Reversible Hypothermia-Induced Inhibition of Human Platelet Activation in Whole Blood in Vitro and in Vivo

Abstract

Abstract : Platelets and other blood components are often transfused in clinical settings associated with hypothermia and a bleeding diathesis, such as cardiopulmonary bypass surgery, other major surgery, and multiple trauma. We examined the hypothesis that hypothermia reversibly inhibits human platelet activation in vitro and in vivo. Platelet activation was studied in normal human volunteers by whole blood flow cytometric analysis of modulation of platelet surface GMP-140 and the glycoprotein (GP) Ib-IX complex in: (a) shed blood emerging from a standardized in vivo bleeding time wound and (b) peripheral blood activated in vitro with either x-thrombin (in the presence of gly-pro-arg-pro, an inhibitor of fibrin polymerization) or the stable thromboxane A2 analogue U46619. Platelets in peripheral whole blood were activated at temperatures between 22 and 37 deg C. The skin temperature of the forearm was maintained at temperatures between 22 and 37 deg C prior to and during the bleeding time incision. Platelet aggregation was studied in shed blood by flow cytometry using a gate on both GPIb-positivity and light scatter and in peripheral blood by aggregometry. In vitro, hypothermia inhibited the rate and extent of both thrombin and U46619-induced: (a) upregulation of GMP-140, (b) downregulation of the GPIb-IX complex, (c) platelet aggregation, (d) platelet shape change, and (e) thromboxane B2 generation. These inhibitory effects of hypothermia were all completely reversed by rewarming the blood to 37 C. In vivo, platelet activation was inhibited by hypothermia as shown by 5 independent assays of shed blood: (1) upregulation of GMP-140, (2) downregulation of the GPIb-IX complex, (3) platelet aggregate formation, (4) thromboxane B2 generation, and (5) the bleeding time.

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