnancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9878639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Faisel, F., Romppanen, E.-L., Hiltunen, M., Helisalmi, S., Laasanen, J., Punnonen, K., Salonen, J. T., Heinonen, S. <strong>Susceptibility to pre-eclampsia in Finnish women is associated with R485K polymorphism in the factor V gene, not with Leiden mutation.</strong> Europ. J. Hum. Genet. 12: 187-191, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14673478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14673478</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14673478">Faisel et al. (2004)</a> analyzed the allele and genotype frequencies of 2 F5 polymorphisms, M385T, R485K, and the R506Q Leiden mutation in 133 Finnish women with preeclampsia (<a href="/entry/189800">189800</a>) and 112 controls. There were statistically significant differences in R485K allele (p = 0.003) and genotype (p = 0.03) frequencies between patients and controls. The A allele of R485K was overrepresented among the patients (12%) compared to the controls (4%), with an odds ratio of 2.8 (95% CI, 1.2-6.2) for combined A genotypes. <a href="#17" class="mim-tip-reference" title="Faisel, F., Romppanen, E.-L., Hiltunen, M., Helisalmi, S., Laasanen, J., Punnonen, K., Salonen, J. T., Heinonen, S. <strong>Susceptibility to pre-eclampsia in Finnish women is associated with R485K polymorphism in the factor V gene, not with Leiden mutation.</strong> Europ. J. Hum. Genet. 12: 187-191, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14673478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14673478</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14673478">Faisel et al. (2004)</a> concluded that genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14673478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Other Diseases</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Heresbach, D., Pagenault, M., Gueret, P., Crenn, P., Heresbach-Le Berre, N., Malledant, Y., Fauchet, R., Horellou, M.-H., Silver, J., Messing, B., Bretagne, J.-F. <strong>Leiden factor V mutation in four patients with small bowel infarctions.</strong> Gastroenterology 113: 322-325, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207293</a>] [<a href="https://doi.org/10.1016/s0016-5085(97)70110-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9207293">Heresbach et al. (1997)</a> added small bowel infarctions to the many thrombotic states in which the factor V Leiden mutation plays a role. They observed the R506Q mutation in 2 cases of arterial and 2 cases of venous small bowel infarction. Two patients were heterozygous and 2 were homozygous. Three of the patients were in their mid-thirties and the fourth was a 45-year-old man. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9207293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Mahmoud, A. E. A., Elias, E., Beauchamp, N., Wilde, J. T. <strong>Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis.</strong> Gut 40: 798-800, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245936</a>] [<a href="https://doi.org/10.1136/gut.40.6.798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245936">Mahmoud et al. (1997)</a> reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (<a href="/entry/600880">600880</a>) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. <a href="#39" class="mim-tip-reference" title="Mahmoud, A. E. A., Elias, E., Beauchamp, N., Wilde, J. T. <strong>Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis.</strong> Gut 40: 798-800, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245936</a>] [<a href="https://doi.org/10.1136/gut.40.6.798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245936">Mahmoud et al. (1997)</a> concluded that the R506Q mutation may be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Leebeek, F. W. G., Lameris, J. S., van Buuren, H. R., Gomez, E., Madretsma, S., Sonneveld, P. <strong>Budd-Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis.</strong> Brit. J. Haemat. 102: 929-931, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734642</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1998.00860.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734642">Leebeek et al. (1998)</a> described a 27-year-old female homozygous for factor V Leiden with Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. She was treated by transjugular intrahepatic portosystemic stent placement followed by local thrombolytic therapy. Venous outflow from the liver was established and the thrombi in the portal and mesenteric veins were lysed completely. <a href="#25" class="mim-tip-reference" title="Gurakan, F., Gurgey, A., Bakkaloglu, A., Kocak, N. <strong>Homozygous factor V Leiden mutation in a child with Budd-Chiari syndrome.</strong> J. Pediat. Gastroent. Nutr. 28: 516-517, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10328130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10328130</a>] [<a href="https://doi.org/10.1097/00005176-199905000-00016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10328130">Gurakan et al. (1999)</a> described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10328130+9734642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="de Bruijn, S. F. T. M., Stam, J., Koopman, M. M. W., Vandenbroucke, J. P. <strong>Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in carriers of hereditary prothrombotic conditions.</strong> Brit. Med. J. 316: 589-592, 1998. Note: Erratum: J. Biol. Chem. 264: 21433 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9518910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9518910</a>] [<a href="https://doi.org/10.1136/bmj.316.7131.589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9518910">De Bruijn et al. (1998)</a> studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9518910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Chung, R. T., Iafrate, A. J., Amrein, P. C., Sahani, D. V., Misdraji, J. <strong>Case 15-2006: a 46-year-old woman with sudden onset of abdominal distention.</strong> New Eng. J. Med. 354: 2166-2175, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707754</a>] [<a href="https://doi.org/10.1056/NEJMcpc069006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707754">Chung et al. (2006)</a> described Budd-Chiari syndrome in a 46-year-old woman who developed rapidly increasing abdominal girth over a period of several days with accumulation of ascites. The disorder was found to be associated with a mutation in JAK2 (V617F; <a href="/entry/147796#0001">147796.0001</a>) and the factor V Leiden mutation. As many as 50% of patients with Budd-Chiari syndrome have a myeloproliferative disorder, either preexisting or diagnosed at the time of the syndrome. However, some patients with the Budd-Chiari syndrome may have a latent myeloproliferative disorder without elevated blood counts. The V617F mutation of the JAK2 gene has been detected in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder (<a href="#46" class="mim-tip-reference" title="Patel, R. K., Lea, N. C., Heneghan, M. A., Westwood, N. B., Milojkovic, D., Thanigaikumar, M., Yallop, D., Arya, R., Pagliuca, A., Gaken, J., Wendon, J., Heaton, N. D., Mufti, G. J. <strong>Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome.</strong> Gastroenterology 130: 2031-2038, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16762626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16762626</a>] [<a href="https://doi.org/10.1053/j.gastro.2006.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16762626">Patel et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16762626+16707754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Debus, O., Koch, H. G., Kurlemann, G., Strater, R., Vielhaber, H., Weber, P., Nowak-Gottl, U. <strong>Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly.</strong> Arch. Dis. Child Fetal Neonatal Ed. 78: F121-F124, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9577282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9577282</a>] [<a href="https://doi.org/10.1136/fn.78.2.f121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9577282">Debus et al. (1998)</a> found that 6 of 24 children with porencephaly (<a href="/entry/175780">175780</a>) were heterozygous for the factor V Leiden mutation. Two of these also had familial raised Lp(a) levels (<a href="/entry/152200">152200</a>) and 1 child also had protein S deficiency (<a href="/entry/612336">612336</a>). An additional 10 children had protein C deficiency, protein S deficiency, or familial raised Lp(a) levels. Five of the 24 children had a positive family history of thrombosis. <a href="#15" class="mim-tip-reference" title="Debus, O., Koch, H. G., Kurlemann, G., Strater, R., Vielhaber, H., Weber, P., Nowak-Gottl, U. <strong>Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly.</strong> Arch. Dis. Child Fetal Neonatal Ed. 78: F121-F124, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9577282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9577282</a>] [<a href="https://doi.org/10.1136/fn.78.2.f121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9577282">Debus et al. (1998)</a> suggested that hereditary thrombophilic states may predispose to perinatal cerebroarterial occlusion and porencephaly. The authors commented that other interacting prenatal factors, such as infection, placental dysfunction, or fetal cardiac arrhythmias, should also be considered as causative factors. <a href="#16" class="mim-tip-reference" title="Debus, O. M., Kosch, A., Strater, R., Rossi, R., Nowak-Gottl, U. <strong>The factor V G1691A mutation is a risk for porencephaly: a case-control study.</strong> Ann. Neurol. 56: 287-290, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15293282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15293282</a>] [<a href="https://doi.org/10.1002/ana.20184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15293282">Debus et al. (2004)</a> found a higher prevalence of the R506Q mutation among 76 patients with porencephaly compared to controls. Eighteen patients were heterozygous and 1 infant was homozygous; 4 controls carried the mutation. The authors suggested that patients with porencephaly have certain prothrombotic risk factors which may contribute to the development of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15293282+9577282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Kerlin, B. A., Yan, S. B., Isemann, B. H., Brandt, J. T., Sood, R., Basson, B. R., Joyce, D. E., Weiler, H., Dhainaut, J.-F. <strong>Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia.</strong> Blood 102: 3085-3092, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12869495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12869495</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12869495">Kerlin et al. (2003)</a> found that 4.1% of 65 patients with sepsis were heterozygous carriers of the factor V Leiden mutation. The 28-day mortality was lower in heterozygous carriers (13.9%) compared to those without the mutation (27.9%, p = 0.013). The mortality benefit of recombinant human activated protein C treatment was similar in both groups. <a href="#31" class="mim-tip-reference" title="Kerlin, B. A., Yan, S. B., Isemann, B. H., Brandt, J. T., Sood, R., Basson, B. R., Joyce, D. E., Weiler, H., Dhainaut, J.