Pharmacological inhibition of plasma coagulation and platelet activation during experimental long-term perfusion

During extracorporeal circulation, initial contact between blood and the artificial surface of the circuit induces an overall activation of the hemostatic system. The objective of this study was to investigate the combined effect of epoprostenol (PGI (2) ), nitric oxide (NO) and nafamostat mesilate (FUT-175, a serine protease inhibitor), on plasma coagulation and platelet activation during experimental long-term perfusion.

Two identical extracorporeal life support (ECLS) circuits were primed with fresh, heparinized human blood, and circulated for 24 h. FUT was given with a bolus dose of 85 mg/l blood at the initiation of the experiment and thereafter as a continuous infusion of 14 mg/l/h. PGI (2), at a rate of 2.4 microg/l/h, was also administered to the experimental circuit, and 120 ppm NO gas was added to the oxygenator sweep gas. The other circuit was used as a control.

Higher platelet count and platelet membrane expression of GPIb were found in the experimental circuits as compared with control circuits. The levels of thrombin/antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2) increased significantly over time in the control circuits but remained low in the experimental circuits. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) decreased rapidly in both circuits but were higher in the control circuits at each time point studied.

The activation of platelets and of the coagulation system encountered during extracorporeal perfusion is consistently inhibited by a combination of PGI (2), NO and FUT-175. The combination of these drugs appears to be more effective than each drug separately.