Recombinant Factor VIIa Combined with Fibrinogen Corrects the Coagulopathy Associated with Cardiopulmonary Bypass Surgery Ex Vivo

Major cardiac surgery and use of cardiopulmonary bypass (CPB) is often associated with the development of a severe coagulopathy, hyperfibrinolysis and increased risk of bleeding. The present ex vivo study challenged the hypotheses that whole blood thrombelastometry, activated with minute amounts of tissue factor, can reveal the development of a coagulopathy following cardiac surgery, and that supplementation with fibrinogen and rFVIIa, alone or in combination, can improve the ex vivo clotting pattern. In total, 22 patients with a median age of 68, undergoing coronary artery bypass grafting or valve surgery with use of CPB were included in the study. Dynamic thrombelastometric clotting profiles were recorded using citrated whole blood activated with dilute tissue factor (Innovin^®, final dilution 1:17000). Blood samples were collected before surgery (control) and immediately following in vivo neutralization of heparin with protamine sulphate. All blood samples for thrombelastometry were treated with heparinase to ensure neutralization of residual heparin. Standard coagulation laboratory parameters and platelet function confirmed the development of a significant coagulopathy following CPB. The post-operative blood samples were spiked with buffer, rFVIIa (2 μg/mL), fibrinogen (1mg/mL), or the combination of rFVIIa+fibrinogen. The post-operative coagulopathy was evident by thromboelastometry as a statistically significant derangements (Wilcoxon signed rank test). There was prolongation of the onset of clotting (CT, from a median value of 183 seconds pre-op to 385 sec post-op), reduced maximum velocity of clot formation (MaxVel, from 17.5 mm*100/sec pre-op to 15.1 post-op) and reduced maximum clot firmness (MCF, from 6234 mm pre-op to 5527 post-op). Ex vivo spiking with rFVIIa shortened the post-operative clot initiation phase (CT) to a median of 232 sec. Fibrinogen also shortened the post-operative clotting time to a median of 246 sec, and additionally increased the MCF to 5839 mm. Finally, the combination of rFVIIa and fibrinogen together corrected the abnormal thromboelastometric findings associated with CPB-coagulopathy into the pre-operative range, i.e. median CT decreased to 155 sec, MaxVel increased to 16.8 mm*100/sec and MCF increased to 5808 mm.

In conclusion, the experiments suggest a potential role of fibrinogen supplementation during control of bleeding following CPB, either alone or in combination with rFVIIa, since the combination corrected the CPB-associated coagulopathy remaining following neutralization of heparin.