-F. <strong>Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia.</strong> Blood 102: 3085-3092, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12869495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12869495</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12869495">Kerlin et al. (2003)</a> suggested that F5 Leiden constitutes a rare example of a balanced gene polymorphism that maintains the F5 Leiden mutation in the general gene pool due to a survival advantage of heterozygotes in severe sepsis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12869495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, <a href="#5" class="mim-tip-reference" title="Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P. <strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong> Arch. Neurol. 61: 1652-1662, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534175</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534175">Casas et al. (2004)</a> found a statistically significant association between ischemic stroke (<a href="/entry/601367">601367</a>) and the R506Q substitution (odds ratio of 1.33). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#44" class="mim-tip-reference" title="Meyer, M., Kutscher, G., Vogel, G. <strong>Simultaneous genotyping for factor V Leiden and prothrombin G20210A variant by a multiplex PCR-SSCP assay on whole blood. (Letter)</strong> Thromb. Haemost. 81: 162-163, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10348711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10348711</a>]" pmid="10348711">Meyer et al. (1999)</a> described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant (<a href="/entry/176930#0009">176930.0009</a>) by a multiplex PCR-SSCP assay on whole blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10348711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Greer, I. A. <strong>The challenge of thrombophilia in maternal-fetal medicine. (Editorial)</strong> New Eng. J. Med. 342: 424-425, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10666435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10666435</a>] [<a href="https://doi.org/10.1056/NEJM200002103420610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10666435">Greer (2000)</a> stated that there is no evidence to support general screening of pregnant women for thrombophilia; however, all pregnant women with a personal or family history of venous thromboembolism should be screened. Drug prophylaxis against venous thromboembolism is warranted for pregnant women with thrombophilia who have had a previous thromboembolic event. Women with thrombophilia who have not had venous thromboembolism require individualized assessment of the defect and of additional risk factors. Screening should be extended to women with a history of second-trimester pregnancy loss (see <a href="/entry/614389">614389</a>), severe or recurrent preeclampsia, or intrauterine growth restriction, although whether antithrombotic therapy will prevent these complications in women with congenital thrombophilia was not known. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10666435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Krawczak, M., Cooper, D. N., Schmidtke, J. <strong>Estimating the efficacy and efficiency of cascade genetic screening.</strong> Am. J. Hum. Genet. 69: 361-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431707</a>] [<a href="https://doi.org/10.1086/321973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431707">Krawczak et al. (2001)</a> described a strategy called 'cascade genetic screening' whereby screening for genetic variants is targeted at the relatives of previously identified carriers rather than being performed at the general population level. They estimated that some 80% of all carriers of the factor V Leiden mutation would be detected if screening were to be targeted specifically at first- to third-degree relatives of patients with venous thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Segal, J. B., Brotman, D. J., Necochea, A. J., Emadi, A., Samal, L., Wilson, L. M., Crim, M. T., Bass, E. B. <strong>Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.</strong> JAMA 301: 2472-2485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19531787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19531787</a>] [<a href="https://doi.org/10.1001/jama.2009.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19531787">Segal et al. (2009)</a> provided a metaanalysis of the predictive value of factor V Leiden for the development of venous thromboembolism using a literature review of 13 relevant articles. Heterozygosity and homozygosity for the mutation in probands were predictive of recurrent venous thromboembolism (OR of 1.56 and 2.65, respectively) compared to individuals without the mutation. In relatives of probands, heterozygosity and homozygosity also predicted venous thromboembolism (OR of 3.5 and 18.0, respectively) compared to family members without the mutation. It remained unknown whether testing for the mutation improved clinical outcome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19531787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#51" class="mim-tip-reference" title="Sarasin, F. P., Bounameaux, H. <strong>Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis.</strong> Brit. Med. J. 316: 95-99, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462312</a>] [<a href="https://doi.org/10.1136/bmj.316.7125.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462312">Sarasin and Bounameaux (1998)</a> used a Markov decision analysis model that incorporated all current data concerning recurrent venous thromboembolism and long-term anticoagulation. The model suggested that the benefits of prolonged oral anticoagulant treatment in factor V Leiden heterozygotes after a first episode of deep vein thrombosis were usually overwhelmed by its risks. <a href="#51" class="mim-tip-reference" title="Sarasin, F. P., Bounameaux, H. <strong>Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis.</strong> Brit. Med. J. 316: 95-99, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462312</a>] [<a href="https://doi.org/10.1136/bmj.316.7125.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462312">Sarasin and Bounameaux (1998)</a> concluded that any decision to promote widespread screening programs to detect factor V Leiden heterozygotes should be questioned in the absence of a clinical benefit provided by extended use of oral anticoagulants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#63" class="mim-tip-reference" title="Zoller, B., Svensson, P. J., He, X., Dahlback, B. <strong>Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.</strong> J. Clin. Invest. 94: 2521-2524, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7989612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7989612</a>] [<a href="https://doi.org/10.1172/JCI117623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7989612">Zoller et al. (1994)</a> identified the R506Q mutation in 47 of 50 Swedish families with inherited APC resistance. There was perfect cosegregation between a low APC ratio and the presence of the mutation in 40 families. However, the cosegregation was not perfect in 7 families, as 12 of 57 APC-resistant family members did not have the mutation. Moreover, in 3 families with APC resistance, the specific R506Q mutation was not found, suggesting another still unidentified cause of inherited APC resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7989612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Dahlback, B., Hildebrand, B. <strong>Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.</strong> Proc. Nat. Acad. Sci. 91: 1396-1400, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8108421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8108421</a>] [<a href="https://doi.org/10.1073/pnas.91.4.1396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8108421">Dahlback and Hildebrand (1994)</a> discovered that the APC cofactor deficient in this disorder was identical to factor V. An affinity-purified factor V corrected the poor anticoagulant response to APC of APC-resistant plasma in a dose-dependent manner. Because the APC-resistant plasma contained normal levels of factor V procoagulant activity, the results indicated that APC resistance was due to a selective defect in the anticoagulant function of factor V. The findings suggested that factor V not only has procoagulant properties after its activation by thrombin, but may also play an important role in the anticoagulant system as cofactor to activated protein C. <a href="#12" class="mim-tip-reference" title="Dahlback, B., Hildebrand, B. <strong>Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.</strong> Proc. Nat. Acad. Sci. 91: 1396-1400, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8108421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8108421</a>] [<a href="https://doi.org/10.1073/pnas.91.4.1396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8108421">Dahlback and Hildebrand (1994)</a> commented on this appropriate, unique, and ingenious means of regulating blood coagulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8108421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Sun, X., Evatt, B., Griffin, J. H. <strong>Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia.</strong> Blood 83: 3120-3125, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8193349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8193349</a>]" pmid="8193349">Sun et al. (1994)</a> stated that APC resistance was 'currently the most common laboratory finding among venous thrombophilic patients.' They presented findings indicating that APC resistance is due to abnormality in factor V and not abnormality in factor VIII, which is also inactivated by APC, and that half of the patients' factor Va is resistant to APC, consistent with dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8193349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family with thrombophilia due to APC resistance, <a href="#2" class="mim-tip-reference" title="Bertina, R. M., Koeleman, B. P. C., Koster, T., Rosendaal, F. R., Dirven, R. J., de Ronde, H., van der Velden, P. A., Reitsma, P. H. <strong>Mutation in blood coagulation factor V associated with resistance to activated protein C.</strong> Nature 369: 64-67, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164741</a>] [<a href="https://doi.org/10.1038/369064a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164741">Bertina et al. (1994)</a> identified a heterozygous R506Q mutation in the F5 gene. Of note, this family came to attention because of symptomatic protein C deficiency. The authors identified the mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8164741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Voorberg, J., Roelse, J., Koopman, R., Buller, H., Berends, F., ten Cate, J. W., Mertens, K., van Mourik, J. A. <strong>Association of idiopathic venous thromboembolism with single point-mutation at arg506 of factor V.