Hyperfibrinolysis and Point-of-Care Thromboelastography: Rapid Detection of Hyperfibrinolysis without Immediate Antifibrinolysis Confers Worse Survival Results Than Prophylaxis, In Liver Transplantation

Bleeding during orthotopic liver transplantation (OLT) can be due to pre-existing conditions associated with the primary disease, peri-operatory complications or systemic disease (such as sepsis or disseminated intravascular coagulation); the procedure itself is associated with pro-hemorrhagic states (reflecting the liver's importance in hemostasis), the most relevant of which is hyperfibrinolysis (HF) –starting in the anhepatic stage after the removal of the host liver, and worsening during reperfusion of the donor organ. Specific prophylaxis minimizes bleeding due to uncontrolled HF; aprotinin was used successfully for prophylaxis until its approval was discontinued. Patients with severe hemorrhages can be stabilized through blood product (BP) transfusion, which is associated with non-negligible morbidity and mortality, and may contribute to decreased survival. Therefore, when HF is identified as a cause of bleeding, it should be addressed and specifically treated with antifibrinolytics; point-of-care (POC) rotational thromboelastography (ROTEG) can quickly evaluate the cumulative function of platelets, coagulation and fibrinolysis, and help identify bleeding due to HF. We have previously found that in our center the use of BP in patients undergoing HF-prophylaxis with aprotinin was identical to those who spontaneously never developed HF, and significantly lower than in those with POC ROTEG-identified HF treated with antifibrinolytics after bleeding had started. We proposed that antifibrinolysis should be instituted as soon as ROTEG-evidence of HF was found, regardless of bleeding status, to decrease the amount of BP transfused. This study aims to determine whether there was a survival difference between the use of prophylaxis and POC ROTEG, as could be suggested by the differences in BP consumption.

We reviewed 293 OLTs performed in our center from January 2004 to December 2009; we excluded 64 transplants which involved pediatric patients (defined as being under 18 years of age), 10 cases with incomplete charts, 30 re-transplants and 14 emergency OLTs for acute toxic hepatic failure. We thus included 175 patients in our survival analysis (Kaplan-Meier).

We found that patients undergoing prophylaxis for HF showed no difference in survival (p=0.810) compared to those who did not undergo prophylaxis and in whom ROTEG demonstrated an absence of spontaneous HF. We also found that those patients who were not subjected to prophylaxis - excluding those transplanted for familial amyloid polyneuropathy (FAP) - and in whom (due to logistic reasons) ROTEG was not available to guide treatment, had no difference in survival (p=0.928) compared to those who had ROTEG-confirmed HF (in whom antifibrinolytic treatment was usually not immediately started). In our series of patients we identified three distinct survival curves. Patients transplanted for FAP (a condition which does not affect liver structure or function, but in which OLT can replace a defective metabolic function), who did not undergo prophylaxis or ROTEG, had an overall survival (OS) of 95.1% at 78.0 months of follow-up; patients without HF (either confirmed by ROTEG or as a result of prophylaxis) had an OS of 87.0%; patients with ROTEG-confirmed HF and those without prophylaxis or ROTEG had an OS of 76.5% (p=0.028).

We conclude that prophylaxis with aprotinin was effective and abolished HF, conferring identical survival results to the subset of patients who spontaneously do not develop HF (as confirmed by ROTEG), while late treatment of confirmed HF with antifibrinolytics produces identical survival results to blind ROTEG-unguided empiricism. Considering patient OS, ROTEG-guided treatment of HF, when not consistently instituted as soon as HF is identified (regardless of bleeding status), confers worse survival results than those previously obtained when HF-prophylaxis was possible using aprotinin. These findings add support to the hypothesis that antifibrinolysis should be started immediately upon recognition of HF on POC ROTEG, to improve overall survival (and, as we previously found, to decrease the consumption of BP). We suggest that operating room protocols should be developed by the surgical and clinical and laboratorial hematology teams, to optimize the choice and dose of antifibrinolytic drugs, and the timing of ROTEG analysis during OLT.

No relevant conflicts of interest to declare.