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.

Characterization, Classification, and Treatment of von Willebrand Diseases: A Critical Appraisal of the Literature and Personal Experiences

“…Interestingly, platelet lysates demonstrated a decrease of large vWF multimers for G1505L and S1506L mutants (group 1 defect) but a normal pattern for the G1505E and R1597W mutants (group 2 defect). Battle et al 46,47 and Michiels et al 22 observed heterogeneity of mild, moderate, and severe type 2A vWD with regard to bleeding symptoms, laboratory phenotypes, and response to DDAVP (Table 6). Mild type 2A vWD is characterized by normal or subnormal values for FVIII:C and vWF:Ag; low vWF:RCo values > 0.20; normal RIPA; a good but transient correction of BT, FVIII:C, and vWF parameters; and large multimers for a few hours after DDAVP ( Fig.…”

“…6). 22,46,47 Most patients with type 2A vWD show only a transient minor or a poor response to DDAVP, with no correction of the BT despite some increase of vWF:RCo (Fig. 6), and therefore are candidates for FVIII/vWF concentrate substitution for the treatment and prophylaxis of bleeding symptoms.…”

“…6), and therefore are candidates for FVIII/vWF concentrate substitution for the treatment and prophylaxis of bleeding symptoms. 22,46,47 Federici et al 85 demonstrated that in type 2A vWD patients with the mutations S1506L and V1665E causing group 1 defects, the response to DDAVP is poor, with no reappearance of the large multimers and with persistence of a strongly prolonged BT and little increase of vWF:RCo. In contrast, in type 2A vWD patients with the mutations R1597W and G1629R causing group 2 defects, DDAVP induced a transient increase of large multimers associated with a transient (1 or 2 hours) correction of BT and transient correction of vWF:RCo to low normal.…”

Guidelines for the Evaluation of Intravenous Desmopressin and von Willebrand Factor/Factor VIII Concentrate in the Treatment and Prophylaxis of Bleedings in von Willebrand Disease Types 1, 2, and 3

“…A minority of type 2A have mild vWD characterized by near normal to slightly prolonged values for BT, normal FVIII:C and vWF:Ag, low vWF:RCo and vWF:CB levels, a normal RIPA, and complete correction of BT and functional vWF parameters to normal for only a few hours, followed by short half-life times for vWF:RCo and vWF:CB. 4,5,12,13 This mild type 2A vWD has a transiently complete response to DDAVP that may be good enough for the treatment and prophylaxis of minor bleedings. [3][4][5]11 Most type 2A vWD patients have pronounced or very low vWF:RCo, prolonged (markedly) BT, PFA-100 CT longer than 250 seconds, and show only a transient minor or a poor response to DDAVP with no correction of the BT despite some increase of vWF:RCo.…”

A Practical Approach to Genetic Testing for von Willebrand Disease

“…However, the mutant vWF has an increased sensitivity to proteolytic degradation in plasma, resulting in decreased plasma high-molecularweight multimers but a normal platelet vWF multimer pattern. 68 The cleavage site in a subset of patients with type 2A vWD was shown to be the Tyr842-Met843 bond, in which mutations may result in a conformational change, resulting in increased sensitivity to proteolysis.…”