Carbon monoxide-releasing molecule-2 decreases fibrinolysis in vitro and in vivo in the rabbit.

Administration of carbon monoxide derived from carbon monoxide-releasing molecules (CORMs) have been demonstrated to enhance coagulation and diminish fibrinolysis in vitro at small concentrations (100-200 μmol/l) in human and rabbit plasma, whereas in vivo administration of large concentrations (>1400 μmol/l) of carbon monoxide has mildly increased bleeding time in vivo in rats. We sought to determine whether CORM-2 [tricarbonyldichlororuthenium (II) dimer] would improve coagulation and attenuate tissue-type plasminogen activator (tPA)-mediated fibrinolysis in rabbit whole blood as determined in vitro by thrombelastography and in an in vivo preclinical rabbit model of ear bleeding time administered intravenous tPA (1 mg/kg). Addition of 200, 400 and 600 μmol/l CORM-2 to whole blood significantly improved coagulation and attenuated fibrinolysis compared with blood without CORM-2. Rabbits administered CORM-2 (10 mg/kg, 279 μmol/l) had a small but significant decrease in bleeding time before tPA administration. Administration of tPA resulted in bleeding times more than six-fold greater than baseline in animals not exposed to CORM-2, whereas rabbits administered CORM-2 had significantly smaller (more than five-fold less) bleeding time values after tPA administration. CORM-2 administration significantly decreases fibrinolytic bleeding in the rabbit in vivo. Additional preclinical investigation of the effects of CORM-2 on coagulopathy (e.g. heparin-mediated or clopidogrel-mediated) utilizing this rabbit model are planned.