</strong> Lancet 343: 1535-1536, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911872</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92939-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7911872">Voorberg et al. (1994)</a> found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7911872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with thrombophilia due to APC resistance, <a href="#58" class="mim-tip-reference" title="Williamson, D., Brown, K., Luddington, R., Baglin, C., Baglin, T. <strong>Factor V Cambridge: a new mutation (arg306-to-thr) associated with resistance to activated protein C.</strong> Blood 91: 1140-1144, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9454742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9454742</a>]" pmid="9454742">Williamson et al. (1998)</a> identified a heterozygous R306T mutation in the F5 gene (<a href="/entry/612309#0003">612309.0003</a>). The mutation was also present in a first-degree relative with APC resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9454742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Caucasian brothers with thrombophilia due to APC resistance, <a href="#45" class="mim-tip-reference" title="Mumford, A. D., McVey, J. H., Morse, C. V., Gomez, K., Steen, M., Norstrom, E. A., Tuddenham, E. G. D., Dahlback, B., Bolton-Maggs, P. H. B. <strong>Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C.</strong> Brit. J. Haemat. 123: 496-501, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14617013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14617013</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04624.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14617013">Mumford et al. (2003)</a> identified compound heterozygosity for 2 mutations in the F5 gene: a missense mutation (I359T; <a href="/entry/612309#0013">612309.0013</a>) and a nonsense mutation (E119X; <a href="/entry/612309#0014">612309.0014</a>). Both brothers developed spontaneous venous thromboses in the second decade of life. One presented at the age of 14 years with thrombosis of the right femoral vein and inferior vena cava; an older brother suffered recurrent episodes of femoral vein thrombosis from the age of 18 years and was managed with long-term warfarin therapy. Heterozygous family members were asymptomatic. The I359T allele was predicted to create an additional consensus site for N-linked glycosylation in factor V, which may have resulted in abnormal N-linked glycosylation within the factor V A2 domain and and reduced susceptibility of factor Va to proteolysis. <a href="#45" class="mim-tip-reference" title="Mumford, A. D., McVey, J. H., Morse, C. V., Gomez, K., Steen, M., Norstrom, E. A., Tuddenham, E. G. D., Dahlback, B., Bolton-Maggs, P. H. B. <strong>Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C.</strong> Brit. J. Haemat. 123: 496-501, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14617013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14617013</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04624.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14617013">Mumford et al. (2003)</a> suggested that the E119X mutation resulted in an mRNA that was recognized and degraded by the cell via a process termed nonsense-mediated decay. Thus, the authors concluded that hemizygosity for the I359T variant was the cause of severe early-onset thrombophilia in these sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14617013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pseudohomozygosity for Factor V Leiden</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Castaman, G., Lunghi, B., Missiaglia, E., Bernardi, F., Rodeghiero, F. <strong>Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for arg506-to-gln (factor V Leiden) and his1299-to-arg substitutions in factor V.</strong> Brit. J. Haemat. 99: 257-261, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9375735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9375735</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1997.3993213.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9375735">Castaman et al. (1997)</a> and <a href="#8" class="mim-tip-reference" title="Castoldi, E., Kalafatis, M., Lunghi, B., Simioni, P., Ioannou, P. A., Petio, M., Girolami, A., Mann, K. G., Bernardi, F. <strong>Molecular bases of pseudo-homozygous APC resistance: the compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma.</strong> Thromb. Haemost. 80: 403-406, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9759618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9759618</a>]" pmid="9759618">Castoldi et al. (1998)</a> described patients with thrombosis who were compound heterozygous for factor V Leiden and a factor V deficiency allele. The patients are referred to as having 'pseudohomozygosity' for factor V Leiden, since they present with venous thromboembolic events. Those with factor V null mutations show only factor V Leiden molecules, and those with deficiency mutations show decreased levels of factor V that are insufficient to protect against thrombosis. <a href="#59" class="mim-tip-reference" title="Zehnder, J. L., Hiraki, D. D., Jones, C. D., Gross, N., Grumet, F. C. <strong>Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford.</strong> Thromb. Haemost. 82: 1097-1099, 1999. Note: Erratum: Thromb. Haemost. 82: XII only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10494770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10494770</a>]" pmid="10494770">Zehnder et al. (1999)</a> identified a man with thrombophilia who was compound heterozygous for factor V Leiden and a null allele of the F5 gene (<a href="/entry/612309#0005">612309.0005</a>). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was pseudohomozygous for factor V Leiden. <a href="#7" class="mim-tip-reference" title="Castaman, G., Tosetto, A., Ruggeri, M., Rodeghiero, F. <strong>Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis.</strong> Brit. J. Haemat. 106: 232-236, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10444192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10444192</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10444192">Castaman et al. (1999)</a> referred to pseudohomozygosity for activated protein C resistance due to the association of heterozygous factor V Leiden mutation and factor V deficiency. Among 7 families with 11 pseudohomozygotes and 45 relatives, 16 relatives were heterozygous factor V Leiden carriers, 9 showed partial factor V deficiency, and 20 had no abnormalities. Deep vein thrombosis occurred in 4 (36.3%) of 11 pseudohomozygous patients versus 6 (37.4%) of 16 factor V Leiden carriers and 1 (5%) of 20 normal relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9759618+10494770+10444192+9375735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Kemkes-Matthes, B., Matthes, K. J., Souri, M., Koseki-Kuno, S., Ichinose, A. <strong>R225H amino acid substitution of protein Z identified in patients with factor V Leiden mutation.</strong> Brit. J. Haemat. 128: 248-252, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15638861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15638861</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2004.05297.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15638861">Kemkes-Matthes et al. (2005)</a> found that the presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; <a href="/entry/176895">176895</a>) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#32" class="mim-tip-reference" title="Koeleman, B. P. C., Reitsma, P. H., Allaart, C. F., Bertina, R. M. <strong>Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families.</strong> Blood 84: 1031-1035, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8049422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8049422</a>]" pmid="8049422">Koeleman et al. (1994)</a> found that heterozygous carriers of both the factor V Leiden mutation and a mutation in the protein C gene were at higher risk of thrombosis compared to patients with either defect alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8049422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Gandrille, S., Greengard, J. S., Alhenc-Gelas, M., Juhan-Vague, I., Abgrall, J. F., Jude, B., Griffin, J. H., Aiach, M., French Network on the behalf of INSERM. <strong>Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients.</strong> Blood 86: 219-224, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795227</a>]" pmid="7795227">Gandrille et al. (1995)</a> detected the R506Q mutation in 15 (14%) of 113 patients with protein C deficiency and in 1 (1%) of 113 healthy controls. There was a significant difference in the allele frequency of the R506Q mutation between heterozygous protein C-deficient patients and protein C-deficient patients with no identified mutation in the PROC gene. The results demonstrated that a significant subset of thrombophilic patients have multiple genetic risk factors, although additional secondary genetic risk factors remained to be identified in a majority of symptomatic protein C-deficient patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Talmon, T., Scharf, J., Mayer, E., Lanir, N., Miller, B., Brenner, B. <strong>Retinal arterial occlusion in a child with factor V Leiden and thermolabile methylene tetrahydrofolate reductase mutations.</strong> Am. J. Ophthal. 124: 689-691, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9372726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9372726</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)70910-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9372726">Talmon et al. (1997)</a> described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for the thermolabile variant of methylene tetrahydrofolate reductase (<a href="/entry/607093#0003">607093.0003</a>). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9372726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Chiusolo, P., Casorelli, I., Rossi, E., Leone, G. <strong>The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.</strong> New Eng. J. Med. 341: 801-806, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477778</a>] [<a href="https://doi.org/10.1056/NEJM199909093411104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477778">De Stefano et al. (1999)</a> examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (<a href="/entry/176930#0009">176930.0009</a>) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Meinardi, J. R., Pelsma, P. M., Koning, H., van der Meer, J., Middeldorp, S., Buller, H. R., Hamulyak, K. <strong>Double-homozygosity for factor V Leiden and the prothrombin gene G20210A variant in a young patient with idiopathic venous thrombosis. (Letter)</strong> Blood 94: 1828-1829, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10507841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10507841</a>]" pmid="10507841">Meinardi et al. (1999)</a> described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10507841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 119 women with a history of venous thromboembolism during pregnancy, <a href="#19" class="mim-tip-reference" title="Gerhardt, A., Scharf, R. E., Beckmann, M. W., Struve, S., Bender, H. G., Pillny, M., Sandmann, W., Zotz, R. B. <strong>Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.