Impact of platelet-red blood cell interactions on thrombosis and abdominal aortic aneurysm formation: Mechanisms and consequences

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Red blood cells (RBCs) influence rheology, and release ADP, ATP and nitric oxide suggesting a role for RBCs in hemostasis and thrombosis. Recently, we have shown that a direct cell interaction between platelets and RBCs via the Fas ligand (FasL)-FasR (CD95) pathway induces the externalization of phosphatidylserine (PS) and thus the formation of a pro-coagulant surface at the RBC membrane. Inhibition or genetic deletion of either FasL or FasR resulted in reduced PS exposure of RBCs and platelets, decreased thrombin generation and reduced thrombus formation in vitro and protection against arterial and venous thrombosis in vivo. In surgical specimens of patients after thrombectomy, direct cell contacts of platelets and RBCs via FasL-FasR were demonstrated. In new preliminary studies, we were able to provide initial evidence that the platelet integrin αIIbβ3 (fibrinogen receptor) serves as a potential ligand for FasR at the RBC membrane. Furthermore, we identified a potential new mechanism via CD36 that regulates PS exposure at the RBC membrane probably via binding to platelet released thrombospondin-1 (TSP-1). Early experiments provide evidence for an impact of platelet-RBC interactions in abdominal aortic aneurysm (AAA) in addition to effects on venous and arterial thrombosis. AAA is frequently characterized by the formation of an intraluminal thrombus (ILT) accompanied by hypoxia within the aortic wall and high thrombin plasma levels. Data from our lab showed migration of platelets and RBCs into the abdominal aortic wall of mice with experimental AAA and reduced progression of AAA in platelet-depleted mice. Moreover, enhanced PS exposure at the platelet and RBC membrane was measured in patients with AAA.To date, the pathways and proteins that link platelet activation and thrombin generation to extracellular matrix (ECM) degradation and AAA progression are largely unknown. Moreover, we believe that different mechanisms of platelet-RBC interactions are responsible for thrombin generation in vascular diseases with thrombotic complications. We hypothesize that RBCs modulate platelet activation and thrombus formation in arterial thrombosis and AAA via different signaling pathways according to the availability of oxygen. Therefore we want to experimentally follow three major objectives in the current proposal. First, we want to identify and characterize new cellular mechanisms of platelet-RBC interactions in hemostasis and thrombosis under normoxia and hypoxia. Second, we want to validate the relevance of platelet-RBC interactions in vascular diseases in experimental mice including arterial thrombosis and AAA. Third, we will analyze the mechanisms of platelet-RBC interactions in patients with AAA as a first translational approach.