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Background: Antiplatelet therapy (APT), mainly aspirin and P2Y12 receptor inhibitors, reduces the incidence of recurrent arterial thrombosis but also increases bleeding risk. Therefore, management of APT in patients with thrombocytopenia, itself an independent risk factor for bleeding, is a clinical challenge with few evidence-based guidelines. Data are lacking on the combined impact of thrombocytopenia and APT on hemostasis. Objectives: To systematically investigate the combined effect of thrombocytopenia and APT in mouse models of hemostasis and thrombosis. Methods: Platelet-depleted mice were repleted with donor platelets inhibited with aspirin and/or clopidogrel at low (2) platelet counts. Hemostasis was assessed in the saphenous vein laser injury model, and thrombosis was assessed in the carotid artery ferric chloride model. Results: In the saphenous vein laser injury model, neither single nor dual APT significantly increased bleeding compared with vehicle at platelet counts >2 × 108/mL. However, for platelet counts

Interplay between platelets, coagulation/fibrinolytic factors, and endothelial cells (ECs) is necessary for effective hemostatic plug formation. This study describes a novel four-dimensional (4D) imaging platform to visualize and quantify hemostatic plug components with high spatiotemporal resolution. Fibrin accumulation following laser-induced endothelial ablation was observed at the EC-platelet plug interface, controlled by the antagonistic balance between fibrin generation and breakdown. Phosphatidylserine (PS) was first detected in close physical proximity to the fibrin ring, followed by exposure across the endothelium. Impaired PS exposure in cyclophilinD mice resulted in a significant reduction in fibrin accumulation. Adoptive transfer and inhibitor studies demonstrated a key role for platelets, but not ECs, in fibrin generation during hemostatic plug formation. Inhibition of fibrinolysis with tranexamic acid (TXA) led to increased fibrin accumulation in WT mice, but not in -/- mice resulted in a significant reduction in fibrin accumulation. Adoptive transfer and inhibitor studies demonstrated a key role for platelets, but not ECs, in fibrin generation during hemostatic plug formation. Inhibition of fibrinolysis with tranexamic acid (TXA) led to increased fibrin accumulation in WT mice, but not in cyclophilinD -/- mice or WT mice treated with antiplatelet drugs. These studies implicate platelets as the functionally dominant procoagulant surface during hemostatic plug formation. In addition, they suggest that impaired fibrin formation due to reduced platelet procoagulant activity is not reversed by TXA treatment.