Red blood cells (RBCs) demonstrate procoagulant properties in vitro, and elevated hematocrit is associated with reduced bleeding and increased thrombosis risk in humans. These observations suggest RBCs contribute to thrombus formation. However, effects of RBCs on thrombosis are difficult to assess because humans and mice with elevated hematocrit typically have coexisting pathologies. Using an experimental model of elevated hematocrit in healthy mice, we measured effects of hematocrit in 2 in vivo clot formation models. We also assessed thrombin generation, platelet-thrombus interactions, and platelet accumulation in thrombi ex vivo, in vitro and in silico. Compared with controls, mice with elevated hematocrit (RBC) formed thrombi at a faster rate and had a shortened vessel occlusion time. Thrombi in control and RBC mice did not differ in size or fibrin content, and there was no difference in levels of circulating thrombin-antithrombin complexes. In vitro, increasing the hematocrit increased thrombin generation in the absence of platelets; however, this effect was reduced in the presence of platelets. In silico, direct numerical simulations of whole blood predicted elevated hematocrit increases the frequency and duration of interactions between platelets and a thrombus. When human whole blood was perfused over collagen at arterial shear rates, elevating the hematocrit increased the rate of platelet deposition and thrombus growth. These data suggest RBCs promote arterial thrombosis by enhancing platelet accumulation at the site of vessel injury. Maintaining a normal hematocrit may reduce arterial thrombosis risk in humans.

The myocardial inflammatory response that occurs as a result of ischemia and reperfusion is similar to that which occurs in other tissues. Activation of the complement system is an integral part of the initiation and maintenance of any inflammatory response. It and other immune system mediators participate in the promotion of neutrophil adherence to endothelium by modulating expression of various adhesion molecules. The complement system also serves an integral role in mediating neutrophil activation, the results of which have been documented in the setting of myocardial ischemia and reperfusion. Another aspect of the complement cascade, which has received little attention with respect to the heart, is the direct effects of complement activation such as endothelial and myocardial cell cytotoxicity mediated by the membrane attack complex. It is likely that this form of tissue injury contributes significantly to myocardial reperfusion injury. Given the numerous contributions of the complement system to the generation of the inflammatory response, and to directly-mediated tissue injury, selective inhibitors of the complement system have great potential to limit reperfusion injury. This has already been demonstrated for the complement inhibitor sCR1. In the future, it is likely that any therapeutic treatment of reperfusion injury will include modulation of the effects of complement activation.

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