</strong> New Eng. J. Med. 342: 374-380, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10666427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10666427</a>] [<a href="https://doi.org/10.1056/NEJM200002103420602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10666427">Gerhardt et al. (2000)</a> found a prevalence of 43.7% for factor V Leiden, as compared with 7.7% among controls (relative risk of venous thromboembolism was 9.3). The prevalence of the 20210G-A prothrombin mutation (<a href="/entry/176930#0009">176930.0009</a>) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated odds ratio, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10666427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Martinelli, I., Taioli, E., Cetin, I., Marinoni, A., Gerosa, S., Villa, M. V., Bozzo, M., Mannucci, P. M. <strong>Mutations in coagulation factors in women with unexplained late fetal loss.</strong> New Eng. J. Med. 343: 1015-1018, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11018168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11018168</a>] [<a href="https://doi.org/10.1056/NEJM200010053431405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11018168">Martinelli et al. (2000)</a> found that both factor V Leiden and the 20210G-A prothrombin mutation were associated with an approximate tripling of the risk of late fetal loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11018168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#33" class="mim-tip-reference" title="Koster, T., Rosendaal, F. R., de Ronde, H., Briet, E., Vandenbroucke, J. P., Bertina, R. M. <strong>Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study.</strong> Lancet 342: 1503-1506, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7902898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7902898</a>] [<a href="https://doi.org/10.1016/s0140-6736(05)80081-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7902898">Koster et al. (1993)</a> detected a poor anticoagulant response to activated protein C in 64 (21%) of 301 unselected consecutive patients younger than 70 years with a first episode of deep vein thrombosis unassociated with malignant disease. The frequency of the defect was 5% among 301 healthy controls. An autosomal dominant mode of transmission of the abnormality was confirmed in families of the probands with the defect. Both parents of a probable homozygote, with an extremely poor response to activated protein C, were found to have the abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7902898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 104 consecutive patients with venous thrombosis and 211 members of 34 families of affected probands, <a href="#55" class="mim-tip-reference" title="Svensson, P. J., Dahlback, B. <strong>Resistance to activated protein C as a basis for venous thrombosis.</strong> New Eng. J. Med. 330: 517-522, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8302317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8302317</a>] [<a href="https://doi.org/10.1056/NEJM199402243300801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8302317">Svensson and Dahlback (1994)</a> determined that the prevalence of APC resistance was as much as 40% in patients with thrombosis. The anticoagulant response to APC was measured with a modified version of the aPTT test and the results were expressed as APC ratios. Thirty-three percent of patients showed an APC ratio below the 5th percentile of the control values. Thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8302317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Majerus, P. W. <strong>Bad blood by mutation.</strong> Nature 369: 14-15, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164730</a>] [<a href="https://doi.org/10.1038/369014a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164730">Majerus (1994)</a> quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden mutation. The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. <a href="#40" class="mim-tip-reference" title="Majerus, P. W. <strong>Bad blood by mutation.</strong> Nature 369: 14-15, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164730</a>] [<a href="https://doi.org/10.1038/369014a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164730">Majerus (1994)</a> suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8164730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Greengard, J. S., Sun, X., Xu, X., Fernandez, J. A., Griffin, J. H., Evatt, B. <strong>Activated protein C resistance caused by arg506gln mutation in factor Va. (Letter)</strong> Lancet 343: 1361-1362, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7910348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7910348</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92497-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7910348">Greengard et al. (1994)</a> identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7910348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beauchamp, N. J., Daly, M. E., Hampton, K. K., Cooper, P. C., Preston, E., Peake, I. R. <strong>High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis.</strong> Brit. J. Haemat. 88: 219-222, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7803250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7803250</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1994.tb05005.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7803250">Beauchamp et al. (1994)</a> identified the R506Q mutation in all affected members of 2 families with inherited APC resistance associated with thrombosis studied in England. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7803250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, <a href="#49" class="mim-tip-reference" title="Ridker, P. M., Hennekens, C. H., Lindpaintner, K., Stampfer, M. J., Eisenberg, P. R., Miletich, J. P. <strong>Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.</strong> New Eng. J. Med. 332: 912-917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7877648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7877648</a>] [<a href="https://doi.org/10.1056/NEJM199504063321403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7877648">Ridker et al. (1995)</a> found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, <a href="#50" class="mim-tip-reference" title="Ridker, P. M., Miletich, J. P., Stampfer, M. J., Goldhaber, S. Z., Lindpaintner, K., Hennekens, C. H. <strong>Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.</strong> Circulation 92: 2800-2802, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586244</a>] [<a href="https://doi.org/10.1161/01.cir.92.10.2800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586244">Ridker et al. (1995)</a> found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7877648+7586244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a population study in southern Germany, <a href="#3" class="mim-tip-reference" title="Braun, A., Muller, B., Rosche, A. A. <strong>Population study of the G1691A mutation (R506Q, FV Leiden) in the human factor V gene that is associated with resistance to activated protein C.</strong> Hum. Genet. 97: 263-264, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566967</a>] [<a href="https://doi.org/10.1007/BF02265279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566967">Braun et al. (1996)</a> found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8566967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a multiethnic survey of 602 Americans, <a href="#24" class="mim-tip-reference" title="Gregg, J. P., Yamane, A. J., Grody, W. W. <strong>Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations.</strong> Am. J. Med. Genet. 73: 334-336, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9415695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9415695</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19971219)73:3<334::aid-ajmg20>3.0.co;2-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9415695">Gregg et al. (1997)</a> found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9415695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The factor V Leiden mutation (<a href="/entry/612309#0001">612309.0001</a>) and the 20210G-A mutation in the prothrombin gene (<a href="/entry/176930#0009">176930.0009</a>) are the most frequent abnormalities associated with venous thromboembolism. <a href="#41" class="mim-tip-reference" title="Martinelli, I., Bucciarelli, P., Margaglione, M., De Stefano, V., Castaman, G., Mannucci, P. M. <strong>The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.</strong> Brit. J. Haemat. 111: 1223-1229, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11167765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11167765</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.02502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11167765">Martinelli et al. (2000)</a> compared the prevalence and incidence rate of venous thromboembolism in relatives with either of these 2 mutations or both. The study population included 1,076 relatives of probands with the prothrombin gene mutation, factor V Leiden, or both, who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were noncarriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were 0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of thrombosis was 2 times higher in carriers of the prothrombin gene mutation, 3 times higher in those with factor V Leiden, and 6 times higher in double carriers than in noncarriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation was slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it was 2 or 3 times higher. From these findings, <a href="#41" class="mim-tip-reference" title="Martinelli, I., Bucciarelli, P., Margaglione, M., De Stefano, V., Castaman, G., Mannucci, P. M. <strong>The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.</strong> Brit. J. Haemat. 111: 1223-1229, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11167765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11167765</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.02502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11167765">Martinelli et al. (2000)</a> concluded that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11167765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Zivelin, A., Mor-Cohen, R., Kovalsky, V., Kornbrot, N., Conard, J., Peyvandi, F., Kyrle, P. A., Bertina, R., Peyvandi, F., Emmerich, J., Seligsohn, U. <strong>Prothrombin 20210G-A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago.</strong> Blood 107: 4666-4668, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493002</a>] [<a href="https://doi.org/10.1182/blood-2005-12-5158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16493002">Zivelin et al. (2006)</a> estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation, factor V Leiden occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage, i.e., thrombosis, was unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, <a href="#37" class="mim-tip-reference" title="Lindqvist, P. G., Svensson, P. J., Dahlback, B., Marsal, K. <strong>Factor V Q-506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss: a possible evolutionary selection mechanism.</strong> Thromb. Haemost. 