Pseudo-Von Willebrand Disease

A number sign (#) is used with this entry because pseudo-von Willebrand disease is caused by mutation in the gene encoding the alpha subunit (GP1BA; 606672) of the GP Ib platelet membrane von Willebrand factor (VWF; 613160) receptor. Mutations in the GP Ib receptor also cause Bernard-Soulier syndrome (231200).

Description

Platelet-type von Willebrand disease, also known as pseudo-von Willebrand disease, is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor by the platelet glycoprotein Ib (GP Ib) receptor complex. Hemostatic function is impaired due to the removal of VWF multimers from the circulation (Murata et al., 1993).

Miller (1996) gave a comprehensive review of the disorder.

Clinical Features

Weiss et al. (1982) demonstrated that the clinical and laboratory findings of von Willebrand disease (VWD; see 193400) can be mimicked by an intrinsic platelet defect, which they observed in 4 generations of a Puerto Rican kindred: great-grandmother, grandmother, father, and 2 daughters. Either X-linked or autosomal dominant inheritance was suggested by the pedigree. There was increased ristocetin-induced platelet aggregation and decreased plasma levels of FVIII-VWF, such as found in type IIB von Willebrand disease. But whereas the physiologic change in VWD type IIB is due to an abnormality in FVIII-VWF, the defect in pseudo-von Willebrand disease resides in the platelets that remove FVIII-VWF at an abnormal rate. Thrombocytopenia occurred in the patients of Weiss et al. (1982) and is observed also in type II von Willebrand disease. Hoyer (1982) speculated that transient neonatal thrombocytopenia observed in the 2 children in the fourth generation of this family may have been due to mother-to-fetus transfer of normal von Willebrand factor.

Miller and Castella (1982) described 5 patients in 3 generations, including one instance of male-to-male transmission, and concluded that the defect involved an intrinsic platelet abnormality affecting FVIII-VWF interactions.

Takahashi et al. (1984) studied 4 patients from 2 Japanese families with pseudo-von Willebrand disease. The patients' platelets aggregated at lower concentrations of ristocetin than those required for normal platelets and demonstrated an increased capacity to bind normal von Willebrand factor. In some cases, normal VWF induced aggregation of these platelets in the absence of ristocetin. Administration of dDAVP (1-desamino-8-D-arginine vasopressin; desmopressin acetate) caused an immediate increase in VWF multimers, followed by a rapid disappearance of VWF multimers in plasma. The authors found that VWF in the form of cryoprecipitate could be given, provided quantities do not exceed those that produce thrombocytopenia. Analysis of platelet membrane glycoproteins from the patients showed 2 distinct bands in the GP I region that migrated differently than normal GP I, and the authors suggested that the defect lies in the GP Ib platelet receptor.

Molecular Genetics

In 7 affected members of a family with pseudo-VWD, Miller et al. (1991) identified a heterozygous mutation in the GP1BA gene (606672.0003). The mutation was absent in 6 unaffected family members.

In a father and 2 daughters with pseudo-VWD, Russell and Roth (1993) identified a mutation in the GP1BA gene (606672.0005). The abnormal receptor displayed increased affinity for von Willebrand factor.