Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass

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Abstract
Our objective was to estimate the in vivo rates of thrombin and fibrin generation to better understand how coagulation is regulated. Studied were 9 males undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and soluble fibrin generation in vivo were based on measured levels of prothrombin activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and soluble fibrin, combined with a computer model of the patient's vascular system that accounted for marker clearance, hemodilution, blood loss, and transfusion. Prior to surgery, the average thrombin generation rate was 0.24 ± 0.11 pmol/s. Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1% was soluble fibrin. The thrombin generation rate did not change after sternotomy or administration of heparin, then rapidly increased 20-fold to 5.60 ± 6.65 pmol/s after 5 minutes of CPB (P = .000 05). Early in CPB each new thrombin generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin generation rate was 2.14 ± 1.88 pmol/s during the remainder of CPB, increasing again to 5.47 ± 4.08 pmol/s after reperfusion of the ischemic heart (P = .000 08). After heparin neutralization with protamine, thrombin generation remained high (5.34 ± 4.01 pmol/s, P = .0002) and total fibrin generation increased, while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and fibrin generation rates were returning to baseline levels. We conclude that cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of nonhemostatic thrombin generation and dysregulated fibrin formation, not just a steady increase in thrombin generation as suggested by previous studies.