Thrombin generation and fibrin formation during cardiopulmonary bypass

Cardiopulmonary bypass (CPB) results in a nonspecific activation of the coagulation system that may be associated with bleeding and thrombosis. To determine the timing and extent of coagulation activation before, during and after CPB we determined the rate of thrombin generation and total and soluble fibrin formation. Two markers of thrombin generation were measured using enzyme immunoassay - prothrombin fragment 1.2 (Fl .2), a stable byproduct of thrombin activation (t 1/2=90 minutes), and thrombin-antithrombin complex (TAT), a product of thrombin inactivation (tl/2=5 min). Fibrin formation rates were based on measured levels of soluble fibrin (tl/2=60 min) as a marker of non-specific (non-hemostatic) fibrin formation and fibrinopeptide A (tl/2=3 min) as a marker of total fibrin formation. Arterial blood samples were obtained before, during and after CPB from 9 subjects age 59±7 years. The generation and formation rates were based on the measured levels of activation markers, clearance rates and effect of hemodilution on marker levels. At baseline the thrombin generation rate (fmol/L/s) was 116±16 (SEM). After sternotomy, prior to CPB it increased to 198±47 and after heparin administration to 243±39. Within 5 min of CPB thrombin production burst to 1210±442 and then fell by 15 min to 5211169 and stayed moderately increased throughout CPB (519±131 - CPB 30 min and 460+100 - prior to reperfusion). Reperfusion of the ischémie heart near the end of CPB stimulated a second thrombin production burst to 2483±734. Post-CPB after heparin neutralization with protamine sulphate thrombin generation dropped to 1622±327 and continued falling to 578±178 at 2 hours post-operatively. Total fibrin formation decreased immediately after going on CPB, remained decreased until CPB ended, and correlated with hemodilution of fibrinogen, prothrombin and other coagulation factors (r = .59, p < 0.001 ). In contrast soluble fibrin formation increased on average 14-fold immediately after going on CPB, spiked again after reperfusion of the ischémie heart, and was correlated with thrombin generation as determined by F 1.2 and TAT levels (r = 0.50, p <0.001). We conclude that CPB results in a general increase in thrombin generation with two major bursts - when CPB starts and when the ischémie heart is reperfused. This increased thrombin generation is associated with an increased soluble fibrin formation reflecting episodes of non-specific fibrin formation. During the post-operative period thrombin generation and fibrin formation then returns to baseline.