Abstract Number: PB0136
Meeting: ISTH 2020 Congress
Background: Platelets are critical for the formation of hemostatic plugs and the pathogenesis of atherothrombosis. Preclinical animal models, especially the mouse, provide an important platform to assess the efficacy and safety of antiplatelet drugs. However, these studies are limited by inherent differences between human and mouse platelets and the species-selectivity of many drugs. Previous mouse models of in vivo human platelet function have proved inadequate due to the presence of confounding mouse platelets.
Aims: We report a new protocol for the adoptive transfer of human platelets into thrombocytopenic NOD/SCID mice; a model where all endogenous platelets are replaced by human platelets in mice accepting xenogeneic tissues.
Methods: Thrombocytopenia in NOD/SCID mice was achieved by injection of anti-GPIbα antibodies, in the presence of a platelet activating factor receptor inhibitor. Human platelets were transfused to a final concentration of 150-400 K/µl followed by infusion of human-vWF. Visualization and quantification of hemostatic plug formation at saphenous vein laser ablation injury sites was done using intravital spinning disk confocal microscopy.
Results: Integrin αIIbβ3-dependent hemostatic platelet plug formation was achieved ~30 seconds after laser ablation injury in humanized platelet mice. Pre-treatment of mice with standard dual antiplatelet therapy (DAPT, Aspirin + Ticagrelor) or PAR1 inhibitor, L-003959712 (vorapaxar analog), mildly prolonged bleeding time (BT) and significantly reduced platelet adhesion at injury sites. Consistent with clinical trials, inhibition of PAR1 in combination with DAPT markedly prolonged BT in our model.
Conclusions: Studies on the anti-hemostatic effect of PAR1-inhibition in the absence and presence of DAPT validate our humanized platelet mouse model as a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs. We propose that this model will also be of great value for the characterization of in vivo hemostatic/thrombotic potential of synthetic platelets, stored platelets or platelets from patients with a platelet function disorder.
To cite this abstract in AMA style:Paul DS, Bergmeier W. Novel Mouse Model for Studying Hemostatic Function of Human Platelets [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/novel-mouse-model-for-studying-hemostatic-function-of-human-platelets/. Accessed December 5, 2021.
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