Advertisement

Elevated hematocrit enhances platelet accumulation following vascular injury

Bethany L. Walton, Marcus Lehmann, Tyler Skorczewski, Lori A. Holle, Joan D. Beckman, Jeremy A. Cribb, Micah J. Mooberry, Adam R. Wufsus, Brian C. Cooley, Jonathan W. Homeister, Rafal Pawlinski, Michael R. Falvo, Nigel S. Key, Aaron L. Fogelson, Keith B. Neeves and Alisa S. Wolberg

Key points

  • Elevated hematocrit independently promotes arterial thrombus formation.

  • During arterial thrombosis, elevated hematocrit enhances platelet accumulation at the site of vessel injury.

Abstract

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 co-existing pathologies. Using an experimental model of elevated hematocrit in healthy mice, we measured effects of hematocrit in two 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 to 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. 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.

  • Submitted October 18, 2016.
  • Accepted February 22, 2017.