HEPARIN-ENHANCED PLASMA PHOSPHOLIPASE A(2) ACTIVITY AND PROSTACYCLIN SYNTHESIS IN PATIENTS UNDERGOING CARDIAC-SURGERY

Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A(2) (PLA(2)) activity, 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)), and thromboxane B-2 (TXB(2)) levels were measured at various times during cardiac surgery. Plasma PLA(2) activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF(1 alpha). TXB(2) concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA(2) activity, 6-keto-PGF(1 alpha), and TXB(2) concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA(2) activity and plasma 6-keto-PGF(1 alpha), but no change in plasma TXB(2) concentrations. Thus the ratio of TXB(2) to 6-keto-PGF(1 alpha) increased significantly after protamine administration. Enhanced plasma PLA(2) activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA(2) was identified as group II PLA(2) by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity, chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA(2) activity and release of PLA(2). The PLA(2) released from the PMN had characteristics similar to those of post-heparin plasma PLA(2). In conclusion, plasma PLA(2) activity and 6-keto-PGF(1 alpha) concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI(2)) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA(2) activity, with an associated increased TXB(2)/6-keto-PGF(1 alpha) ratio.