Peroxynitrite Decreases Hemostasis in Human Plasma In Vitro

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Abstract

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.

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