Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 128107007, 359711001, 359717002, 359732009; ICD10CM: D68.02, D68.020, D68.021, D68.022, D68.023, D68.029; ORPHA: 166081, 166084, 166087, 166090, 166093, 903; DO: 0060574;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | von Willebrand disease, types 2A, 2B, 2M, and 2N | 613554 | Autosomal dominant; Autosomal recessive | 3 | VWF | 613160 |
A number sign (#) is used with this entry because von Willebrand disease (VWD) type 2 is caused by mutation in the gene encoding von Willebrand factor (VWF; 613160), which maps to chromosome 12p13.
Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. It results from a defect in platelet aggregation due to defects in the von Willebrand factor. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; 300841). F8 is mutated in hemophilia A (306700) (review by Goodeve, 2010).
Whereas von Willebrand disease types 1 (193400) and 3 (277480) are characterized by quantitative defects in the VWF gene, von Willebrand disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is characterized by qualitative abnormalities of the VWF protein. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8. VWD2 accounts for 20 to 30% of cases of VWD (Mannucci, 2004; Sadler et al., 2006; Lillicrap, 2009; Goodeve, 2010).
For a general discussion and a classification of the types of von Willebrand disease, see VWD type 1 (193400).
Von Willebrand disease type 2, like VWD type 1, is characterized by excessive mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery (Mannucci, 2004). The delineation of different subtypes of VWD type 2 does not reflect clinical differences, but rather different mutant VWF protein phenotypes, which may affect diagnosis, treatment, and counseling (Sadler et al., 2006).
Inheritance of VWD type 2 is generally autosomal dominant, although some cases are characterized by autosomal recessive transmission (Mannucci, 2004).
Von Willebrand Disease Type 2A
The mutant VWF protein in von Willebrand disease type 2A has decreased platelet adhesion due to a selective deficiency of high molecular weight multimers. The decrease in large multimers can be due to (1) a failure to synthesize the multimers ('group 1') or (2) enhanced ADAMTS13 (604134)-mediated proteolysis of the secreted high molecular weight protein ('group 2'). Regardless of mechanism in type 2A, the loss of large multimers is associated with decreased VWF-platelet interactions and/or decreased VWF-connective tissue interactions (reviews by Sadler et al., 2006 and Lillicrap, 2009).
Historically, type 2A was subclassified into types IIA, IIC, IID, and IIE. The mutant VWF in type IIA showed increased proteolysis by ADAMTS13; type IIC showed impaired multimerization in the Golgi apparatus due to mutation in the VWF propeptide (Zimmerman and Ruggeri, 1987); type IID showed impaired dimerization in the endoplasmic reticulum due to mutations in the C-terminal domain; and type IIE showed impaired intersubunit disulfide bond formation in the Golgi apparatus (Sadler et al., 2006) and a lack of outer proteolytic bands on gel electrophoresis, indicating reduced proteolysis (Zimmerman et al., 1986). All these subtypes showed dominant inheritance except for IIC, which showed recessive inheritance. These subtypes of type 2A are no longer used because the discrimination has not shown clinical utility; all are now referred to as type 2A (Sadler et al., 2006).
Gralnick et al. (1985) found that in VWD type 2A, inhibition of a calcium-dependent protease in vitro resulted in correction of the abnormal multimeric structure. This suggested that an abnormal VWF protein synthesized in this disorder is susceptible to proteolytic degradation, a process which may play an important role in phenotypic expression of the disease.
Von Willebrand Disease Type 2B
The mutant VWF protein in VWD type 2B shows increased affinity to platelet GP1BA (606672), resulting in increased platelet aggregation, and increased proteolysis of VWF subunits causing a decrease of large VWF multimers. Patients often have secondary thrombocytopenia due to platelet consumption (Sadler et al., 2006).
Othman and Favaloro (2008) reviewed the complexity of VWD type 2B, noting that atypical forms with complete VWF monomers, no mutations in the A1 domain, or with giant platelets have also been reported, suggesting the presence of phenotypic modifiers.
Saba et al. (1985) found chronic thrombocytopenia, in vivo platelet aggregate formation, and spontaneous platelet aggregation in vitro in affected members of a family with VWD type 2B. The 4 affected family members identified were a man and 2 sons and a daughter by 2 different wives.
