Platelets in Patients with Normal Multimeric Structure

Variant von Willebrand disease designated as type I New York or type Malmo is characterized by enhanced ristocetin-induced platelet agglutination with normal von Willebrand factor multimeric distribution in plasma. We have studied four such patients belonging to three unrelated families and found in all of them a unique cytosine-to-thymine transition changing the codon for Pro" (CCG) to Leu (CIG). In three patients the mutant allele also had a silent mutation in the codon for Ser"W (TCG -TCA). Both nucleotide changes are present in the von Willebrand factor pseudogene; however, the characterization of distinctive markers where the gene and pseudogene differ, as well as the examination of amplified cDNA derived from platelet mRNA, confirmed that the abnormality occurs in the von Willebrand factor gene of the patients. Moreover, recombinant expression of the isolated glycoprotein lb-binding domain of von Willebrand factor provided direct evidence that the Pro" -Leu mutation is responsible for enhanced platelet reactivity to lower ristocetin concentrations. These results define a new structural element affecting the affinity of von Willebrand factor for glycoprotein lb and establish the molecular basis of a variant form of von Willebrand disease. (J. Clin. Invest. 1993. 91:2169-2177.)