Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia

Summary

Although prothrombin complex concentrate (PCC) is increasingly used for the treatment of trauma-induced coagulopathy, few studies have investigated the impact and safety of PCC for this indication. The present study was performed to assess PCC for treatment of coagulopathy after blunt liver injury under severe hypothermia. Coagulopathy in 14 anaesthetised pigs was induced by haemodilution. Subsequently, standardised blunt liver injury was induced under severe hypothermia (32.8–33.2°C). Animals were randomised to receive either PCC (35 IU kg^-1) or saline (control). Coagulation was assessed over the following 2 hours by thromboelastometry and thrombin generation. Internal organs were examined to determine presence of emboli. The administration of PCC showed a significant reduction in blood loss (p=0.002 vs. controls) and a significant increase in the rate of survival (p=0.022 vs. controls). Plasma thrombin generation in the PCC group increased considerably above baseline levels, with significant increases in peak thrombin levels and endogenous thrombin potential versus controls throughout the follow-up period. In addition, PT decreased significantly in the PCC group versus the control group. However, only slight improvements in thromboelastometry variables were observed. Histology showed an equal degree of liver injury in both groups, and no thromboembolism. In severely hypothermic pigs, the application of PCC corrected trauma-induced coagulopathy and reduced blood loss. Thus, the infusion of PCC might be a reasonable approach to reduce the need for blood cell transfusion in trauma. Furthermore, the impact and safety of PCC application can be monitored through thrombin generation and thromboelastometry under hypothermia.

Note: This study was performed at the RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074 Aachen, Germany.

Keywords

Haemostasis - shock - thromboelastometry - trauma - prothrombin complex concentrate (PCC) - thrombin generation

Notes

^* Both authors equally contributed to this paper.

• References

• 1 Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and treatment in the injured patient. World J Surg 2007; 31: 1055-1064.
• 2 Søreide K, Krüger AJ, Vårdal AL. et al. Epidemiology and contemporary patterns of trauma deaths: changing place, similar pace, older face. World J Surg 2007; 31: 2092-2103.
• 3 Hess JR, Brohi K, Dutton RP. et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008; 65: 748-754.
• 4 Godier A, Susen S, Samama CM. Treatment of massive bleeding with prothrombin complex concentrate: Argument against. J Thromb Haemost 2010; 8: 2592-2595.
• 5 Tanaka KA, Szlam F. Treatment of massive bleeding with prothrombin complex concentrate: Argument for. J Thromb Haemost 2010; 8: 2589-2591.
• 6 Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic managment of patients treated with vitamin K antagonists. Anesthesiology 2008; 109: 918-926.
• 7 Sørensen B, Spahn DR, Innerhofer P. et al. Clinical review: Prothrombin complex concentrates – evaluation of safety and thrombogenicity. Crit Care 2011; 15: 201.
• 8 Kalina U, Bickhard H, Schulte S. Biochemical comparison of seven commercially available prothrombin complex concentrates. Int J Clin Pract 2008; 62: 1614-1622.
• 9 Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care 2008; 12: R105.
• 10 Schick KS, Fertmann JM, Jauch KW. et al. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care 2009; 13: R191.
• 11 Schöchl H, Nienaber U, Hofer G. et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 2010; 14: R55.
• 12 Dickneite G, Pragst I. Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model. Br J Anaesth 2009; 102: 345-354.
• 13 Dickneite G, Doerr B, Kaspereit F. Characterization of the coagulation deficit in porcine dilutional coagulopathy and substitution with a prothrombin complex concentrate. Anesth Analg 2008; 106: 1070-1077.
• 14 Dickneite G, Dörr B, Kaspereit F. et al. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of hemodilutional coagulopathy in a porcine trauma model. J Trauma 2010; 68: 1151-1157.
• 15 Luna GK, Maier RV, Pavlin EG. et al. Incidence and Effect of Hypothermia in Seriously Injured Patients. J Trauma 1987; 27: 1014-1018.
• 16 Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion 2009; 49: 2652-2660.
• 17 Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. Guide for the care and use of laboratory animals, 7th Edn.. Washington DC: National Academy Press; 1996. .
• 18 Bush JA, Jensen WN, Cartwright GE. et al. Blood volume studies in normal and anemic swine. Am J Physiol 1955; 181: 9-14.
• 19 Grottke O, Braunschweig T, Philippen B. et al. A new model for blunt liver injuries in the swine. Eur Surg Res 2010; 44: 65-73.
• 20 Grottke O, Braunschweig T, Henzler D. et al. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 2010; 14: R62.
• 21 Grottke O, Braunschweig T, Spronk HM. et al. Increasing concentrations of prothrombin complex concentrate induce DIC in a pig model of coagulopathy with blunt liver injury. Blood 2011; 118: 1943-1951.
• 22 Grottke O, Braunschweig T, Zimmermann L. et al. Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs. Br J Anaesth 2010; 105: 789-797.
• 23 Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008; 106: 1366-1375.
• 24 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32: 249-253.
• 25 Meng ZH, Wolberg AS, Monroe DM. et al. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma 2003; 55: 886-891.
• 26 Tchaikovski SN, van Vlijmen BJM, Rosing J. et al. Development of a calibrated automated thrombography based thrombin generation test in mouse plasma. J Thromb Haemost 2007; 5: 2079-2086.
• 27 Schols SE, Lancé MD, Feijge MA. et al. Impaired thrombin generation and fibrin clot formation in patients with dilutional coagulopathy during major surgery. Thromb Haemost 2010; 103: 318-328.
• 28 Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81: 360-365.
• 29 Karlsson M, Ternstrom L, Hyllner M. et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102: 137-144.
• 30 Fenger-Eriksen C, Jensen TM, Kristensen BS. et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7: 795-802.
• 31 Rahe-Meyer N, Solomon C, Winterhalter M. et al. Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery. J Thorac Cardiovasc Surg 2009; 138: 694-702.
• 32 Rahe-Meyer N, Pichlmaier M, Haverich A. et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth 2009; 102: 785-792.
• 33 Ozier Y, Hunt BJ. Fibrinogen concentrate for management of bleeding: against indiscriminate use. J Thromb Haemost 2011; 9: 6-8.
• 34 Rahe-Meyer N, Sørensen B.. Fibrinogen concentrate for management of bleeding. J Thromb Haemost 2011; 9: 1-5.
• 35 Rossaint R, Bouillon B, Cerny V. et al. Management of bleeding following major trauma: an updated European guideline. Crit Care 2010; 14: R52.
• 36 Dusel CH, Grundmann C, Eich S. et al. Identification of prothrombin as a major thrombogenic agent in prothrombin complex concentrates. Blood Coagul Fibrinolysis 2004; 15: 405-411.
• 37 Mitterlechner T, Innerhofer P, Streif W. et al. Prothrombin complex concentrate and recombinant prothrombin alone or in combination with recombinant factor X and FVIIa in dilutional coagulopathy: a porcine model. J Thromb Haemost 2011; 9: 729-737.
• 38 Johansson PI, Svendsen MS, Salado J. et al. Investigation of the thrombin-generating capacity, evaluated by thrombogram, and clot formation evaluated by thrombelastography of platelets stored in the blood bank for up to 7 days. Vox Sang 2008; 94: 113-118.