Integration of platelets and coagulation to maintain hemostasis in vivo

About This Grant

Project summary Despite therapeutic advances, patients with impaired coagulation face persistent risks of acute bleeding and chronic tissue damage. Current treatment strategies focus on enhancing thrombin generation, including new therapeutics targeting endogenous anticoagulant pathways. These "hemostasis rebalancing" strategies have shown promise in clinical trials, with potential benefits over factor replacement or bypassing agents. Building on this concept, our proposed studies explore whether hemostatic rebalancing can be achieved by suppressing negative internal regulators of platelet signaling to enhance platelet activation. Preliminary data demonstrate that reduced thrombin production in the context of coagulation deficiency limits platelet-mediated hemostatic plug stability. Genetic disruption of GPCR receptor kinase (GRK) family members, which typically limit platelet reactivity, enhances platelet activation and reduces bleeding in a hemophilia model, even without restoring coagulation factor levels. Thus, we hypothesize that targeting GRKs and other platelet signaling regulators will rebalance hemostasis and attenuate bleeding in coagulation disorders. We will explore this hypothesis in two Aims. First, we will investigate the role of reduced platelet activation in the pathologic bleeding associated with coagulation disorders. Our studies will determine the mechanisms by which thrombin-mediated platelet activation contributes to the maintenance of hemostasis over time. Second, we will investigate the effect of increasing platelet reactivity on hemostatic plug structure and function in contexts of pathologic bleeding. The effect of platelet-specific GRK deficiency on platelet function in normal and hemophilic mice will be determined, as will the effect of pharmacologic GRK antagonism on human blood from healthy donors and hemophilia patients. We will also investigate the prothrombotic potential of platelet sensitization in contexts of coagulation deficiency. The comprehensive research strategy proposed will include state-of-the-art imaging to analyze hemostatic plug structure and function in vivo in mouse models, as well as microfluidic flow chamber studies to assess human blood in vitro. Overall, these mechanistic and translational studies aim to establish a proof of concept that enhancing platelet activation is an effective hemostasis rebalancing strategy to mitigate bleeding when coagulation is impaired.