A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding

Abstract

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.

Deciphering the coagulation profile through the dynamics of thrombin activity

“…Even though the thrombin dynamics method has shown its added value to thrombin generation data in several clinical studies in the past years, the meaning of each parameter in the wider context of coagulation has yet to be investigated [14][15][16][17][18][19][20][21][22] . In this study, we investigated the effect of four major coagulation factors (prothrombin, FV, FX, and antithrombin) on five thrombin dynamics parameters (PC tot , PC max , T-AT, T-α 2 M, and TDC).…”

“…To define what is abnormal we defined normal values for thrombin dynamics parameters PC tot , PC max ,T-AT, T-α 2 M, and TDC and compared these results to previously acquired thrombin dynamics data. Supplementary Table 2 shows an overview of previous clinical thrombin dynamics studies and how the respective patient populations relate to the newly established normal ranges [14][15][16][17][18][19][20][21][22] .…”

“…The TG curve is the net result of prothrombin conversion and thrombin inactivation and therefore, the prothrombin conversion curve can be calculated from a TG curve. Thrombin inactivation was predicted by the previously described and validated computational model 14,19,26,44 . This model consists of a set of ordinary differential equations, which describe the rate of thrombin inactivation in time based on the plasma AT, α 2 M and fibrinogen level and the free thrombin concentration at each point in time (Eqs.…”

“…The dynamics of thrombin generation have been studied in multiple clinical settings over the past years to study the balance between pro-and anticoagulant mechanisms, and to perform in silico experimentation to generate hypotheses [14][15][16][17][18][19][20][21][22] . Recently, questions have started to emerge about the influence of individual coagulation factor levels on the parameters of prothrombin conversion and thrombin inactivation.…”

Tailoring the effect of antithrombin-targeting therapy in haemophilia A using in silico thrombin generation

“…In the present study, we quantified prothrombin conversion and thrombin inactivation in haemophilia A using thrombin dynamics analysis 11 and investigated inter-patient variation. Additionally, we studied the effect of novel AT targeting treatment strategies on TG using in silico experimentation 21 .…”