Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10)
- PMID: 11307814
Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10)
Abstract
The recent discovery of five patients with coumarin sensitive FIX-variants due to a missense mutation in the FIX propeptide, either Ala-10Val or Ala-10Thr, has highlighted a novel type of genetic predisposition to bleeding during oral anticoagulant therapy (OAT). In the present study, we report six additional patients with such FIX variants. Haplotype analysis of FIX polymorphisms revealed a founder effect in the five German and Swiss patients with the Val-10 variant. Also, four Thr-10 variants detected in Germany, Switzerland and Great Britain derived from a common founder. Two Thr-10 variants from USA showed an independent de novo origin at a CpG dinucleotide that in general represents a mutation hotspot. These findings implicate the existence of additional subjects with corresponding variants in the populations of various countries. Even though the rare occurrence of these variants does not justify a general aPTT screening during OAT, it is recommended to monitor each bleeding event during OAT in males in order to exclude a genetic predisposition to bleeding by means of the following testing strategy: a) aPTT-testing in each bleeding complication of male patients during OAT, b) if aPTT is disproportionately prolonged, determination of FIX:C, and c) if FIX:C is disproportionately decreased as compared to FII:C, FVII:C and FX:C, sequencing of exon 2 of the FIX gene. This strategy will provide a cost-effective and safe procedure to identify patients that carry the FIX variants. Moreover, such a strategy accumulates data about the prevalence of these FIX mutations in a given population.
Similar articles
-
Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy.Br J Haematol. 1997 Jul;98(1):240-4. doi: 10.1046/j.1365-2141.1997.2213036.x. Br J Haematol. 1997. PMID: 9233593
-
Congenital hypersensitivity to vitamin K antagonists due to FIX propeptide mutation at locus -10: a (not so) rare cause of bleeding under oral anticoagulant therapy in Switzerland.Swiss Med Wkly. 2008 Feb 23;138(7-8):100-7. doi: 10.4414/smw.2008.12022. Swiss Med Wkly. 2008. PMID: 18293119
-
No indication for APTT screening in patients on oral anticoagulant therapy.Thromb Haemost. 1999 Mar;81(3):364-6. Thromb Haemost. 1999. PMID: 10102461 Clinical Trial.
-
The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark.Dan Med Bull. 2002 Nov;49(4):318-45. Dan Med Bull. 2002. PMID: 12553167 Review.
-
[Genetic predisposition to bleeding during oral anticoagulants treatment].An Sist Sanit Navar. 2008 Sep-Dec;31(3):247-57. An Sist Sanit Navar. 2008. PMID: 19165291 Review. Spanish.
Cited by
-
Clinical significance of gene-diagnosis for defects in coagulation factors and inhibitors.Wien Klin Wochenschr. 2003 Aug 14;115(13-14):475-81. doi: 10.1007/BF03041031. Wien Klin Wochenschr. 2003. PMID: 13677266 Review.
-
Life-threatening bleeding under vitamin K antagonists in spite of an INR in the therapeutic range.J Thromb Thrombolysis. 2011 Aug;32(2):232-7. doi: 10.1007/s11239-011-0580-y. J Thromb Thrombolysis. 2011. PMID: 21416391 Review. No abstract available.
-
Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.P R Health Sci J. 2017 Sep;36(3):165-172. P R Health Sci J. 2017. PMID: 28915306 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical