Platelet-RBC interaction via TSP-1 and CD36 is critical for thrombus formation and hemostasis

Introduction Recently,a direct interaction of platelets and red blood cells (RBCs) via FasL-FasR interaction was found to be important for the externalization of phosphatidylserine (PS) at the RBC membrane, that attributes a direct role for RBCs to thrombin generation and thrombus formation and stabilization upon hemostasis and thrombosis [ 1 ]. Interestingly, we found a novel interplay of platelets and RBCs by platelet-released TSP-1 and CD36 on RBCs, inducing PS exposure and contributing to thrombus formation and thrombosis. Method TSP-1-deficient and CD36 cell-type-specific (RBCs and platelets) knock-out mice were analyzed in experimental mouse models of arterial thrombosis. Blood samples from both mouse strains as well as human whole blood from healthy volunteers were analyzed using the flow chamber system as well as flow cytometry to determine PS exposure and TSP-1 binding. Results Initially, we analyzed platelet adhesion and thrombus formation under flow using a dynamic flow chamber system. This analysis involved CD36 antibody-treated human whole blood, as well as whole blood from CD36 cell-type-specific (RBCs and platelets) knock-out mice, to determine the contribution of CD36 on RBCs to thrombus formation ex vivo . Next, we demonstrated that 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. In addition, we showed that recombinant (r)TSP-1 not only induces PS exposure at the surface of isolated RBCs but also activates various intracellular signaling pathways, including ROS generation via the binding of the erythroid CD36. Furthermore, inhibition of CD36 restricted to RBCs significantly reduced thrombus formation on collagen and on collagen+TSP-1 and thrombus formation was significantly reduced on the collagen+TSP-1 matrix compared to the collagen matrix when CD36 was blocked on RBCs. In contrast, inhibition of CD36 on platelets did not alter thrombus formation on collagen but on a collagen+TSP-1 matrix under flow conditions. Finally, genetic deletion of either CD36 (RBC restricted) or TSP-1 protected mice against experimental induced thrombosis using the mesenteric artery and the ligated carotid artery models. Conclusion 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. Thus, TSP-1-CD36 axis may represent a promising candidate in order to target platelet-RBC interaction in patients with AAA and therefore reduce platelet-RBC-mediated effects in AAA formation. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany