Mechanisms of thrombin generation during surgery and cardiopulmonary bypass [see comments]

Abstract

Although in vitro studies have been invaluable in revealing the complex biochemistry of the blood coagulation system, the mechanisms involved during the in vivo response to hypercoagulable stimuli are still unclear. We have used plasma-based enzyme-linked immunosorbent assays (ELISAs) to study the mechanisms by which the coagulation system is activated in vivo during human cardiopulmonary bypass (CPB) surgery (n = 8). A novel immunoassay for factor XIIa was used to detect activation of the contact system, factor IX activation peptide (FIXAP) was used as a marker for activation of factor IX, and prothrombin fragment F1 + 2 (F1 + 2) was used as a marker for thrombin generation. The ELISA for FIXAP is described for the first time herein. F1 + 2 levels increased early in response to surgical intervention: from a baseline of 38.7 +/- 9.7 ng/mL (mean +/-SE), levels increased rapidly during surgery and bypass to a maximum of 448.5 +/- 92.0 ng/mL. A modest yet significant increase in factor XIIa levels from 3.47 +/- 0.54 ng/mL to 4.33 +/- 0.85 ng/mL was evident during surgery before bypass, but no further significant increase was detected on establishing extracorporeal circulation. FIXAP levels demonstrated a small and late increase during surgery from 4.98 +/- 0.55 ng/mL to a maximum of 10.20 +/- 1.23 ng/mL, the increase beginning at the time of near maximal F1 + 2 levels. There was no association between activation of the contact system (factor XIIa levels) and the generation of thrombin (F1 + 2 levels). However, a strong association (r = .705) was apparent between the generation of thrombin (F1 + 2 levels) and activation of factor IX (FIXAP levels), despite the delay between the activation of prothrombin and factor IX. The data do not support the established view that contact activation resulting from exposure of blood to foreign surfaces is the major procoagulant stimulus in CPB. Instead, the results suggest that the main trigger to coagulation during CPB surgery was provided via the tissue factor-factor VIIa mechanism in response to the cutting of blood vessels, which directly activated factor X and then prothrombin. The late activation of factor IX, which presumably also contributed to maximal prothrombin activation, could have arisen due to direct tissue factor-factor VIIa action, or by secondary feedback action of thrombin on the intrinsic system.

Perioperative management of aspirin resistance after off‐pump coronary artery bypass grafting: possible role for aprotinin

“…Thrombin formation in cardiac surgery patients has been attributed to surgical trauma, 2 contact activation of blood from the cardiopulmonary bypass circuit, 1 ischemia‐reperfusion injury, 12 and unstable coronary artery disease 6 . Despite prior studies demonstrating that pressure damage to the SVG causes the luminal expression of TF, 11 the primary stimulus for thrombin, the contribution of the newly grafted SVG to perioperative thrombin formation has been largely ignored.…”

“…This study, however, was underpowered to show the effect of aprotinin on SVG failure or to address the mechanism of this intriguing effect on aspirin responsiveness. The prothrombin fragment F1.2 is an established marker of thrombin generation during cardiac surgery 2 . In a previous report from an OPCAB cohort not given aprotinin, patients who developed SVG failure by Day 5 showed a sixfold increase in coronary sinus F1.2 levels just after protamine administration 6 .…”

“…The factors, mechanism, and best means for preventing and/or treating this acquired ASA‐R have not been established. Thrombin production occurs during cardiac surgery despite heparin administration, with peak levels seen just after protamine administration 1,2 . Although thrombin production is important for normal hemostasis, its excessive formation plays a pivotal role in the development of consumptive coagulopathy 3 and thrombosis 4 .…”

A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery

“…Exposure of blood to the extracorporeal circuit and hypothermia 59,60 led to impairment of the hemostatic system and excessive bleeding. Activation of both intrinsic 61 and extrinsic 62,63 pathways results in excessive thrombin 62,64‐67 and fibrinolytic 68‐74 activity, which can lead to consumption of PLTs and labile coagulation factors 65,66,75 . The risk of development of excessive, nonsurgical bleeding is influenced by the type of procedure, 76,77 the duration of CPB, 49,50,59,78,79 and multiple other patient‐related factors (age, sex, body surface area [BSA], coexisting disease, preoperative hematocrit, etc.)…”

Three‐factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis

“…Coagulopathy following cardiovascular surgery and CPB is due to multiple factors including hyperfibrinolysis , platelet dysfunction and dilutional changes. Our bleeding algorithm for postoperative management focuses on targeted haemostatic interventions to address acquired factor deficiencies and improve whole blood clot formation as part of a pragmatic and multimodal approach to perioperative bleeding .…”