Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies

Abstract

BackgroundFibrinogen and prothrombin have been suggested to become rate limiting in trauma associated coagulopathy. Administration of fibrinogen is now recommended, however, the importance of prothrombin to patient outcome is unknown.MethodsWe have utilized two trauma patient databases (database 1 n = 358 and database 2 n = 331) to investigate the relationship of plasma prothrombin concentration on clinical outcome and coagulation status. Database 1 has been used to assess the relationship of plasma prothrombin to administered packed red blood cells (PRBC), clinical outcome and coagulation biomarkers (Prothrombin Time (PT), ROTEM EXTEM Coagulation Time (CT) and Maximum Clot Firmness (MCF)). ROC analyses have been performed to investigate the ability of admission coagulation biomarkers to predict low prothrombin concentration (database 1), massive transfusion and 24 h mortality (database 1 and 2). The importance of prothrombin was further investigated in vitro by PT and ROTEM assays in the presence of a prothrombin neutralizing monoclonal antibody and following step-wise dilution.ResultsPatients who survived the first 24 h had higher admission prothrombin levels compared to those who died (94 vs.67 IU/dL). Patients with lower transfusion requirements within the first 24 h (≤10 units of PRBCs) also had higher admission prothrombin levels compared to patients with massive transfusion demands (>10 units of PRBCs) (95 vs.62 IU/dL). Admission PT, in comparison to admission ROTEM EXTEM CT and MCF, was found to be a better predictor of prothrombin concentration <60 IU/dL (AUC 0.94 in database 1), of massive transfusion (AUC 0.92 and 0.81 in database 1 and 2 respectively) and 24 h mortality (AUC 0.90 and 0.78 in database 1 and 2, respectively). In vitro experiments supported a critical role for prothrombin in coagulation and demonstrated that PT and ROTEM EXTEM CT are sensitive methods to measure low prothrombin concentration.DiscussionOur analyses suggest that prothrombin concentration at admission is predictive of mortality and transfusion and indicates that prothrombin and fibrinogen are rate limiting in coagulopathy.ConclusionsAdmission PT is predictive of low prothrombin concentration and clinical outcome. PT could therefore be used as a surrogate for prothrombin concentration and further evaluation of point-of-care devices for faster PT analysis is warranted.

Preclinical evaluation of point‐of‐care prothrombin time as a biomarker test to guide prothrombin replacement therapy in coagulopathic bleeding

“…We have previously observed that prothrombin below 60 IU/dL (60% of normal) was associated with coagulopathy and an increased mortality and transfusion demand in trauma patients. 15 Therefore taken together the data supports that CoaguChek XS Pro could be used to trigger prothrombin therapy in coagulopathic patients since all patients with prothrombin below 60% would benefit from replenishment and would be treated with MEDI8111. Furthermore, since the POC test would be used to set a PT threshold for treatment rather than an absolute prothrombin concentration this addresses previously reported concerns around the accuracy of POC assays particularly in the most severely bleeding coagulopathic trauma patients.…”

“…We have previously confirmed a link between critically low prothrombin concentration at admission and clinical outcome in trauma patients and demonstrated that lab measured PT is a good predictor of prothrombin concentration . In addition, we have provided prior evidence that PT is a more sensitive and specific biomarker than the commonly used ROTEM EXTEM CT and MCF for predicting massive blood transfusion and mortality . In this paper we have evaluated CoaguChek XS Pro in preclinical models of dilutional coagulopathy and the potential utility of POC PT tests to guide replacement of prothrombin in bleeding trauma patients.…”

“…MEDI8111 is intended to be given as a fixed rather than titrated dose to all patients below a coagulopathic threshold. We have previously observed that prothrombin below 60 IU/dL (60% of normal) was associated with coagulopathy and an increased mortality and transfusion demand in trauma patients . Therefore taken together the data supports that CoaguChek XS Pro could be used to trigger prothrombin therapy in coagulopathic patients since all patients with prothrombin below 60% would benefit from replenishment and would be treated with MEDI8111.…”

“…MEDI8111, produced by MedImmune, is being evaluated for the indication of coagulopathy due to severe bleeding in trauma. We have previously confirmed a link between critically low prothrombin concentration at admission and clinical outcome in trauma patients and demonstrated that lab measured PT is a good predictor of prothrombin concentration . In addition, we have provided prior evidence that PT is a more sensitive and specific biomarker than the commonly used ROTEM EXTEM CT and MCF for predicting massive blood transfusion and mortality .…”

“…We have shown that median prothrombin plasma concentration is a good predictor of 24‐hour mortality and transfusion. Furthermore, PT is predictive of prothrombin concentration of less than 60 IU/dL (60% of normal) and of transfusion demand and clinical outcome . The correlation between prolonged PT and increased patient mortality has also been shown by others supporting its utility as a predictive biomarker of outcome.…”