A new von Willebrand variant (type I, New York): increased ristocetin- induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers

Abstract

We report three members of a family who had reduced levels of plasma von Willebrand factor (vWF) and increased ristocetin-induced platelet aggregation (RIPA) (aggregation of platelet-rich plasma with ristocetin at a concentration of 0.45 mg/mL), as previously reported in type IIB and pseudo-von Willebrand's disease (vWD). However, in contrast to the latter two disorders in which the larger vWF multimers are absent in plasma, the entire range of vWF multimers was observed in the patients' plasma after sodium dodecyl sulfate-agarose gel electrophoresis, and all vWF multimers (including the largest) were present in the same proportion as in normal plasma and type I vWD. Thus, despite increased RIPA, the levels and multimeric pattern of vWF in this family's plasma were indistinguishable from those in type I vWD in which RIPA is usually decreased. Addition of ristocetin to the patients' platelet- rich plasma resulted in the removal of vWF (and, more selectively, of the large multimers) at lower concentrations of ristocetin than normal, as in type IIB and pseudo-vWD. The defect in the patients was localized to their vWF, which had an enhanced capacity for aggregating washed normal platelets in the presence of low concentrations of ristocetin and for aggregating pseudo-vWD platelets (in the absence of ristocetin). Both glycoproteins (GP) Ib and IIb-IIIa were involved in the enhanced aggregation response. RIPA (at low ristocetin concentrations) in the patients' platelet-rich plasma was abolished by a monoclonal antibody (AP1) to GPIb and was markedly reduced by monoclonal antibodies (10E5 and LJP9) that block adenosine diphosphate and thrombin-induced binding of vWF and fibrinogen to GPIIb-IIIa but was unaffected by an antibody (LJP5) that only blocks vWF binding. Partial inhibition of the initial aggregation slope (and complete inhibition of second phase aggregation) was achieved with creatine phosphate/creatine phosphokinase. EDTA blocked second-phase aggregation but was without effect on the initial slope. The findings in this family combine some features of both type I vWD (normal pattern of vWF multimers in plasma) and type IIB vWD (increased RIPA) and further demonstrate the increasing complexity of the structure-function relationships in vWD.

Prevalence of type 2b ‘Malmö/New York’ von Willebrand disease in Italy: the role of von Willebrand factor gene conversion

“…Diagnosis of VWD2B is based on heightened ristocetin-induced platelet aggregation (RIPA) in platelet-rich plasma (PRP). VWD2B ÔMalmo¨ [3] or New York [4]Õ, previously reported as type I, is associated with increased RIPA at low concentrations of ristocetin but normal HMWM and no thrombocytopenia after stress situations. This peculiar VWD2B variant is caused by the mutation 3797C>T (P1266L) [5] in the VWF gene [6].…”

“…In the DVT study, the incidence of recurrent VTE after 3 and 6 months met the non-inferiority criterion of standard enoxaparin/warfarin therapy. In the PE study, the incidence of recurrent VTE was higher in the idraparinux group compared with the standardtherapy group after 3 and 6 months, and it did not meet the non-inferiority criterion [4]. Following an initial 3-6-month course of warfarin after a first VTE event, the prolonged prophylaxis for recurrent events with idraparinux vs. placebo for 6 months resulted in a relative risk reduction of 72.7% with idraparinux.…”

Contribution of genetical analysis for diagnosis of von Willebrand’s disease type 2B

“…In these cases, the suspicion of VWD type 2B diagnosis may occur before surgery and the abnormal RIPA could provide substitution treatment. Yet, as it has been reported, the use of DDAVP could be proposed in this family, because in this type 2B, with normal large VWF multimers, thrombocytopenia was not observed after administration of DDAVP [4].…”

“…After sequencing exon 28, a heterozygous P1266L mutation, with 3789 G>A polymorphism was found in all individuals. This abnormality was reported in the type 2B Malmö or type 1 New York, phenotype characterized by enhanced RIPA with normal platelet count and VWF multimeric distribution in plasma [4]. The association of the P1226L substitution and 3789 G>A polymorphism was recently reported in a case of VWF gene conversion with the pseudogene.…”

The molecular biology of von Willebrand disease

“…The mode of inheritance in type 3 VWD is autosomal recessive, and in some cases is a manifestation of homozygous or compound heterozygous recessive effects of mutations that may cause type 1 VWD in the heterozygous state (Weiss & Sussman, 1986;Randi et al, 1993;Castaman et al, 1995;Eikenboom et al, 1998). The parents of affected individuals are generally asymptomatic and have normal phenotypic laboratory data (Ruggeri & Zimmerman, 1987;Nichols et al, 1991;Eikenboom et al, 1992).…”