Characterization of 25 monoclonal antibodies to factor VIII-von Willebrand factor: relationship between ristocetin-induced platelet aggregation and platelet adherence to subendothelium.
We have studied the role of factor VIII-von Willebrand factor (FVIII-vWF) in both platelet adherence to subendothelium and ristocetin-induced platelet aggregation using monoclonal antibodies to human FVIII-vWF. Twenty-five monoclonal antibodies were obtained, two of which were directed to the factor VIII moiety of FVIII-vWF; one of these two completely inhibited the procoagulant activity (FVIII:C). The remaining 23 monoclonal antibodies were directed to the von Willebrand factor moiety of FVIII-vWF. The ability of the latter monoclonal antibodies to inhibit platelet adherence to arterial subendothelium was investigated with a perfusion model. According to the number of platelets adhering to the subendothelium, three groups of monoclonal antibodies could be discerned: (A) antibodies not affecting platelet adherence; (B) antibodies that inhibited platelet adherence to the level as observed when von Willebrand's disease plasma was tested; and (C) antibodies that completely inhibited both platelet adherence to subendothelium and ristocetin-induced platelet aggregation. The two antibodies present in group C competed for the same or closely related epitope(s) present on FVIII-vWF. These results demonstrate that a domain is present on the FVIII-vWF molecule that is associated both with ristocetin-induced aggregation and with the ability of FVIII-vWF to support platelet adherence to the subendothelium. Based on these observations, it is concluded that ristocetin-induced binding of FVIII-vWF to platelets reflects, at least in part, a physiologic mechanism regulating the function of FVIII-vWF in primary hemostasis.
D000911:Antibodies, Monoclonal / Q000276:immunology*; D001202:Ascitic Fluid / Q000276:immunology; D001667:Binding, Competitive; D001779:Blood Coagulation Factors / Q000276:immunology*; D004727:Endothelium; D005169:Factor VIII / Q000276:immunology*; D006801:Humans; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation / Q000187:drug effects*; D012310:Ristocetin / Q000494:pharmacology*; D014841:von Willebrand Factor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001779:Blood Coagulation Factors; D014841:von Willebrand Factor; D012310:Ristocetin; D005169:Factor VIII