79: 69-73, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9459326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9459326</a>]" pmid="9459326">Lindqvist et al. (1998)</a> found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation. <a href="#38" class="mim-tip-reference" title="Lindqvist, P. G., Zoller, B., Dahlback, B. <strong>Improved hemoglobin status and reduced menstrual blood loss among female carriers of factor V Leiden: an evolutionary advantage? (Letter)</strong> Thromb. Haemost. 86: 1122-1123, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11686338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11686338</a>]" pmid="11686338">Lindqvist et al. (2001)</a> found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11686338+16493002+9459326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Greengard, J. S., Sun, X., Xu, X., Fernandez, J. A., Griffin, J. H., Evatt, B. <strong>Activated protein C resistance caused by arg506gln mutation in factor Va. (Letter)</strong> Lancet 343: 1361-1362, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7910348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7910348</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92497-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7910348">Greengard et al. (1994)</a> proposed that thrombophilia associated with APC resistance caused by factor V mutations be designated 'thrombophilia V.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7910348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Cui, J., Eitzman, D. T., Westrick, R. J., Christie, P. D., Xu, Z. J., Yang, A. Y., Purkayastha, A. A., Yang, T. L., Metz, A. L., Gallagher, K. P., Tyson, J. A., Rosenberg, R. D., Ginsburg, D. <strong>Spontaneous thrombosis in mice carrying the factor V Leiden mutation.</strong> Blood 96: 4222-4226, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110695</a>]" pmid="11110695">Cui et al. (2000)</a> generated mice carrying the R504Q mutation, homologous to human R506Q, inserted into the endogenous murine factor V gene. Adult heterozygous and homozygous mice were viable and fertile and exhibited normal survival. Compared with wildtype mice, adult homozygous mice demonstrated a marked increase in spontaneous tissue fibrin deposition. On a mixed genetic background, homozygous mice developed disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. <a href="#10" class="mim-tip-reference" title="Cui, J., Eitzman, D. T., Westrick, R. J., Christie, P. D., Xu, Z. J., Yang, A. Y., Purkayastha, A. A., Yang, T. L., Metz, A. L., Gallagher, K. P., Tyson, J. A., Rosenberg, R. D., Ginsburg, D. <strong>Spontaneous thrombosis in mice carrying the factor V Leiden mutation.</strong> Blood 96: 4222-4226, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110695</a>]" pmid="11110695">Cui et al. (2000)</a> suggested that these results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within factor V among mammalian species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1056/NEJM200002103420602" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199412083312305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(94)92497-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM200002103420610" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19971219)73:3<334::aid-ajmg20>3.0.co;2-j" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462312</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/bmj.316.7125.95" target="_blank">Full Text</a>]
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<a id="52" class="mim-anchor"></a>
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<a id="Segal2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Segal, J. B., Brotman, D. J., Necochea, A. J., Emadi, A., Samal, L., Wilson, L. M., Crim, M. T., Bass, E. B.
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<strong>Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.</strong>
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JAMA 301: 2472-2485, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19531787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19531787</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19531787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/jama.2009.853" target="_blank">Full Text</a>]
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<a id="53" class="mim-anchor"></a>
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<a id="Simioni1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simioni, P., Prandoni, P., Lensing, A. W. A., Scudeller, A., Sardella, C., Prins, M. H., Villalta, S., Dazzi, F., Girolami, A.
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<strong>The risk of recurrent venous thromboembolism in patients with an arg506-to-gln mutation in the gene for factor V (factor V Leiden).</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9010145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9010145</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9010145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199702063360602" target="_blank">Full Text</a>]
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<a id="54" class="mim-anchor"></a>
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<a id="Sun1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sun, X., Evatt, B., Griffin, J. H.
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<strong>Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia.</strong>
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Blood 83: 3120-3125, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8193349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8193349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8193349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Svensson1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Svensson, P. J., Dahlback, B.
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<strong>Resistance to activated protein C as a basis for venous thrombosis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8302317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8302317</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8302317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199402243300801" target="_blank">Full Text</a>]
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<a id="Talmon1997" class="mim-anchor"></a>
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Talmon, T., Scharf, J., Mayer, E., Lanir, N., Miller, B., Brenner, B.
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<strong>Retinal arterial occlusion in a child with factor V Leiden and thermolabile methylene tetrahydrofolate reductase mutations.</strong>
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Am. J. Ophthal. 124: 689-691, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9372726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9372726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9372726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(14)70910-9" target="_blank">Full Text</a>]
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<a id="57" class="mim-anchor"></a>
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<a id="Voorberg1994" class="mim-anchor"></a>
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Voorberg, J., Roelse, J., Koopman, R., Buller, H., Berends, F., ten Cate, J. W., Mertens, K., van Mourik, J. A.
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<strong>Association of idiopathic venous thromboembolism with single point-mutation at arg506 of factor V.</strong>
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Lancet 343: 1535-1536, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911872</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7911872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(94)92939-4" target="_blank">Full Text</a>]
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<a id="Williamson1998" class="mim-anchor"></a>
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Williamson, D., Brown, K., Luddington, R., Baglin, C., Baglin, T.
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<strong>Factor V Cambridge: a new mutation (arg306-to-thr) associated with resistance to activated protein C.</strong>
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Blood 91: 1140-1144, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9454742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9454742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9454742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Zehnder1999" class="mim-anchor"></a>
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Zehnder, J. L., Hiraki, D. D., Jones, C. D., Gross, N., Grumet, F. C.
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<strong>Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford.</strong>
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Thromb. Haemost. 82: 1097-1099, 1999. Note: Erratum: Thromb. Haemost. 82: XII only, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10494770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10494770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10494770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="60" class="mim-anchor"></a>
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<a id="Zehnder1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zehnder, J. L., Jain, M.
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<strong>Recurrent thrombosis due to compound heterozygosity for factor V Leiden and factor V deficiency.</strong>
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Blood Coagul. Fibrinolysis 7: 361-362, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8735145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8735145</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8735145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1097/00001721-199604000-00012" target="_blank">Full Text</a>]
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<a id="61" class="mim-anchor"></a>
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<a id="Zivelin2006" class="mim-anchor"></a>
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Zivelin, A., Mor-Cohen, R., Kovalsky, V., Kornbrot, N., Conard, J., Peyvandi, F., Kyrle, P. A., Bertina, R., Peyvandi, F., Emmerich, J., Seligsohn, U.
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<strong>Prothrombin 20210G-A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago.</strong>
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Blood 107: 4666-4668, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16493002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1182/blood-2005-12-5158" target="_blank">Full Text</a>]
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<a id="Zoller1994" class="mim-anchor"></a>
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Zoller, B., Dahlback, B.
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<strong>Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis.</strong>
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Lancet 343: 1536-1538, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7911873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7911873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7911873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(94)92940-8" target="_blank">Full Text</a>]
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<a id="Zoller1994" class="mim-anchor"></a>
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Zoller, B., Svensson, P. J., He, X., Dahlback, B.
