Early Heparin Administration Attenuates Tissue Factor-mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

Background: We tested the hypothesis that heparin administration prior to the emergence of tissue factor (TF) would increase plasma TF pathway inhibitor (TFPI) and attenuate TF-mediated thrombin generation during simulated cardiopulmonary bypass (CPB).

Methods: Human blood was recirculated for 120 minutes using an oxygenator and roller pump. Four groups were examined: control group (heparin 3.75 U/mL, in donor blood, n = 7), rTF group (heparin + recombinant TF 1000 pg/mL, in donor blood, n = 7), TFPI boost group (heparin, in preheparinized donor blood, n = 8), and rTF + TFPI boost group (heparin + rTF, in preheparinized blood, n = 7). In the two TFPI boost groups, 50 U/kg of heparin was given to the donors intravenously five minutes before donation to boost plasma TFPI levels. Total plasma TFPI, thrombin-antithrombin complex, and prothrombin fragment F1+2 levels were measured before and during CPB.

Results: Preheparinization increased total plasma TFPI levels by a factor of 8.0. Administration of rTF significantly enhanced the generation of F1+2 (p = 0.0002). The heparin-induced TFPI elevation reduced both thrombin-antithrombin complex and F1+2 to control levels in rTF + TFPI boost group (p = 0.0158 for thrombin-antithrombin complex, p < 0.0001 for F1+2 ). F1+2 levels were at all times lower than control levels in TFPI boost group (p < 0.0001).

Conclusions: Heparin-induced TFPI elevation attenuates TF-mediated thrombin generation. Early heparin administration prior to the emergence of plasma TF may represent a novel strategy for controlling thrombin generation by the extrinsic coagulation pathway during CPB.