Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

Abstract

We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by fl-thromboglobulin and platelet factor 4 release.The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/ IIIa) complex totally inhibits the SPA.The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification ofthe patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes enhanced RIPA, SPA, and thrombocytopenia.

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

“…Large multimers are synthesized normally, as confirmed by the normal platelet VWF content seen in type 2B VWD, but currently cannot be detected in vivo for their removal. Enhanced ristocetininduced platelet aggregation (RIPA), spontaneous platelet aggregation (SPA) [14][15][16] and sometimes thrombocytopenia are also part of the type 2B VWD phenotype. 17 Thrombocytopenia may be persistent or transient but is commonly worse after DDAVP infusion, pregnancy, exercise or surgery.…”

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

“…The disorder was named Montreal platelet syndrome (MPS). 2 Several studies have now shown that some patients with type 2B von Willebrand disease (VWD) present with macrothrombocytopenia [4][5][6][7][8] and spontaneous platelet aggregation in vitro, [4][5][6][7]9 features found in MPS. 10 A diagnosis of type 2 VWD is suggested by a discrepantly low ristocetin cofactor activity (VWF:RCo) compared with the VWF antigen (VWF:Ag; [VWF:RCo/VWF:Ag ratio Ͻ 0.7]).…”

von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure.

“…The affected patients also exhibit absence of the largest vWF multimers in plasma, probably owing to their spontaneous binding to circulating platelets (7). In some cases, this interaction may induce in vivo platelet aggregation and thrombocytopenia (8,9), which always occur in type IIB von Willebrand disease after administration of 1-deamino-8-D-arginine vasopressin (DDAVP)' (10). Different gene mutations have been identified in a number ofthese patients (3,(11)(12)(13) and all have been found to be localized in a domain of vWF, the disulfide loop created by the linkage of Cys5" and Cys695, that has been indicated as an important element in the regulation of vWF binding to GP lb (2,3).…”