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<strong>Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.</strong>
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J. Clin. Invest. 94: 2521-2524, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7989612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7989612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7989612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI117623" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 6/27/2011
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Cassandra L. Kniffin - reorganized : 10/8/2008<br>Cassandra L. Kniffin - updated : 9/24/2008
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 2/19/1993
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carol : 06/04/2019
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carol : 08/21/2017<br>carol : 08/17/2017<br>carol : 02/16/2015<br>carol : 4/1/2013<br>terry : 11/13/2012<br>terry : 8/22/2012<br>carol : 2/28/2012<br>ckniffin : 2/23/2012<br>alopez : 12/13/2011<br>carol : 7/7/2011<br>carol : 7/7/2011<br>ckniffin : 6/27/2011<br>terry : 6/3/2011<br>carol : 4/7/2011<br>carol : 1/5/2011<br>terry : 9/9/2010<br>wwang : 9/3/2010<br>ckniffin : 8/25/2010<br>ckniffin : 11/10/2009<br>terry : 6/3/2009<br>carol : 11/20/2008<br>carol : 10/9/2008<br>carol : 10/8/2008<br>ckniffin : 10/8/2008<br>ckniffin : 9/24/2008<br>mimadm : 5/10/1995<br>terry : 5/5/1994<br>carol : 4/12/1994<br>carol : 3/18/1993<br>carol : 2/19/1993
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<strong>#</strong> 188055
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THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE; THPH2
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ACTIVATED PROTEIN C RESISTANCE<br />
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APC RESISTANCE<br />
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THROMBOPHILIA DUE TO DEFICIENCY OF ACTIVATED PROTEIN C COFACTOR<br />
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PROC COFACTOR DEFICIENCY<br />
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PCCF DEFICIENCY<br />
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THROMBOPHILIA V
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Other entities represented in this entry:
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<span class="h3 mim-font">
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THROMBOPHILIA DUE TO FACTOR V LEIDEN, INCLUDED
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<strong>ICD10CM:</strong> D68.51;
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<strong>DO:</strong> 0111902;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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<th>
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Phenotype
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</th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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<th>
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Phenotype <br /> mapping key
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</th>
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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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1q24.2
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<span class="mim-font">
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{Thrombophilia, susceptibility to, due to factor V Leiden}
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<span class="mim-font">
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188055
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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F5
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<span class="mim-font">
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612309
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<span class="mim-font">
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1q24.2
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<span class="mim-font">
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Thrombophilia 2 due to activated protein C resistance
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<span class="mim-font">
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188055
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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F5
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<span class="mim-font">
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612309
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that the disorder is caused by heterozygous mutation in the gene that encodes factor V (F5; 612309) on chromosome 1q24.</p>
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<strong>Description</strong>
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<p>Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; 612283) and results in a tendency to thrombosis.</p><p>See also factor V deficiency (227400), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V.</p><p>The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; 612309.0001), named after the town in the Netherlands where Bertina et al. (1994) discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</h4>
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<p>Dahlback et al. (1993) reported a family in which 5 individuals spanning 3 generations had adult-onset thromboembolic disease, most often deep venous thrombosis of the legs, inherited in an autosomal dominant pattern. Laboratory studies of patients' plasma demonstrated a poor anticoagulant response upon the addition of activated protein C (APC; 612283), as measured by the lack of prolongation of clotting time in an activated partial thromboplastin time (aPTT) assay. In addition, 14 of 19 tested family members showed a similar defect in this assay. Known coagulation defects and serum autoantibodies or inhibitors to APC were excluded. Two additional unrelated patients with thrombophilia and inherited poor response to APC were identified using this novel assay. The thromboembolic events occurred during pregnancy or in the postpartum period in the 2 additional families. Dahlback et al. (1993) concluded that these individuals were lacking a previously unrecognized cofactor for APC that was responsible for the subnormal APC effects in the degradation of factors Va and VIIIa (300841). </p><p>Greengard et al. (1994) reported variability of thrombosis in a family in which 4 sibs were homozygous for the R560Q mutation. The oldest son, who was homozygous, developed deep vein thrombosis (DVT) of the leg after an injury to that extremity at age 18 years. Two weeks later, during treatment with warfarin, he developed a DVT of the other leg. A clip was placed on the inferior vena cava and warfarin therapy was continued for 2 years. He later developed severe bilateral postphlebitic syndrome with chronic leg ulcers. Another son, who was heterozygous, developed a spontaneous DVT of the leg at age 23 years. The youngest son, who was homozygous, had a spontaneous pulmonary embolus confirmed by pulmonary angiography at the age of 16 years. This recurred 1 year later after the discontinuation of warfarin treatment. At the age of 24, he had a DVT of the right leg when he was not receiving warfarin; he was treated for 6 months. Four months after the discontinuation of treatment, he had a recurrent DVT in the right leg. The heterozygous mother developed a DVT of the left leg during her most recent pregnancy at the age of 37. Two daughters, aged 28 and 33 years, who were homozygous for the mutation, and the father, who was heterozygous, had not developed thrombosis. Greengard et al. (1994) noted that the daughters had not been exposed to risk factors, such as major surgical procedures, the use of oral contraceptives, or pregnancy. </p><p>Zoller and Dahlback (1994) studied a large kindred in which familial thrombophilia and APC resistance was inherited as an autosomal dominant trait, and all affected individuals had the R506Q mutation. </p><p>Among 47 Swedish families with APC resistance and the R506Q mutation, Zoller et al. (1994) observed that by age 33 years, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestations of venous thrombosis. In a majority of both heterozygous and homozygous individuals, thrombosis was associated with risk factors, most commonly pregnancy, oral contraceptives, trauma, and surgery. </p><p>Pipe et al. (1996) reported a patient with neonatal purpura fulminans associated with heterozygosity for the R506Q mutation. At 8 hours of age, the neonate had progressive purpuric skin lesions and later had evidence of microvascular hemorrhagic thrombosis in the brain. The infant was treated with fresh frozen plasma infusions and had complete resolution of the skin lesions and no apparent long-term complications. </p><p>Simioni et al. (1997) found heterozygosity for factor V Leiden in 41 (16.3%) of 251 unselected patients with a first episode of symptomatic deep vein thrombosis diagnosed by venography. The cumulative incidence of recurrent venous thromboembolism after follow-up of up to 8 years was 39.7% among carriers of the mutation, as compared with 18.3% among patients without the mutation. </p><p>Jackson and Luplow (1998) described 2 adults with purpura fulminans related to sepsis who were found to be heterozygous for the factor V Leiden mutation. Each patient survived disseminated intravascular coagulation, shock, and digital necrosis, but eventually required digit amputations. The first patient was a 42-year-old man with Streptococcus pneumoniae. Acrocyanosis progressed to dry gangrene of all the fingers and toes; however, the skin of the forehead, ears, and nose recovered without scarring. The second patient was a 40-year-old woman with septicemia due to Bacteroides fragilis and Fusobacterium species. </p><p>In a male neonate with inferior vena cava thrombosis, complicated by bilateral adrenal hemorrhage and left renal vein thrombosis Gorbe et al. (1999) identified a homozygous factor V Leiden mutation. The infant improved with intravenous administration of dopamine-dobutamine and low doses of heparin. An associated persistent ductus arteriosus detected by echocardiography was ligated during hospitalization. </p><p>In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. </p>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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<p><strong><em>Role in Pregnancy Complications</em></strong></p><p>
