Humanized GPIb?-von Willebrand factor interaction in the mouse.

ABSTRACT: The interaction of platelet glycoprotein Ib? (GPIb?) with von Willebrand factor (VWF) initiates hemostasis after vascular injury and also contributes to pathological thrombosis. GPIb? binding to the VWF A1 domain (VWFA1) is a target for antithrombotic intervention, but attempts to develop pharmacologic inhibitors have been hindered by the lack of animal models because of the species specificity of the interaction. To address this problem, we generated a knockin mouse with Vwf exon 28-encoding domains A1 and A2 replaced by the human homolog (VWF^h28). VWF^h28 mice (M1HA) were crossbred with a transgenic mouse strain expressing human GPIb? on platelets (mGPIb?^null;hGPIb?^Tg; H1MA) to generate a new strain (H1HA) with humanized GPIb?-VWFA1 binding. Plasma VWF levels in the latter 3 strains were similar to those of wild-type mice (M1MA). Compared with the strains that had homospecific GPIb?-VWF pairing (M1MA and H1HA), M1HA mice of those with heterospecific pairing had a markedly greater prolongation of tail bleeding time and attenuation of thrombogenesis after injury to the carotid artery than H1MA mice. Measurements of GPIb?-VWFA1 binding affinity by surface plasmon resonance agreed with the extent of observed functional defects. Ristocetin-induced platelet aggregation was similar in H1HA mouse and human platelet-rich plasma, and it was comparably inhibited by monoclonal antibody NMC-4, which is known to block human GPIb?-VWFA1 binding, which also inhibited FeCl₃-induced mouse carotid artery thrombosis. Thus, the H1HA mouse strain is a fully humanized model of platelet GPIb?-VWFA1 binding that provides mechanistic and pharmacologic information relevant to human hemostatic and thrombotic disorders.

SUBMITTER: Kanaji S 

PROVIDER: S-EPMC6177644 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature