Role of Red Cells in Thrombosis and Hemostasis

Until recently it has been assumed that red blood cells (RBCs) play mainly a passive role in hemostasis and thrombosis, but now some studies have uncovered several novel roles for them in both of these processes. The best-known effects of RBCs in clotting in vivo are rheological, involving laminar shearing plus aggregation and deformability of RBCs. In addition, RBCs have specific receptors for platelets and fibrin(ogen) that may be involved in thrombosis. Furthermore, in the contraction of blood clots, the trapping of RBCs in the platelet-fibrin network and subsequent physical changes may be important for hemostasis and thrombosis. Contracted blood clots develop a remarkable structure, with a meshwork of fibrin and platelet aggregates on the exterior of the clot and a close-packed, tessellated array of compressed polyhedral RBCs within. The structure and properties of contracted clots vary depending on the relative amounts of platelets, fibrinogen and RBCs and the conditions of clotting. Such close-packed arrays of polyhedral erythrocytes, or polyhedrocytes, have also been observed in human arterial and especially venous thrombi taken from patients. The mechanical nature of this RBC shape change was confirmed by polyhedrocyte formation from the forces of centrifugation of blood without clotting. Many experiments suggest that polyhedrocytes are more prevalent under conditions associated with thrombosis and could be a marker of prothrombotic conditions. Consistent with this hypothesis, RBC membranes have been found to be a major source of exposure of phosphatidylserine, which forms a procoagulant surface to generate thrombin. Platelets (with their cytoskeletal motility proteins) and fibrin(ogen) (as the substrate bridging platelets for contraction) are required to generate the forces necessary to segregate platelets/fibrin from RBCs and to compress these cells into a tightly packed array. Clots formed after puncture of the mouse saphenous vein are composed primarily of polyhedrocytes, suggesting that they may be important in venous hemostasis. Moreover, the permeability of contracted clots is nearly the same as that of the endothelial cell lining, consistent with their functional significance. These results demonstrate how contracted clots form an impermeable barrier important for hemostasis and wound healing and also to restore flow past obstructive thrombi. On the other hand, they also help explain how fibrinolysis is greatly retarded after clots contract, as a result of these striking structural changes. In summary, RBCs may perform a dual role, both helping to stem bleeding but at the same time contributing to thrombosis in a variety of ways, including when the tightly packed array of RBCs in a contracted clot blocks blood flow and resists dissolution.