title: Hemostatic Therapy Using Tranexamic Acid and Coagulation Factor Concentrates in a Model of Traumatic Liver Injury.
abstract: The potential clinical benefits of targeted therapy with coagulation factor concentrates (e.g., fibrinogen) and antifibrinolytic agents (e.g., tranexamic acid [TXA]) for the treatment of trauma-induced coagulopathy are increasingly recognized. We hypothesized that human fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC), administered as combined therapy with TXA, would provide additive effects for reducing blood loss in an animal trauma model.
  
  
  
  Thirty-six pigs were subjected to 2 consecutive blunt liver injuries, resulting in severe hemorrhagic shock and coagulopathy. Intervention comprised saline (control group); TXA (15 mg kg, TXA group); TXA and FC (90 mg kg, TXA-FC); or TXA, FC, and PCC (20 U kg, TXA-FC-PCC). Blood loss, thromboelastometry (ROTEM), measures of thrombin generation, platelet activation, and global coagulation variables were monitored for 4 hours. Tissue sections were examined to determine the occurrence of thromboembolic events.
  
  
  
  Total blood loss was similar in the TXA-FC and TXA-FC-PCC groups (mean ± SD: 1012 ± 86 mL and 1037 ± 118 mL, respectively; P = 1.000). These values were both lower (P < 0.001) than the TXA group (1579 ± 306 mL). Blood loss in all 3 intervention groups was lower (P < 0.001) than in the control group (2376 ± 478 mL). After trauma and resuscitation, but before study intervention, plasma fibrinogen levels were severely depleted (median for the whole study population: 66 mg dL; interquartile range: 51-108 mg dL) and clot strength was decreased (EXTEM whole-blood maximum clot firmness [MCF]: 53 ± 5 mm). Compared with controls, TXA inhibited fibrinolysis and stabilized MCF and clotting time. The addition of FC restored and stabilized hemostasis to a greater extent than TXA alone; the addition of PCC had no statistically significant impact on blood loss, clot strength (MCF), or clotting time, but it increased thrombin generation. There were no significant differences among the study groups regarding platelet activation. No thrombi or microthrombi were observed in any group at necropsy.
  
  
  
  The early use of TXA and FC reduced blood loss and improved coagulation measurements in a porcine model of blunt liver injury and hemorrhagic shock. FC, administered in addition to TXA, was highly effective in reducing blood loss. The lack of statistically significant reduction in blood loss when PCC was added to TXA and FC may be attributable to the absence of thrombin generation impairment in this model.
authors.affiliation: From the *Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany; †Institute for Laboratory Animal Science, RWTH Aachen University Hospital, Aachen, Germany; ‡Laboratory for Clinical Thrombosis and Haemostasis, Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands; and §Department of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Zentai
authors.forename: Paola E J
authors.initials: PE
authors.lastname: van der Meijden
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.forename: Nicolai
authors.initials: N
authors.lastname: Hueck
authors.forename: Markus
authors.initials: M
authors.lastname: Honickel
authors.forename: Henri M H
authors.initials: HM
authors.lastname: Spronk
authors.forename: Rolf
authors.initials: R
authors.lastname: Rossaint
authors.forename: Oliver
authors.initials: O
authors.lastname: Grottke
mesh_terms: D000007:Abdominal Injuries / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005340:Fibrinogen / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D008099:Liver / Q000293:injuries*; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D012771:Shock, Hemorrhagic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D034421:Sus scrofa; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014148:Tranexamic Acid / Q000494:pharmacology*; D014949:Wounds, Nonpenetrating / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000933:Antifibrinolytic Agents; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D014148:Tranexamic Acid; D005340:Fibrinogen; D013917:Thrombin