Proteolytic processing of von Willebrand factor subunit: Heterogeneity in type-IIA von Willebrand disease

Abstract

Type IIA von Willebrand disease (vWD) is a heterogeneous disorder for which two different pathogenetic mechanisms have been proposed: increased proteolytic susceptibility of von Willebrand factor (vWF), and/or interference of its post-translational processing. Subunit analysis of vWF in type-IIA vWD has revealed an increased relative proportion of the 176- and 140-kDa subunit-derived fragments, suggesting an augmented fragmentation of vWF, even in the resting state. We analyzed the subunit pattern of vWF in plasma from five previously described patients with type-IIA vWD. All of them showed the above-mentioned pattern. In addition, the presence of a new band with an apparent molecular mass of 200 kDa, not described in normal individuals or in patients with vWD, was repeatedly observed in one of these patients. This patient also exhibited an abnormal vWF multimeric structure in platelets and in plasma, before and after desmopressin administration, when the blood was collected either in the presence or in the absence of proteinase inhibitors. We believe that an abnormal primary structure of vWF could be responsible for this abnormal proteolytic fragmentation pattern, as well as for the abnormal multimerization of vWF. Moreover, an abnormal susceptibility to proteolysis appears to be present, as suggested by the increase in the relative proportion of the 176-kDa fragment observed in the same patient. Future sequencing studies and genetic analysis may clarify whether there are one or two different defects related to the vWF of that patient. Our results indicate that the subunit analysis of vWF may reveal additional defects present in type-IIA vWD that may help our understanding of the pathogenesis of such disease.

Classification and Characterization of Hereditary Types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (Unclassifiable) von Willebrand Disease

“…These data are completely in line with the observed heterogeneity of mild, moderate, and severe type 2A VWD with regard to bleeding symptoms, laboratory phenotypes, and response to DDAVP (Batlle et al[34,35] and Michiels et al[7] [Table 1]). In our experience, mild type 2A VWD is characterized by normal or subnormal values for FVIII:C and VWF:Ag, VWF:RCo values greater than 0.20, normal RIPA at ristocetin concentrations of 1.2 or 1.75 mg/mL, and shows a complete but transient correction of BT, FVIII:C and VWF parameters, and large multimers for a few hours after DDAVP(Tables 1, 2, Fig.…”

Intravenous DDAVP and Factor VIII-von Willebrand Factor Concentrate for the Treatment and Prophylaxis of Bleedings in Patients With von Willebrand Disease Type 1, 2 and 3

“…A minority of type 2A have mild VWD featured by near normal to prolonged values for BT, normal FVIII:C and VWF:Ag, low VWF:RCO and VWF:CB, a normal RIPA and complete correction correction of BT and functional VWF parameters to normal for only a few hours followed by short half life times for VWF:RCo and CWF:CB (4,5,20,21). 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 (Fig.…”

Effects of inflammatory cytokines on the release and cleavage of the endothelial cell–derived ultralarge von Willebrand factor multimers under flow

“…14 Increased proteolysis is associated with bleeding disorders such as the type 2A von Willebrand disease. 15 In addition to these permanent defects, the ULVWF/ADAMTS13 control mechanism may also be influenced either by rapid and excessive ULVWF release or a transient inhibition of ULVWF cleavage by ADAMTS13. Increased plasma levels of VWF have been reported in a wide variety of disease states, such as bacterial or viral infections, 16,17 trauma, 18 autoimmune diseases, 19,20 and coronary and peripheral artery diseases.…”