The heterogeneity of type IIA von Willebrand's disease: studies with protease inhibitors

Abstract

The absence of large von Willebrand factor (vWF) multimers from plasma is a characteristic of Type IIA von Willebrand's disease (vWD) and is thought to contribute to the clinical expression of this disorder. Recently, three IIA patients have been reported in whom intermediate and large multimers could be restored if blood were collected in 5 mm EDTA, 6 mmol/L N-ethylmaleimide, and 1 mmol/L leupeptin. This suggested that absence of large multimers resulted from in vitro proteolysis. We have now collected blood from ten Type IIA vWD patients in these inhibitors but were not able to detect large multimers in the plasma of any of them. In addition, intermediate-sized multimers were reduced or completely absent in all. The inclusion of inhibitors in the citrate anticoagulant, as compared to citrate alone, was found to increase the relative proportion of intermediate multimers in some patients but had no effect in others, and in none did it restore large multimers to plasma. The results with platelet vWF were more varied. Four patients showed an absence or decrease of large multimers, whereas in seven patients large multimers were present. When compared with citrate anticoagulant alone, the inclusion of inhibitors in the anticoagulant had little or no effect on the platelet multimeric pattern. 1-Deamino-8- D-Arginine Vasopressin (DDAVP) was administered to six patients from five families. Two patients from one family showed complete correction and a third patient showed almost complete correction of her bleeding time. Two patients showed minimal correction and one showed no detectable correction. An increase in multimer size after DDAVP tended to be associated with correction of the bleeding time. However, in no case did the largest multimers appear in plasma even in patients with complete bleeding time correction. The presence or absence of inhibitors in the anticoagulant had little or no effect on the multimeric pattern after DDAVP. These results indicate that Type IIA vWD is a heterogeneous disorder in which absence of largest and intermediate multimers is an in vivo phenomenon.

Advances in the therapy of von Willebrand disease

“…A poor and short-lasting response is seen in patients with type 1 vWD with low platelet vWF. In type 2A vWD, FVIII:C levels are usually increased by DDAVP, but the BT is shortened in only a few patients [7]. A poor response would be predicted in type 2M because vWF is dysfunctional in this subtype.…”

The problem of diagnosing von Willebrand's disease

“…These mutations cause the absence of large vWF multimers either by impairing multimer assembly within the cell or by promoting the clearance of large multimers from the circulation. possibly by proteolysis [23]. A distinct set of mutations within the vWF propeptide causes a recessive form of vWD Type 2A by impairing multimer assembly [23.24].…”

1‐desamino‐8‐arginine‐vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease

“…In patients with type 1 vWd with normal platelet vWf, the prolonged bleeding time is usually corrected [1-6]. Some studies have described hemostatic improvement after DDAVP in type 2A vWd, while others studies have shown a lack of benefit in type 2A vWd [7,81. DDAVP therapy is not considered a useful and/or safe form of therapy in type 2B vWd since its administration has been associated with thrombocytopenia and circulating platelet aggregates [9-131. To determine the effect(s) of DDAVP on platelet counts in type 2B vWd, we have administered DDAVP to three type 2B vWd patients with different missense mutations and examined their hemostatic response(s).…”