Increased platelet phosphatidylserine exposure and caspase activation in chronic uremia

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Abstract
Platelet activation is associated with exposure of the aminophospholipid phosphatidylserine (PS) to the outer hemi-leaflet of the plasma membrane bilayer, which seems to be involved in the coagulation process. Because platelet activation may occur in patients suffering from chronic uremia, which is frequently associated with a thrombophilic tendency, we studied whether uremic platelets show an increased propensity to expose PS on the outer membrane leaflet and whether this process is linked with important functional and molecular changes. Flow cytometric percentage of annexin V-positive platelets, a measure of PS externalization, was significantly elevated (P < 0.001) in uremic patients when compared to normal controls under both unstimulated and agonist-stimulated conditions. Uremic platelet procoagulant activity, as measured by thrombin generation, was more than twice as high (4.13 +/- 0.3 micro mL(-1)) as that found in normal controls (1.86 +/- 0.2 micro mL(-1)). Two independent assays showed that the enzymatic activity of caspase-3, a protease involved in the loss of membrane PS asymmetry, was significantly greater in the platelets of uremic subjects than in those of healthy controls. PS exposure in agonist-stimulated platelets was markedly reduced by inhibition of caspase-3 activity but was not affected by inhibition of calpain activity. These results support the view that the thrombophilic susceptibility of uremic patients may be partly ascribed to increased PS exposure to the outer membrane leaflet of platelets. This process seems to be causally linked to an increase in caspase-3 activity, particularly during platelet activation.