Evidence of Platelet Activation at Medically Used Hypothermia and Mechanistic Data Indicating ADP as a Key Mediator and Therapeutic Target

• DOI: 10.1161/atvbaha.111.226373
• Publication Date: 2011-04-22T04:56:56Z
• Authors: Andreas Straub; Stefanie Krajewski; Jan David Hohmann; Erik Westein; Fu Jia; Nicole Bassler; Carly Selan; Julia Kurz; Hans Peter Wendel; Shala Dezfouli; Yuping Yuan; Harshal Nandurkar; Shaun Jackson; Michael J. Hickey; Karlheinz Peter
• Keywords: Blood Platelets; 0301 basic medicine; Analysis of Variance; Membrane Glycoproteins; Hydrolysis; Apyrase; Fibrinogen; Leukopenia; Platelet Activation; 3. Good health; Adenosine Diphosphate; Mice, Inbred C57BL; Mice; P-Selectin; 03 medical and health sciences; Platelet Adhesiveness; Fibrinolytic Agents; Platelet Glycoprotein GPIb-IX Complex; Antigens, CD; Hypothermia, Induced; Animals; Humans; Platelet Aggregation Inhibitors

Objective— Hypothermia is used in various clinical settings to inhibit ischemia-related organ damage. However, prothrombotic effects have been described as potential side effects. This study aimed to elucidate the mechanism of hypothermia-induced platelet activation and subsequent prothrombotic events and to develop preventative pharmacological strategies applicable during clinically used hypothermia.

Methods and Results—

Platelet function was investigated ex vivo and in vivo at clinically used hypothermia (28°C/18°C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl 3 -injured murine mesenteric arteries revealed increased platelet thrombus formation with hypothermia. Ex vivo flow chamber experiments indicated increased platelet-fibrinogen adhesion under hypothermia. We show that hypothermia results in reduced ADP hydrolysis via reduction of CD39 (E-NTPDase1) activity, resulting in increased levels of ADP and subsequent augmented primary and secondary platelet activation. In vivo administration of ADP receptor P 2 Y 12 antagonists and recombinant soluble CD39 prevented hypothermia-induced thrombus formation and thrombocytopenia, respectively.

Conclusion— The platelet agonist ADP plays a key role in hypothermia-induced platelet activation. Inhibition of receptor binding or hydrolysis of ADP has the potential to protect platelets against hypothermia-induced activation. Our findings provide a rational basis for further evaluation of novel antithrombotic strategies in clinically applied hypothermia.