Holmberg et al. (1986) reported a Swedish family in which 8 members had a variant of VWD type 2B, referred to as 'type 2 Malmo.' There was a mild bleeding disorder, and laboratory studies showed that platelets aggregated at much lower ristocetin concentrations than normal. The bleeding time was variously prolonged, and VWF:Ag, VWF activity, and F8 were decreased. All VWF multimers were present, and there was no thrombocytopenia. The defect in this family, inherited as an autosomal dominant, resembled that of type 2B because of the response to ristocetin, but differed because all VWF multimers were present. Weiss and Sussman (1986) reported a similarly affected family, and referred to this variant as 'type I New York' (Sadler et al., 2006). Wylie et al. (1988) also described this variant and noted that there was no spontaneous aggregation of platelets. Holmberg et al. (1993) reviewed the family reported by Holmberg et al. (1986) and reported another affected German family. Affected individuals had only mild bleeding. Sadler et al. (2006) emphasized that the variant reported by Wylie et al. (1988) and others was a form of VWD type 2B, with increased sensitivity to ristocetin in vivo.
Donner et al. (1987) described 2 families with an apparently autosomal recessive form of type 2B von Willebrand disease. The patients presented in infancy with thrombocytopenia.
Murray et al. (1991) found evidence of gonadal mosaicism in the father of 2 sibs with VWD type 2B who had inherited the same VWF gene, as marked by polymorphisms, i.e., haplotype, as did 7 unaffected sibs.
Jackson et al. (2009) identified a heterozygous V1316M substitution (613160.0007) in affected members of a large French Canadian family with VWD type 2B that had been described originally by Lacombe and D'Angelo (1963); Milton and Frojmovic (1979), and Milton et al. (1984) referred to the disorder in the family as 'Montreal platelet syndrome.' Affected individuals had lifelong bruising; some patients had severe postoperative bleeding, postpartum hemorrhage, and gastrointestinal bleeding. A significant proportion of platelets occurred in microaggregates typically containing 2 to 6 platelets, and the aggregation could be increased by stirring. Milton and Frojmovic (1979) suggested that the appearance of abnormally large platelets was related to a defect in the mechanism that regulates platelet size and shape during shape change. Jackson et al. (2009) found that affected family members had macrothrombocytopenia, borderline to normal VWF antigen, low ristocetin cofactor activity, and normal factor VIII coagulant activity, all consistent with VWD type 2B.
Von Willebrand Disease Type 2M
The mutant VWF protein in VWD type 2M shows decreased platelet adhesion without a deficiency of high molecular weight multimers. This functional defect is caused by mutations that disrupt VWF binding to platelets or to subendothelium, consistent with a loss of function (Sadler et al., 2006).
Stepanian et al. (2003) reported a French mother and son with VWD type 2M. Both patients had a moderate bleeding syndrome with epistaxis and easy bruising. Laboratory studies showed mildly decreased VWF antigen levels, normal multimers, and severely decreased VWF functional activity. Factor VIII was mildly decreased and platelet counts were normal.
Von Willebrand Disease Type 2N
The mutant VWF protein in VWD type 2N shows markedly decreased binding affinity for factor VIII, and this may be confused with mild hemophilia A (306700) (Sadler et al., 2006). The phenotype is characterized by a disproportionate decrease in F8 compared to VWF:Ag. VWD type 2N usually shows autosomal recessive inheritance (Sadler et al., 2006). Gaucher et al. (1991) noted that the phenotype resembled hemophilia A, or F8 deficiency, but showed autosomal recessive instead of X-linked inheritance.
Mazurier et al. (1990) reported a 50-year-old French woman, born of consanguineous parents, with VWD type 2N (previously designated the 'Normandy' variant). She had a lifelong history of excessive bleeding, and laboratory data showed decreased factor VIII, subnormal bleeding time, and normal VWF multimers. VWF isolated from patient plasma was unable to bind factor VIII. Lopez-Fernandez et al. (1992) described a brother and sister with VWD characterized by abnormal binding of von Willebrand factor to factor VIII. They were presumably homozygous for a recessive VWF defect. Hilbert et al. (2004) reported 2 unrelated French patients with VWD type 2N. Both were adults with lifelong histories of mucocutaneous bleeding and menorrhagia. Laboratory studies showed a dramatic decrease in VWF F8-binding capacity.
