Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden

Summary Type IIB of von Willebrand's disease (vWD) is a variant in which the structurally abnormal von Willebrand factor (vWF) shows an increased affinity for the platelet vWF receptor, glycoprotein Ib (GPIb). This may sometimes give rise to platelet aggregation and thrombocytopenia in vivo. In 20 patients from nine unrelated families with type IIB vWD from Denmark, Germany and Sweden we studied the molecular defect by amplification and direct sequencing of parts of exon 28 which encode for the vWF domain that interacts with platelet GPIb. Three different point mutations were identified one of which has not previously been reported. Fifteen patients from five families were heterozygous for the Arg⁵⁴³Trp substitution. The mutation had occurred independently in all five families and in two of them represented a de novo mutation. In one of these families the father, though asymptomatic and with normal laboratory test results, carried the mutation in heterozygous form. In three families, four affected members were found to be heterozygous for the Arg⁵⁴³°Cys substitution. The mutations were of different origin at least in two of the families. The third substitution, Val⁵⁵⁴Leu, which has not previously been described, was found in one patient and was due to a de novo mutation. In most of the patients spontaneous thrombocytopenia had been recorded on at least one occasion. Five of the patients with the Arg⁵⁴³Trp substitution and the one with the Val⁵⁵⁵Leu substitution had all had bleeding associated with thrombocytopenia in the neonatal period of early infancy.