Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target

Andreas Straub, Stefanie Krajewski, Jan David Hohmann, Erik Westein, Fu Jia, Nicole Bassler, Carly Selan, Julia Kurz, Hans Wendel, Shala Dezfouli, Yu-Ping Yuan, Harshal Nandurkar, Shaun Jackson, Michael Hickey, Karlheinz Peter

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 (28A?C/18A?C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl3-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 P2Y12 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. A? 2011 American Heart Association, Inc.
Original languageEnglish
Pages (from-to)1607 - 1616
Number of pages10
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume31
Issue number7
DOIs
Publication statusPublished - 2011

Cite this

Straub, Andreas ; Krajewski, Stefanie ; Hohmann, Jan David ; Westein, Erik ; Jia, Fu ; Bassler, Nicole ; Selan, Carly ; Kurz, Julia ; Wendel, Hans ; Dezfouli, Shala ; Yuan, Yu-Ping ; Nandurkar, Harshal ; Jackson, Shaun ; Hickey, Michael ; Peter, Karlheinz. / Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target. In: Arteriosclerosis, Thrombosis and Vascular Biology. 2011 ; Vol. 31, No. 7. pp. 1607 - 1616.
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title = "Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target",
abstract = "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 (28A?C/18A?C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl3-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 P2Y12 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. A? 2011 American Heart Association, Inc.",
author = "Andreas Straub and Stefanie Krajewski and Hohmann, {Jan David} and Erik Westein and Fu Jia and Nicole Bassler and Carly Selan and Julia Kurz and Hans Wendel and Shala Dezfouli and Yu-Ping Yuan and Harshal Nandurkar and Shaun Jackson and Michael Hickey and Karlheinz Peter",
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volume = "31",
pages = "1607 -- 1616",
journal = "Arteriosclerosis, Thrombosis and Vascular Biology",
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Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target. / Straub, Andreas; Krajewski, Stefanie; Hohmann, Jan David; Westein, Erik; Jia, Fu; Bassler, Nicole; Selan, Carly; Kurz, Julia; Wendel, Hans; Dezfouli, Shala; Yuan, Yu-Ping; Nandurkar, Harshal; Jackson, Shaun; Hickey, Michael; Peter, Karlheinz.

In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 31, No. 7, 2011, p. 1607 - 1616.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target

AU - Straub, Andreas

AU - Krajewski, Stefanie

AU - Hohmann, Jan David

AU - Westein, Erik

AU - Jia, Fu

AU - Bassler, Nicole

AU - Selan, Carly

AU - Kurz, Julia

AU - Wendel, Hans

AU - Dezfouli, Shala

AU - Yuan, Yu-Ping

AU - Nandurkar, Harshal

AU - Jackson, Shaun

AU - Hickey, Michael

AU - Peter, Karlheinz

PY - 2011

Y1 - 2011

N2 - 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 (28A?C/18A?C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl3-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 P2Y12 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. A? 2011 American Heart Association, Inc.

AB - 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 (28A?C/18A?C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl3-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 P2Y12 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. A? 2011 American Heart Association, Inc.

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U2 - 10.1161/ATVBAHA.111.226373

DO - 10.1161/ATVBAHA.111.226373

M3 - Article

VL - 31

SP - 1607

EP - 1616

JO - Arteriosclerosis, Thrombosis and Vascular Biology

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SN - 1079-5642

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