Von Willebrand Disease Type 2CB
Riddell et al. (2009) proposed a new subtype of VWF characterized by clinically significant bleeding episodes due to a mutant VWF protein with defective collagen binding, termed 'VWF 2CB.' Laboratory studies showed normal values of VWF:RCo to VWF:Ag (RCo:Ag), normal VWF multimer analysis, and normal ristocetin-induced platelet aggregation, but markedly reduced ratios of VWF collagen-binding activity to VWF antigen (CB:Ag) against type III collagen and type I collagen. Riddell et al. (2009) concluded that the defect was distinct from VWF type 2M, in that type 2M is also characterized by impaired binding to platelet GP1BA and can show a full range of associated VWF multimers.
An association between aortic stenosis and hemorrhage from gastrointestinal angiodysplasia has long been recognized. Remarkably, aortic valve replacement, rather than bowel resection, corrects the bleeding. Warkentin et al. (1992) pointed out that aortic stenosis can be complicated by acquired von Willebrand disease type 2A which is corrected by valve replacement, and hypothesized that acquired VWD was the link. They suggested that in patients with aortic stenosis there is an accelerated clearance of the largest VWF multimers as a result of accelerated platelet/VWF interactions in blood flowing through the stenotic aortic valve.
Chey et al. (1992) described gastric angiodysplasia in association with type 2B VWD. Endoscopic electrocautery performed acutely and followed by long-term estrogen/progesterone therapy was accompanied by no recurrence of bleeding during 11 months of follow-up. Lavabre-Bertrand et al. (1994) corroborated the usefulness of estrogen-progesterone therapy for the bleeding of digestive angiodysplasia on the basis of observations in a 59-year-old man with VWD and life-threatening digestive bleeding.
Von Willebrand disease is often treated with the vasopressin analog desmopressin acetate (1-desamino-8-D-arginine vasopressin; dDAVP), which raises the level of factor VIII/von Willebrand factor in plasma. Holmberg et al. (1983) showed that dDAVP is contraindicated in type 2B VWD because it produces thrombocytopenia in such patients by release of an abnormal factor VIII/von Willebrand factor with platelet-aggregating properties.
Hall et al. (1987) described 3 monoclonal antibodies produced against von Willebrand factor antigen by conventional hybridoma technique. These antibodies inhibited factor VIII ristocetin cofactor activity but did not inhibit factor VIII coagulant activity. Hall et al. (1987) found that the antibodies were useful in differentiating types 1 and 2 VWD. Since desmopressin may be ineffective or even contraindicated in treating patients with type 2 VWD, the differentiation is of clinical importance.
In a review of VWD type 2N, Mazurier (1992) stated that the deficiency of factor VIII could be corrected by infusion of a VWF concentrate almost devoid of factor VIII coagulant activity, and that this treatment was more effective than infusion of factor VIII itself.
Riddell et al. (2009) noted that patients with VWF type 2CB, which is characterized by clinically significant bleeding episodes due to a mutant VWF protein with defective collagen binding, show good functional response to treatment with DDAVP. DDAVP causes a rise in VWF:CB resulting from an overall increase in the amount of circulating VWF, even though the qualitative defect in collagen binding remains.
Verweij et al. (1988) used RFLPs to demonstrate that the mutation in von Willebrand disease type 2A is in the gene for von Willebrand factor on chromosome 12p13.
Von Willebrand Disease Type 2A
Mutations causing the enhanced proteolysis phenotype lie within or near domain A2 (exon 28) of the VWF gene, which is the site of the ADAMTS13 (604134) cleavage sequence between residues tyr1605 and met1606. Mutations interfering with multimerization occur in regions involved in dimer or multimer assembly, such as the VWF propeptide, the N-terminal D3 domain, the A2 domain, and the C terminus (James and Lillicrap, 2008).
In affected members of a family with von Willebrand disease type 2A, Iannuzzi et al. (1991) identified a 4883T-C heterozygous mutation in the VWF (I865T; 613160.0001). The I865R substitution was located immediately adjacent to 2 other previously identified mutations that also result in type 2A von Willebrand disease (R834W, 613160.0002 and V844D, 613160.0003; Ginsburg et al., 1989), suggesting a clustering for these mutations in a portion of the protein critical for proteolysis.
Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are located within a 32-amino acid segment in the midportion of the 2,813-amino acid VWF coding sequence. Type 2A von Willebrand disease is characterized by normal or only moderately decreased levels of von Willebrand factor, the absence of large and intermediate VWF multimers, and increased VWF proteolysis with an increase in the plasma levels of the 176-kD VWF proteolytic fragment. The ADAMTS13 (604134) proteolytic-cleavage site is located between tyr842 and met843 (numbering based on the mature protein).
