Type 2M von Willebrand disease variant characterized by abnormal von Willebrand factor multimerization

We describe a von Willebrand disease (VWD) variant characterized by low pla sma and platelet von Willebrand factor (VWF), impaired ristocetin-induced V WF binding to platelet glycoprotein Ib (GPIb), and abnormal VWF multimer pa ttern not associated with the absence of large forms. A C-to-T transition a t nucleotide 4120 in exon 28 of the VWF gene was found; this mutation intro duces a cysteine at the codon for Arg 611 of mature VWF. In addition to the decreased factor VIII (FVIII) and VWF levels, ristocetin-induced platelet aggregation (RIPA) was almost absent, and VWF ristocetin cofactor activity (VWF:RCo) was significantly more decreased than VWF antigen. The patients ( mother and son) also showed a defect in VWF collagen-binding activity Plasm a VWF multimers were decreased, with no limit in the size of large forms, a nd the normal discontinuous multimer organization was replaced by a diffuse smear, especially detectable in the large forms. This picture was emphasiz ed by 1 -deamino-8-D-arginine vasopressin (DDAVP) infusion, so that the abn ormal VWF multimers appeared to have a molecular weight higher than those p resent in, or released by, human umbilical vein endothelial cells. DDAVP al so increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo. We include this variant in typ e 2M VWD, focusing on the abnormality in GPIb-dependent VWF function. We ad vance that this defect depends on the mutation in the GPIb binding domain o f VWF rather than the abnormal VWF multimer pattern.