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Brenner et al. (1996) observed 2 patients with the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) who were heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. </p><p>Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. However, there was no difference between the 2 groups regarding preeclampsia or intrauterine growth retardation. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. </p><p>Kupferminc et al. (1999) identified the factor V R506Q mutation in 22 of 110 women with obstetrical complications, including severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth, and in 7 of 110 women with normal pregnancies (p = 0.003). In 24 of the women with complications, as compared with 9 women without complications, homozygosity for the 677C-T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR; 607093.0003) was also found. Overall, 57 women with obstetrical complications had a thrombophilic mutation, as compared with 19 women with normal pregnancies (p less than 0.001). Anticardiolipin antibodies or deficiency of protein S, protein C, or antithrombin III were detected in an additional 14 women with complications, as compared with 1 woman with a normal pregnancy (p less than 0.001). Kupferminc et al. (1999) recommended that women with such obstetrical complications should be tested for genetic and acquired markers of thrombophilia because these complications tend to recur in subsequent pregnancies. </p><p>Faisel et al. (2004) analyzed the allele and genotype frequencies of 2 F5 polymorphisms, M385T, R485K, and the R506Q Leiden mutation in 133 Finnish women with preeclampsia (189800) and 112 controls. There were statistically significant differences in R485K allele (p = 0.003) and genotype (p = 0.03) frequencies between patients and controls. The A allele of R485K was overrepresented among the patients (12%) compared to the controls (4%), with an odds ratio of 2.8 (95% CI, 1.2-6.2) for combined A genotypes. Faisel et al. (2004) concluded that genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility. </p><p><strong><em>Role in Other Diseases</em></strong></p><p>
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Heresbach et al. (1997) added small bowel infarctions to the many thrombotic states in which the factor V Leiden mutation plays a role. They observed the R506Q mutation in 2 cases of arterial and 2 cases of venous small bowel infarction. Two patients were heterozygous and 2 were homozygous. Three of the patients were in their mid-thirties and the fourth was a 45-year-old man. </p><p>Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation may be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. </p><p>Leebeek et al. (1998) described a 27-year-old female homozygous for factor V Leiden with Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. She was treated by transjugular intrahepatic portosystemic stent placement followed by local thrombolytic therapy. Venous outflow from the liver was established and the thrombi in the portal and mesenteric veins were lysed completely. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. </p><p>De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. </p><p>Chung et al. (2006) described Budd-Chiari syndrome in a 46-year-old woman who developed rapidly increasing abdominal girth over a period of several days with accumulation of ascites. The disorder was found to be associated with a mutation in JAK2 (V617F; 147796.0001) and the factor V Leiden mutation. As many as 50% of patients with Budd-Chiari syndrome have a myeloproliferative disorder, either preexisting or diagnosed at the time of the syndrome. However, some patients with the Budd-Chiari syndrome may have a latent myeloproliferative disorder without elevated blood counts. The V617F mutation of the JAK2 gene has been detected in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder (Patel et al., 2006). </p><p>Debus et al. (1998) found that 6 of 24 children with porencephaly (175780) were heterozygous for the factor V Leiden mutation. Two of these also had familial raised Lp(a) levels (152200) and 1 child also had protein S deficiency (612336). An additional 10 children had protein C deficiency, protein S deficiency, or familial raised Lp(a) levels. Five of the 24 children had a positive family history of thrombosis. Debus et al. (1998) suggested that hereditary thrombophilic states may predispose to perinatal cerebroarterial occlusion and porencephaly. The authors commented that other interacting prenatal factors, such as infection, placental dysfunction, or fetal cardiac arrhythmias, should also be considered as causative factors. Debus et al. (2004) found a higher prevalence of the R506Q mutation among 76 patients with porencephaly compared to controls. Eighteen patients were heterozygous and 1 infant was homozygous; 4 controls carried the mutation. The authors suggested that patients with porencephaly have certain prothrombotic risk factors which may contribute to the development of the disorder. </p><p>Kerlin et al. (2003) found that 4.1% of 65 patients with sepsis were heterozygous carriers of the factor V Leiden mutation. The 28-day mortality was lower in heterozygous carriers (13.9%) compared to those without the mutation (27.9%, p = 0.013). The mortality benefit of recombinant human activated protein C treatment was similar in both groups. Kerlin et al. (2003) suggested that F5 Leiden constitutes a rare example of a balanced gene polymorphism that maintains the F5 Leiden mutation in the general gene pool due to a survival advantage of heterozygotes in severe sepsis. </p><p>In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (odds ratio of 1.33). </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant (176930.0009) by a multiplex PCR-SSCP assay on whole blood. </p><p>Greer (2000) stated that there is no evidence to support general screening of pregnant women for thrombophilia; however, all pregnant women with a personal or family history of venous thromboembolism should be screened. Drug prophylaxis against venous thromboembolism is warranted for pregnant women with thrombophilia who have had a previous thromboembolic event. Women with thrombophilia who have not had venous thromboembolism require individualized assessment of the defect and of additional risk factors. Screening should be extended to women with a history of second-trimester pregnancy loss (see 614389), severe or recurrent preeclampsia, or intrauterine growth restriction, although whether antithrombotic therapy will prevent these complications in women with congenital thrombophilia was not known. </p><p>Krawczak et al. (2001) described a strategy called 'cascade genetic screening' whereby screening for genetic variants is targeted at the relatives of previously identified carriers rather than being performed at the general population level. They estimated that some 80% of all carriers of the factor V Leiden mutation would be detected if screening were to be targeted specifically at first- to third-degree relatives of patients with venous thrombosis. </p><p>Segal et al. (2009) provided a metaanalysis of the predictive value of factor V Leiden for the development of venous thromboembolism using a literature review of 13 relevant articles. Heterozygosity and homozygosity for the mutation in probands were predictive of recurrent venous thromboembolism (OR of 1.56 and 2.65, respectively) compared to individuals without the mutation. In relatives of probands, heterozygosity and homozygosity also predicted venous thromboembolism (OR of 3.5 and 18.0, respectively) compared to family members without the mutation. It remained unknown whether testing for the mutation improved clinical outcome. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</h4>
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<span class="mim-text-font">
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<p>Sarasin and Bounameaux (1998) used a Markov decision analysis model that incorporated all current data concerning recurrent venous thromboembolism and long-term anticoagulation. The model suggested that the benefits of prolonged oral anticoagulant treatment in factor V Leiden heterozygotes after a first episode of deep vein thrombosis were usually overwhelmed by its risks. Sarasin and Bounameaux (1998) concluded that any decision to promote widespread screening programs to detect factor V Leiden heterozygotes should be questioned in the absence of a clinical benefit provided by extended use of oral anticoagulants. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Heterogeneity</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zoller et al. (1994) identified the R506Q mutation in 47 of 50 Swedish families with inherited APC resistance. There was perfect cosegregation between a low APC ratio and the presence of the mutation in 40 families. However, the cosegregation was not perfect in 7 families, as 12 of 57 APC-resistant family members did not have the mutation. Moreover, in 3 families with APC resistance, the specific R506Q mutation was not found, suggesting another still unidentified cause of inherited APC resistance. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Dahlback and Hildebrand (1994) discovered that the APC cofactor deficient in this disorder was identical to factor V. An affinity-purified factor V corrected the poor anticoagulant response to APC of APC-resistant plasma in a dose-dependent manner. Because the APC-resistant plasma contained normal levels of factor V procoagulant activity, the results indicated that APC resistance was due to a selective defect in the anticoagulant function of factor V. The findings suggested that factor V not only has procoagulant properties after its activation by thrombin, but may also play an important role in the anticoagulant system as cofactor to activated protein C. Dahlback and Hildebrand (1994) commented on this appropriate, unique, and ingenious means of regulating blood coagulation. </p><p>Sun et al. (1994) stated that APC resistance was 'currently the most common laboratory finding among venous thrombophilic patients.' They presented findings indicating that APC resistance is due to abnormality in factor V and not abnormality in factor VIII, which is also inactivated by APC, and that half of the patients' factor Va is resistant to APC, consistent with dominant inheritance. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In affected members of a family with thrombophilia due to APC resistance, Bertina et al. (1994) identified a heterozygous R506Q mutation in the F5 gene. Of note, this family came to attention because of symptomatic protein C deficiency. The authors identified the mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. </p><p>Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. </p><p>In a patient with thrombophilia due to APC resistance, Williamson et al. (1998) identified a heterozygous R306T mutation in the F5 gene (612309.0003). The mutation was also present in a first-degree relative with APC resistance. </p><p>In 2 Caucasian brothers with thrombophilia due to APC resistance, Mumford et al. (2003) identified compound heterozygosity for 2 mutations in the F5 gene: a missense mutation (I359T; 612309.0013) and a nonsense mutation (E119X; 612309.0014). Both brothers developed spontaneous venous thromboses in the second decade of life. One presented at the age of 14 years with thrombosis of the right femoral vein and inferior vena cava; an older brother suffered recurrent episodes of femoral vein thrombosis from the age of 18 years and was managed with long-term warfarin therapy. Heterozygous family members were asymptomatic. The I359T allele was predicted to create an additional consensus site for N-linked glycosylation in factor V, which may have resulted in abnormal N-linked glycosylation within the factor V A2 domain and and reduced susceptibility of factor Va to proteolysis. Mumford et al. (2003) suggested that the E119X mutation resulted in an mRNA that was recognized and degraded by the cell via a process termed nonsense-mediated decay. Thus, the authors concluded that hemizygosity for the I359T variant was the cause of severe early-onset thrombophilia in these sibs. </p><p><strong><em>Pseudohomozygosity for Factor V Leiden</em></strong></p><p>
