Abstract
BackgroundReports including our own describe that intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Our recent study shows that plasma Hb concentrations correlate directly with platelet activation in patients with paroxysmal nocturnal hemoglobinuria (PNH). The binding of Hb to glycoprotein1bα (GP1bα) increases platelet activation. A peptide AA1-50, designed from N-terminal amino acid sequence of GP1bα significantly inhibits the Hb binding to GP1bα as well as Hb-induced platelet activation. This study further examined if the Hb-mediated platelet activation plays any significant role in thrombus formation on subendothelium matrix under physiological flow shear stresses and the inhibition of Hb-platelet interaction can abrogate the above effects of Hb.Methods and ResultsStudy performed thrombus formation assay in vitro by perfusing whole blood over immobilized VWF or collagen type I in presence of Hb under shear stresses simulating arterial or venous flow. The Hb concentrations ranging from 5 to 10 μM, commonly observed level in plasma of the hemolytic patients including PNH, dose-dependently increased thrombus formation on immobilized VWF under higher shear stress of 25 dyne/cm2, but not at 5 dyne/cm2. The above Hb concentrations also increased thrombus formation on immobilized collagen under both shear stresses of 5 and 25 dyne/cm2. The peptide AA1-50 abrogated invariably the above effects of Hb on thrombus formation.Conclusions and SignificanceThis study therefore indicates that the Hb-induced platelet activation plays a crucial role in thrombus formation on immobilized VWF or collagen under physiological flow shear stresses. Thus suggesting a probable role of this mechanism in facilitating thrombosis under hemolytic conditions.
Highlights
Intravascular hemolysis increases the risk of thrombosis in hemolytic disorders
To develop more insight into the prothrombotic role of extracellular Hb this study further examined if the Hb concentrations, commonly observed levels in hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) [1,2,3,4] can induce thrombus formation on subendothelium matrix under physiological flow shear stresses in vitro; and if the inhibition of Hb-platelet interaction can abrogate the above effects of Hb
The Hb concentrations ranging from 5 to 10 μM, commonly observed level in plasma of the hemolytic patients, increased the formation of platelet thrombus in a concentration-dependent manner when perfused with whole blood over immobilized VWF (100 μg/mL, purified from plasma of normal individual) under shear stress of 25 dyne/cm2 simulating arterial blood flow (Fig 1A, 1B4 and 1B5)
Summary
Intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Studies including our own describe a significant association between the elevated plasma Hb and vascular dysfunction and prothrombotic events in hemolytic disorders including PNH [1,2,3,4]. To develop more insight into the prothrombotic role of extracellular Hb this study further examined if the Hb concentrations, commonly observed levels in hemolytic patients including PNH [1,2,3,4] can induce thrombus formation on subendothelium matrix under physiological flow shear stresses in vitro; and if the inhibition of Hb-platelet interaction can abrogate the above effects of Hb. Reports including our own describe that intravascular hemolysis increases the risk of thrombosis in hemolytic disorders. Our recent study shows that plasma Hb concentrations correlate directly with platelet activation in patients with paroxysmal nocturnal hemoglobinuria (PNH).
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