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.

Carbon monoxide-releasing molecule-2 enhances coagulation in rabbit plasma and decreases bleeding time in clopidogrel/aspirin-treated rabbits.

Administration of carbon monoxide derived from carbon monoxide-releasing molecules has been demonstrated to enhance coagulation in vitro at small concentrations (100-200 µmol/l) in human and rabbit plasma. We sought to determine if carbon monoxide-releasing molecule-2 [tricarbonyldichlororuthenium (II) dimer, CORM-2] would improve coagulation in rabbit plasma in vitro via thrombelastography and in an in vivo preclinical rabbit model of ear bleeding time following administration of clopidogrel (20 mg/kg) with aspirin (10 mg/kg) via gavage. Addition of 100 µmol/l CORM-2 to rabbit plasma significantly improved coagulation. This procoagulant effect was blocked by pre-exposure of plasma to an agent that converts hemefibrinogen to methemefibrinogen in human plasma, preventing carbon monoxide binding and enhancement of coagulation. Rabbit ear bleeding time was 5.8 ±â€Š1.1 min 2-3 h after clopidogrel/aspirin administration. Bleeding time significantly decreased to 2.6 ±â€Š0.6 min, 5 min after administration of CORM-2 (10 mg/kg; 279 µmol/l 'best-case' instantaneous concentration) intravenously. CORM-2 enhances plasmatic coagulation in a manner similar to that of human plasma in vitro, and plasmatic coagulation is enhanced in vivo by CORM-2 as well. Additional preclinical investigation of the effects of CORM-2 on coagulopathy (e.g. heparin or hemodilution mediated) utilizing this rabbit model is planned.