Von Willebrand Disease Type 2A/IIE
Schneppenheim et al. (2010) reported a high frequency (29%) of VWD type 2A subtype IIE among patients with type 2A studied in their laboratory. Type IIE is associated with a reduction of high molecular weight (HMW) VWF multimers and a lack of outer proteolytic bands on gel electrophoresis, indicating reduced proteolysis. Genetic analysis of 38 such index cases identified 22 different mutations in the VWF gene, most of them affecting cysteine residues clustered in the D3 domain. The most common mutation was Y1146C (613160.0039), which was found in 12 (32%) probands. In vitro expression studies indicated that the Y1146C-mutant protein caused a severe reduction in or lack of HMW monomers and decreased secreted VWF antigen levels. However, clinical symptoms were heterogeneous among carriers, ranging from mild to severe bleeding. Schneppenheim et al. (2010) suggested that several mechanisms likely act in concert to produce subtype IIE, including decreased secretion of VWF, the change of a cysteine residue which may impact multimerization, and decreased half-life of the mutant protein. Altered ADAMTS13-mediated proteolysis did not appear to be a major primary factor.
Von Willebrand Disease Type 2B
Mutations causing VWD type 2B tend to cluster within or near the A1 domain of the VWF gene, which mediates platelet GP1BA (606672) binding. The mutations appear to enhance platelet binding of VWF by stabilizing the bound conformation (Sadler et al., 2006).
In patients with VWD type 2B, Randi et al. (1991) identified 3 different heterozygous mutations in exon 28 of the VWF gene (613160.0005-613160.0007) within the domain that interacts with platelet glycoprotein GP1BA, resulting in a loss of function. Patient plasma showed a decrease in large VWF multimers due to spontaneous binding of VWF to platelets and subsequent clearance from the circulation. The region of VWF that binds to GP1BA has been localized to a peptide including amino acids 480 to 718 of the mature subunit that is encoded by exon 28.
In affected members of a Swedish family (Holmberg et al., 1986) and a German family with a variant of VWD type 2B, Holmberg et al. (1993) identified a heterozygous mutation in the VWF gene (P1266L; 613160.0033). The phenotype was unique in that there was a mild bleeding disorder, and laboratory studies showed that platelets aggregated at much lower ristocetin concentrations than normal.
Von Willebrand Disease Type 2M
In a French mother and son with VWD type 2M, Stepanian et al. (2003) identified a heterozygous mutation in the VWF gene (S1285F; 613160.0030) that altered the folding of the A1 loop and prevented the correct exposure of VWF binding sites to GP1BA. The findings were consistent with a loss of function.
Von Willebrand Disease Type 2N
Mutations that cause VWD type 2N usually occur in the F8-binding site of VWF, which lies between ser764 and arg1035. However, mutations outside of this region have also been reported (Hilbert et al., 2004).
In a 50-year-old French woman with VWD type 2N reported by Mazurier et al. (1990), Gaucher et al. (1991) identified a homozygous mutation in the VWF gene (T28M in the mature subunit; 613160.0011).
Mazurier et al. (2002) reported a 20-year-old French woman with VWD type 2N who was compound heterozygosity for 2 mutations in the VWF gene (Y357X, 613160.0035 and C1060R, 613160.0036). She had very low levels of VWF and F8, and absent binding of VWF to F8. Clinical features included epistaxis, hematomas, and hematemesis throughout childhood. The diagnosis was complicated at first because 2 male first cousins had F8 deficiency (306700) due to a hemizygous mutation in the F8 gene (C179G; 300841.0268).
Hilbert et al. (2004) reported 2 unrelated French patients with type 2N VWD who were compound heterozygous for R854Q (613160.0013) and another pathogenic mutation (Y795C, 613160.0031 and C804F, 613160.0032, respectively).
Von Willebrand Disease Type 2CB
In affected members of 2 unrelated families with von Willebrand disease type 2CB, Riddell et al. (2009) identified heterozygous mutations in the collagen-binding A3 domain of the VWF gene (W1745C; 613160.0040 and S1783A; 613160.0042, respectively). The authors noted that VWD type 2M is associated with mutations in the A1 domain of VWF.
Rayes et al. (2010) and Golder et al. (2010) independently developed mouse models of VWD type 2B that recapitulated the human phenotype.
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