Interplay Between Thrombospondin-1 and CD36 Modulates Platelet-RBC Interaction in Thrombosis and Abdominal Aneurysm Formation.

Red blood cells (RBCs) contribute to hemostasis and thrombosis by interacting with platelets via the FasL-FasR pathway to induce procoagulant activity and thrombin formation. Here, we identified a novel mechanism of platelet-RBC interaction via the CD36-TSP-1 (thrombospondin-1) signaling pathway that plays a prominent role in arterial thrombosis and abdominal aortic aneurysm (AAA) formation and progression. AAA is a life-threatening atherosclerotic-related disease, characterized by the progressive dilation of the abdominal aorta, due to chronic inflammation and extracellular matrix remodeling/degradation within the vessel wall. The objective of the present study was to elucidate a new mechanism of platelet-RBC interaction via the TSP1-CD36 axis and its significance for arterial thrombosis and the pathology of AAA. TSP-1-deficient and CD36 cell-type-specific (RBCs and platelets) knock-out mice were analyzed in experimental mouse models of arterial thrombosis and AAA. Blood samples from patients with AAA from peripheral sites (laminar flow) and from inside the aneurysm segment (turbulent flow) were analyzed by flow cytometry and compared with age-matched controls. After platelet activation, platelet-released TSP-1 binds to CD36 at the RBC and platelet membrane to enhance procoagulant activity of both cells, leading to platelet aggregation and thrombosis. Patients with AAA exhibit enhanced procoagulant activity, elevated TSP-1 and CD36 plasma levels, as well as increased exposure of TSP-1 and CD36 at the RBC and platelet surface. In addition, biomechanically stress in the aneurysmal segment reinforces CD36 externalization on RBCs and platelets as well as the formation of platelet-RBC aggregates. In line, genetic deletion of either CD36 (RBC restricted) or TSP-1 protected mice against experimentally induced AAA formation. Our findings imply that CD36 on RBCs and platelets, as well as platelet-released TSP-1, contribute to procoagulant activity, playing a crucial role in arterial thrombosis and AAA progression.