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CARDIOVASCULAR ANESTHESIA

Peroxynitrite Decreases Hemostasis in Human Plasma In Vitro

Vance G. Nielsen, MD^*, John P. Crow, PhD, Ashish Mogal, MD^*, Fen Zhou, MD^*, and Dale A. Parks, PhD^*,,

Departments of *Anesthesiology, Physiology and Biophysics, and Pediatrics, The Center for Free Radical Biology, The University of Alabama at Birmingham, Birmingham, Alabama, and the Departments of Pharmacology and Toxicology, The University of Arkansas for Medical Sciences, Little Rock, Arkansas

Address correspondence and reprint requests to Vance G. Nielsen, MD, Associate Professor, Department of Anesthesiology, The University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35249–6810. Address email to vance.nielsen{at}ccc.uab.edu

Coagulopathy has been associated with clinical scenarios that involve reactive nitrogen species such as peroxynitrite (OONO^–). Further, OONO^– decreases tissue factor and fibrinogen function in vitro. Thus, we hypothesized that exposure of plasma to the OONO^– generated with 3-morpholinosydnonimine (SIN-1), a molecule that produces both nitric oxide and superoxide, would result in a decrease in hemostatic function via diminished coagulation protein activity. Hemostatic function of plasma exposed to SIN-1 (0, 1, 5, and 10 mM for 60 min at 37°C) was assessed with thrombelastography, activated partial thromboplastin time, and prothrombin time in the presence or absence of superoxide dismutase (SOD) or an OONO^– scavenger. SIN-1 exposure resulted in a significant (P < 0.05), dose-dependent decrease in plasma hemostatic function and concurrent significant (P < 0.05) decreases in activities of factor VII, factor VIII complex, and factor X. Fibrinogen concentration was not affected by SIN-1. Antithrombin and protein C activity also decreased significantly (P < 0.05). Coincubation with SOD or an OONO^– scavenger significantly (P < 0.05) attenuated SIN-1 mediated changes in hemostasis and procoagulant/anticoagulant activity. We conclude that OONO^– may decrease hemostatic function in human plasma by nitration of key procoagulants and that OONO^– may play a significant role in hemorrhagic states.

IMPLICATIONS: Coagulopathy has been associated with clinical scenarios involving reactive nitrogen species such as peroxynitrite. It was determined that exposure of human plasma to peroxynitrite generated by 3-morpholinosydnonimine resulted in hypocoagulability measured by prothrombin time, activated partial thromboplastin time, and thrombelastography. Peroxynitrite may play a significant role in hemorrhagic states.

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