Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass

Abstract

Recently, lower thrombin generation has been associated with excess bleeding post-cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti-TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55–111 ng/ml, P < 0.0001), and VWF (144–170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 μg/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients.

Use of prothrombin complex concentrate for management of coagulopathy after cardiac surgery: a propensity score matched comparison to plasma

“…5 In an in vitro study, PCC was found to be more potent in restoring post-CPB thrombin generation than plasma. 7 This may in part explain why the use of PCC as part of a multifaceted management of coagulopathy seems to have a greater blood-sparing effects than plasma. Supportive clinical data, however, is limited.…”

“…This conversion is consistent with in vitro observations that post-CPB impaired thrombin generation can be corrected by 15 mg kg À1 of plasma or 25 IU kg À1 of PCC. 7…”

“…1,4 Concerning the latter, impaired thrombin generation is increasingly recognised to be an important contributor to the coagulopathy of cardiac surgery. 5,6 While plasma may effectively restore thrombin generation and is an integral part of transfusion algorithms, 4,7 it has important shortcomings. 8 It requires ABO blood group compatibility matching and thawing, which can delay therapy.…”

“…It can also lead to adverse events including allergic reactions, transfusion-related acute lung injury (TRALI), transfusion associated circulatory overload (TACO), transmission of infectious diseases, and thromboembolic events. 8,9 Moreover, as large volumes (10e15 ml kg À1 ) of plasma are needed to effectively raise thrombin generation, 7 it can lead to substantial haemodilution resulting in additional red cell transfusions.…”

“…9 Moreover, in vitro studies suggest that PCCs may be more effective than plasma in enhancing thrombin generation after cardiac surgery. 7 In contrast, as PCCs do not contain the full, balanced complement of procoagulants and anticoagulants that are present in plasma, they may be less effective or carry a higher risk for thrombotic events and acute kidney injury (AKI) than plasma for management of coagulopathy. 10,11 Despite the potential advantages of PCCs over plasma, there are few direct comparisons between the two therapies for managing the coagulopathy of cardiac surgery.…”