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Castaman et al. (1997) and Castoldi et al. (1998) described patients with thrombosis who were compound heterozygous for factor V Leiden and a factor V deficiency allele. The patients are referred to as having 'pseudohomozygosity' for factor V Leiden, since they present with venous thromboembolic events. Those with factor V null mutations show only factor V Leiden molecules, and those with deficiency mutations show decreased levels of factor V that are insufficient to protect against thrombosis. Zehnder et al. (1999) identified a man with thrombophilia who was compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was pseudohomozygous for factor V Leiden. Castaman et al. (1999) referred to pseudohomozygosity for activated protein C resistance due to the association of heterozygous factor V Leiden mutation and factor V deficiency. Among 7 families with 11 pseudohomozygotes and 45 relatives, 16 relatives were heterozygous factor V Leiden carriers, 9 showed partial factor V deficiency, and 20 had no abnormalities. Deep vein thrombosis occurred in 4 (36.3%) of 11 pseudohomozygous patients versus 6 (37.4%) of 16 factor V Leiden carriers and 1 (5%) of 20 normal relatives. </p><p><strong><em>Modifier Genes</em></strong></p><p>
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Kemkes-Matthes et al. (2005) found that the presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. </p>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Koeleman et al. (1994) found that heterozygous carriers of both the factor V Leiden mutation and a mutation in the protein C gene were at higher risk of thrombosis compared to patients with either defect alone. </p><p>Gandrille et al. (1995) detected the R506Q mutation in 15 (14%) of 113 patients with protein C deficiency and in 1 (1%) of 113 healthy controls. There was a significant difference in the allele frequency of the R506Q mutation between heterozygous protein C-deficient patients and protein C-deficient patients with no identified mutation in the PROC gene. The results demonstrated that a significant subset of thrombophilic patients have multiple genetic risk factors, although additional secondary genetic risk factors remained to be identified in a majority of symptomatic protein C-deficient patients. </p><p>Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for the thermolabile variant of methylene tetrahydrofolate reductase (607093.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. </p><p>De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. </p><p>Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. </p><p>Among 119 women with a history of venous thromboembolism during pregnancy, Gerhardt et al. (2000) found a prevalence of 43.7% for factor V Leiden, as compared with 7.7% among controls (relative risk of venous thromboembolism was 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated odds ratio, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. </p><p>Martinelli et al. (2000) found that both factor V Leiden and the 20210G-A prothrombin mutation were associated with an approximate tripling of the risk of late fetal loss. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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<span class="mim-text-font">
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<p>Koster et al. (1993) detected a poor anticoagulant response to activated protein C in 64 (21%) of 301 unselected consecutive patients younger than 70 years with a first episode of deep vein thrombosis unassociated with malignant disease. The frequency of the defect was 5% among 301 healthy controls. An autosomal dominant mode of transmission of the abnormality was confirmed in families of the probands with the defect. Both parents of a probable homozygote, with an extremely poor response to activated protein C, were found to have the abnormality. </p><p>In a study of 104 consecutive patients with venous thrombosis and 211 members of 34 families of affected probands, Svensson and Dahlback (1994) determined that the prevalence of APC resistance was as much as 40% in patients with thrombosis. The anticoagulant response to APC was measured with a modified version of the aPTT test and the results were expressed as APC ratios. Thirty-three percent of patients showed an APC ratio below the 5th percentile of the control values. Thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members. </p><p>Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden mutation. The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. </p><p>Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. </p><p>Beauchamp et al. (1994) identified the R506Q mutation in all affected members of 2 families with inherited APC resistance associated with thrombosis studied in England. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. </p><p>Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. </p><p>In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. </p><p>In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. </p><p>The factor V Leiden mutation (612309.0001) and the 20210G-A mutation in the prothrombin gene (176930.0009) are the most frequent abnormalities associated with venous thromboembolism. Martinelli et al. (2000) compared the prevalence and incidence rate of venous thromboembolism in relatives with either of these 2 mutations or both. The study population included 1,076 relatives of probands with the prothrombin gene mutation, factor V Leiden, or both, who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were noncarriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were 0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of thrombosis was 2 times higher in carriers of the prothrombin gene mutation, 3 times higher in those with factor V Leiden, and 6 times higher in double carriers than in noncarriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation was slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it was 2 or 3 times higher. From these findings, Martinelli et al. (2000) concluded that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations. </p><p>Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation, factor V Leiden occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage, i.e., thrombosis, was unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation. Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Greengard et al. (1994) proposed that thrombophilia associated with APC resistance caused by factor V mutations be designated 'thrombophilia V.' </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Cui et al. (2000) generated mice carrying the R504Q mutation, homologous to human R506Q, inserted into the endogenous murine factor V gene. Adult heterozygous and homozygous mice were viable and fertile and exhibited normal survival. Compared with wildtype mice, adult homozygous mice demonstrated a marked increase in spontaneous tissue fibrin deposition. On a mixed genetic background, homozygous mice developed disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. Cui et al. (2000) suggested that these results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within factor V among mammalian species. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Hallam et al. (1995); Rees et al. (1999); Zehnder and Jain (1996)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Beauchamp, N. J., Daly, M. E., Hampton, K. K., Cooper, P. C., Preston, E., Peake, I. R.
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<strong>High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis.</strong>
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Brit. J. Haemat. 88: 219-222, 1994.
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Bertina, R. M., Koeleman, B. P. C., Koster, T., Rosendaal, F. R., Dirven, R. J., de Ronde, H., van der Velden, P. A., Reitsma, P. H.
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<strong>Mutation in blood coagulation factor V associated with resistance to activated protein C.</strong>
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Braun, A., Muller, B., Rosche, A. A.
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<strong>Population study of the G1691A mutation (R506Q, FV Leiden) in the human factor V gene that is associated with resistance to activated protein C.</strong>
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Hum. Genet. 97: 263-264, 1996.
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Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P.
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Castaman, G., Lunghi, B., Missiaglia, E., Bernardi, F., Rodeghiero, F.
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<strong>Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for arg506-to-gln (factor V Leiden) and his1299-to-arg substitutions in factor V.</strong>
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Castaman, G., Tosetto, A., Ruggeri, M., Rodeghiero, F.
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<strong>Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis.</strong>
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Castoldi, E., Kalafatis, M., Lunghi, B., Simioni, P., Ioannou, P. A., Petio, M., Girolami, A., Mann, K. G., Bernardi, F.
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<strong>Molecular bases of pseudo-homozygous APC resistance: the compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma.</strong>
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Thromb. Haemost. 80: 403-406, 1998.
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Chung, R. T., Iafrate, A. J., Amrein, P. C., Sahani, D. V., Misdraji, J.
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<strong>Case 15-2006: a 46-year-old woman with sudden onset of abdominal distention.</strong>
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Dahlback, B., Carlsson, M., Svensson, P. J.
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Dahlback, B., Hildebrand, B.
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<strong>Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.</strong>
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Proc. Nat. Acad. Sci. 91: 1396-1400, 1994.
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de Bruijn, S. F. T. M., Stam, J., Koopman, M. M. W., Vandenbroucke, J. P.
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<strong>Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in carriers of hereditary prothrombotic conditions.</strong>
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De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Chiusolo, P., Casorelli, I., Rossi, E., Leone, G.
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<strong>The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.</strong>
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New Eng. J. Med. 341: 801-806, 1999.
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Debus, O., Koch, H. G., Kurlemann, G., Strater, R., Vielhaber, H., Weber, P., Nowak-Gottl, U.
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<strong>Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly.</strong>
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Arch. Dis. Child Fetal Neonatal Ed. 78: F121-F124, 1998.
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