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 (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.

Defective fibrin deposition and thrombus stability in Bambi−/− mice are mediated by elevated anticoagulant function

“…Formation of a stable thrombus after vascular injury requires the concerted action of vessel wall components (e.g. extravascular tissue factor, subendothelial matrix, and activated EC), the coagulation system, platelets, and, as recently demonstrated, other cells including red blood cells and neutrophils . The importance of neutrophil accumulation mediated by lymphocyte function‐associated antigen 1 (LFA‐1) expressed on neutrophils and ICAM‐1 expressed on EC in the laser‐induced thrombosis model of the cremaster arterioles has recently been demonstrated .…”

“…It involves concerted roles of the vessel wall, platelets, and other blood cells (e.g. neutrophils, red blood cells), as well as the coagulation cascade . Using experimental mouse models of thrombosis, or human blood in ex vivo flow assays, previous studies have shown that thrombi exhibit a heterogeneous composition with a core of closely packed, activated platelets that is overlaid by a shell of less‐activated platelets .…”

“…neutrophils, red blood cells), as well as the coagulation cascade. [1][2][3][4][5][6] Using experimental mouse models of thrombosis, or human blood in ex vivo flow assays, previous studies have shown that thrombi exhibit a heterogeneous composition with a core of closely packed, activated platelets that is overlaid by a shell of less-activated platelets. 3,7 The core of the thrombus (compared to the shell) has reduced porosity and solute transport that effectively increases the local thrombin concentration leading to more efficient fibrin deposition and thrombus stabilization.…”

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

“…In fact the ETP plateaued once the platelet count reached a certain level (approximately 100*10 9 platelets/L) but the peak still increases with further ascending platelet counts . The influence of erythrocyte count on WB‐TG is less explored, but a recent study found that at a normal platelet concentration of 200*10 9 /L the peak of WB‐TG was significantly augmented by increasing hematocrit from 0.2 to 0.45, whereas the ETP was largely unchanged . Therefore, the lower counts of platelets and erythrocytes in cirrhotic patients might have induced differential impact on the peak and ETP of WB‐TG, and caused the above‐observed discordance.…”

Hematocrit and incidence of venous thromboembolism

“…The risk of VTE in the Tromsø and ARIC general population studies, however, appears to be increased at hematocrit levels much lower than for polycythemia vera. Mechanistically, high hematocrit increases platelet margination and adhesiveness . However, a more important mechanism by which hematocrit may increase VTE risk is via increased blood viscosity and venous stasis …”