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 (RBCHIGH) formed thrombi at a faster rate and had a shortened vessel occlusion time. Thrombi in control and RBCHIGH 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.Whenhumanwhole 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.
Bibliographical noteFunding Information:
The authors thank Erica Sparkenbaugh for advice, James R. Byrnes for reading the manuscript, and Kenzie S. McConnell for assistance with data processing. This study was supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute, (R56HL094740 and R01HL126974) (A.S.W.), (R01HL120728) (K.B.N., A.L.F.), and (R01HL126864) (A.L.F.), (1UL1TR001111) (NC TraCS Institute/A.S.W.), (T32HL069768 and T32HL007149) (University of North Carolina), National Science Foundation CAREER Award (CBET-1351672) (K.B.N.) and grant DMS-1521748) (A.L.F.), American Heart Association (14GRNT20410094) (K.B.N.), and by the National Center for Advancing Translational Sciences.
© 2017 by The American Society of Hematology.