title: Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies.
abstract: BACKGROUND
  Fibrinogen 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Patients 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.
  
  
  CONCLUSIONS
  Our analyses suggest that prothrombin concentration at admission is predictive of mortality and transfusion and indicates that prothrombin and fibrinogen are rate limiting in coagulopathy.
  
  
  CONCLUSIONS
  Admission 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.
authors.affiliation: Personalised HealthCare and Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden. Clare.a.balendran@astrazeneca.com.
authors.forename: Clare A
authors.initials: CA
authors.lastname: Balendran
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.|Present address: Leaflet Biotech Consulting, Jungfrudansen 8, 171 56, Solna, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Lövgren
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Kenny M
authors.initials: KM
authors.lastname: Hansson
authors.affiliation: Early Clinical Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Nelander
authors.affiliation: Early Clinical Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Marita
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Johansson
authors.affiliation: Centre for Trauma Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Karim
authors.initials: K
authors.lastname: Brohi
authors.affiliation: Department of General and Surgical Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fries
authors.affiliation: Early Clinical Development, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Berggren
mesh_terms: D000328:Adult; D005260:Female; D006470:Hemorrhage / Q000628:therapy*; D006801:Humans; D007020:Hypoprothrombinemias / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D010949:Plasma; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011517:Prothrombin Time; D016896:Treatment Outcome; D055815:Young Adult
keywords: Biomarker; Coagulopathy; PT; Prothrombin; ROTEM; Severe bleeding