title: Elevated hematocrit enhances platelet accumulation following vascular 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 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 RBCHIGHmice 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Walton
authors.affiliation: Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Department of Mathematics and Statistics, Cornell College, Mount Vernon, IA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Skorczewski
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Holle
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Joan D
authors.initials: JD
authors.lastname: Beckman
authors.affiliation: Department of Physics and Astronomy, and.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Cribb
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Mooberry
authors.affiliation: Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wufsus
authors.affiliation: McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Homeister
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.|McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.affiliation: Department of Physics and Astronomy, and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Falvo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.|McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Nigel S
authors.identifier: 0000-0002-8930-4304
authors.initials: NS
authors.lastname: Key
authors.affiliation: Department of Mathematics and.|Department of Bioengineering, University of Utah, Salt Lake City, UT; and.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Fogelson
authors.affiliation: Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO.|Department of Pediatrics, University of Colorado-Denver, Aurora, CO.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Neeves
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.|McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Alisa S
authors.identifier: 0000-0002-2845-2303
authors.initials: AS
authors.lastname: Wolberg
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000378:metabolism*; D001158:Arteries / Q000293:injuries / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets; D005260:Female; D006400:Hematocrit; D006801:Humans; D008297:Male; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D033081:Shear Strength; D013927:Thrombosis / Q000378:metabolism*; D057772:Vascular System Injuries / Q000378:metabolism*
chemical_list: C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases