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Animal Models of Trauma Induced Coagulopathy

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Abstract

Animal models serve an essential role in the study of trauma-induced coagulopathy by allowing the control of experimental variables in a reproducible setting and serve as a platform for therapeutic testing. Large animal models offer advantages in terms of clinical realism, while small animal models are frequently used in mechanistic studies. In addition to traditional coagulation assays such as prothrombin time and activated thromboplastin time, more recent studies have used thromboelastography/thromboelastometry, platelet function testing, and measured the concentrations of circulating clotting factors. Models of isolated injury, such as hemorrhage, sepsis, and acidosis, have demonstrated an overall hypocoagulopathic state. In contrast, traumatic brain injury (TBI) with or without additional injuries induces an immediate activation of the coagulation system. Platelet and endothelial dysfunction has been documented in greater detail in TBI models relative to non-TBI models. Complex, multiple-insult models have shown hypocoagulopathic derangements that positively correlate with increases in injury severity. Aggressive crystalloid resuscitation, while aimed at reversing hypotension following trauma, creates hemodilution-induced coagulopathy. Artificial colloids can induce a hypocoagulopathic state, while plasma-based agents have shown promise in reversing both coagulation cascade derangements and platelet dysfunction. Animal models have enhanced our mechanistic understanding of TIC and served as a laboratory for testing promising therapies. However, future studies should more closely examine the temporal changes in coagulation immediately post-injury, collect pre-intervention coagulation data, and develop robust models of hyperfibrinolysis.

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References

  1. Russell WMS, Burch RL. The principles of humane experimental technique. London, UK: Methuen; 1959.

    Google Scholar 

  2. Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med. 1980;303(8):436–44.

    Article  CAS  PubMed  Google Scholar 

  3. Davies CL, Newman RJ, Molyneux SG, Grahame-Smith DG. The relationship between plasma catecholamines and severity of injury in man. J Trauma. 1984;24(2):99–105.

    Article  CAS  PubMed  Google Scholar 

  4. Sefrin P. Catecholamines in the serum of multiple trauma patients – mediators of ARDS? Prog Clin Biol Res. 1987;236A:477–86.

    CAS  PubMed  Google Scholar 

  5. von Känel R, Dimsdale JE. Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo. Eur J Haematol. 2000;65(6):357–69.

    Article  Google Scholar 

  6. Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med. 2005;15(8):302–8.

    Article  CAS  PubMed  Google Scholar 

  7. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating adrenaline levels at admission predict increased mortality after trauma. J Trauma Acute Care Surg. 2012;72(2):428–36.

    CAS  PubMed  Google Scholar 

  8. Cutfield GR, Francis CM, Foëx P, Jones LA, Ryder WA. Isoflurane and large coronary artery haemodynamics. A study in dogs. Br J Anaesth. 1988;60(7):784–90.

    Article  CAS  PubMed  Google Scholar 

  9. Priebe HJ. Differential effects of isoflurane on regional right and left ventricular performances, and on coronary, systemic, and pulmonary hemodynamics in the dog. Anesthesiology. 1987;66(3):262–72.

    Article  CAS  PubMed  Google Scholar 

  10. Aneman A, Pontén J, Fändriks L, Eisenhofer G, Friberg P, Biber B. Splanchnic and renal sympathetic activity in relation to hemodynamics during isoflurane administration in pigs. Anesth Analg. 1995;80(1):135–42.

    CAS  PubMed  Google Scholar 

  11. Sellgren J, Pontén J, Wallin BG. Characteristics of muscle nerve sympathetic activity during general anesthesia in humans. Acta Anaesthesiol Scand. 1992;36(4):336–45.

    Article  CAS  PubMed  Google Scholar 

  12. Deegan R, He HB, Wood AJ, Wood M. Effect of enflurane and isoflurane on norepinephrine kinetics: a new approach to assessment of sympathetic function during anesthesia. Anesth Analg. 1993;77(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  13. Chappell D, Heindl B, Jacob M, Annecke T, Chen C, Rehm M, Conzen P, Becker BF. Sevoflurane reduces leukocyte and platelet adhesion after ischemia-reperfusion by protecting the endothelial glycocalyx. Anesthesiology. 2011;115(3):483–91.

    Article  CAS  PubMed  Google Scholar 

  14. Harr JN, Moore EE, Stringham J, Wohlauer MV, Fragoso M, Jones WL, Gamboni F, Sillman CC, Banerjee A. Isoflurane prevents acute lung injury through ADP-mediated platelet inhibition. Surgery. 2012;152(2):270–6.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Horosz B, Malec-Milewska M. Inadvertent intraoperative hypothermia. Anaesthesiol Intensive Ther. 2013;45(1):38–43.

    Article  PubMed  Google Scholar 

  16. Straub A, Krajewski S, Hohnmann JD, Westein E, Kia F, Bassler N, Selan C, Kurz J, Wendel HP, Dezfouli S, Yuan Y, Nandurkar H, Jackson S, Hickey MJ, Peter K. Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target. Arterioscler Thromb Vasc Biol. 2011;31(7):1607–16.

    Article  CAS  PubMed  Google Scholar 

  17. Lindenblatt N, Menger MD, Klar E, Vollmar B. Sustained hypothermia accelerates microvascular thrombus formation in mice. Am J Physiol Heart Circ Physiol. 2005;289(6):H2680–7.

    Article  CAS  PubMed  Google Scholar 

  18. Faraday N, Rosenfeld BA. In vitro hypothermia enhances platelet GPIIb-IIIa activation and P-selectin expression. Anesthesiology. 1998;88(6):1579–85.

    Article  CAS  PubMed  Google Scholar 

  19. Straub A, Schlebold D, Wendel HP, Hamilton C, Wagner T, Schmid E, Dietz K, Ziemer G. Using reagent-supported thromboelastometry (ROTEM) to monitor haemostatic changes in congenital heart surgery employing deep hypothermic circulatory arrest. Eur J Cardiothorac Surg. 2008;34(3):641–7.

    Article  PubMed  Google Scholar 

  20. Hall MW, Goodman PD, Alston SM, Solen KA. Hypothermia-induced platelet aggregation in heparinized flowing human blood: identification of a high responder subpopulation. Am J Hematol. 2002;69(1):45–55.

    Article  PubMed  Google Scholar 

  21. Hall MW, Hopkins RO, Long JW, Mohammad SF, Solen KA. Hypothermia-induced platelet aggregation and cognitive decline in coronary artery bypass surgery: a pilot study. Perfusion. 2005;20(3):157–67.

    Article  PubMed  Google Scholar 

  22. Augoustides JG. Fatal intraoperative thrombosis in contemporary adult thoracic aortic surgery requiring deep hypothermic circulatory arrest: observations from the literature, 1993–2006. J Thorac Cardiovasc Surg. 2007;134(4):1069–70.

    Article  PubMed  Google Scholar 

  23. Davidson CJ, Hirt RP, Lal K, Snell P, Elgar G, Tuddenham EG, McVey JH. Molecular evolution of the vertebrate blood coagulation network. Thromb Haemost. 2003;89(3):420–8.

    CAS  PubMed  Google Scholar 

  24. Foley SR, Solano C, Simonova G, Spanevello MM, Bird RJ, Semple JW, Jackson DE, Schibler A, Fraser JF, Fung YL. A comprehensive study of ovine haemostasis to assess suitability to model human coagulation. Thromb Res. 2014;134(2):468–73.

    Article  CAS  PubMed  Google Scholar 

  25. Pichler L. Parameters of coagulation and fibrinolysis in different animal species – a literature based comparison. Wien Tierärtzl Mschr. 2008;95:282–95.

    CAS  Google Scholar 

  26. Kase F, Pospisil J. Comparison of the blood clotting mechanisms in man and some common laboratory animals. Acta Univ Carol Med Monogr. 1987;119:11–22.

    CAS  PubMed  Google Scholar 

  27. Massicottee P, Mitchell L, Andrew M. A comparative study of coagulation systems in newborn animals. Pediatr Res. 1986;20(10):961–5.

    Article  Google Scholar 

  28. Siller-Matula JM, Plasenzotti R, Spiel A, Quehenberger P, Jilma B. Interspecies differences in coagulation profile. Thromb Haemost. 2008;100(3):397–404.

    CAS  PubMed  Google Scholar 

  29. Wiinberg B, Kristensen AT. Thromboelastography in veterinary medicine. Semin Thromb Hemost. 2010;36(7):747–56.

    Article  PubMed  Google Scholar 

  30. Giacomini A, Legovini P, Gessoni G, Antico F, Valverde S, Salvadego MM, Manoni F. Platelet count and parameters determined by the Bayer ADVIA 120 in reference subjects and patients. Clin Lab Hematol. 2001;23(3):181–6.

    Article  CAS  Google Scholar 

  31. Wolfensohn W, Lloyd M. Handbook of laboratory animal management and welfare. 3rd ed. Oxford, UK: Blackwell Publishing; 2003.

    Book  Google Scholar 

  32. Tsakiris DA, Scudder L, Hodivala-Dilke K, Hynes RO, Coller BS. Hemostasis in the mouse (Mus musculus): a review. Thromb Haemost. 1999;81(2):177–88.

    CAS  PubMed  Google Scholar 

  33. Levin J, Ebbe S. Why are recently published platelet counts in normal mice so low? Blood. 1994;83(12):3829–31.

    CAS  PubMed  Google Scholar 

  34. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol. 1990;12(1):95–104.

    Article  CAS  PubMed  Google Scholar 

  35. Li C, Yang X, Feng J, Lei P, Wang Y. Proinflammatory and prothrombotic status in emphysematous rats exposed to intermittent hypoxia. Int J Clin Exp Pathol. 2015;8(1):374–83.

    PubMed  PubMed Central  Google Scholar 

  36. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95(2):362–72.

    CAS  PubMed  Google Scholar 

  37. Karges HE, Funk KA, Ronneberger H. Activity of coagulation and fibrinolysis parameters in animals. Arzneimittelforschung. 1994;44(6):793–7.

    CAS  PubMed  Google Scholar 

  38. Sweeney JD, Novak EK, Reddington M, Takeuchi KH, Swank RT. The RIIIS/J inbred mouse strain as a model for von Willebrand disease. Blood. 1990;76(11):2258–65.

    CAS  PubMed  Google Scholar 

  39. Velik-Salchner C, Schnürer C, Fries D, Müssigang PR, Moser PL, Streif W, Kolbitsch C, Lorenz IH. Normal values for thromboelastography (ROTEM) and selected coagulation parameters in porcine blood. Thromb Res. 2006;117(5):597–602.

    Article  CAS  PubMed  Google Scholar 

  40. Tsang VC, Wyatt CR, Damian RT. Comparative thermometric coagulation studies of plasmas from normal outbred Swiss Webster mice and persons. Am J Vet Res. 1979;40(6):857–62.

    CAS  PubMed  Google Scholar 

  41. Estève F, Grimaux M, Migaud-Fressart M, Stötzer KE, Amiral J. Individual and quantitative rapid testing of D. dimer using an automated system. XIIIth International Congress on Fibrinolysis and Thrombolysis. 1990; Barcelona, Spain.

    Google Scholar 

  42. Schöchl H, Solomon C, Schulz A, Voelckel W, Hanke A, Van Griensven M, Redl H, Bahrami S. Thromboelastometry (TEG) findings in disseminated intravascular coagulation in a pig model of endotoxemia. Mol Med. 2011;17(3–4):266–72.

    PubMed  PubMed Central  Google Scholar 

  43. Ravanant C, Freund M, Dol F, Cadroy Y, Roussi J, Incardona F, Maffrand JP, Boneu B, Drouet L, Legrand C, Herbert JM, Cazenave JP. Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species. Blood Coagul Fibrinolysis. 1995;6(5):446–55.

    Article  Google Scholar 

  44. Asakura H, Suga Y, Aoshnima K, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Takami A, Miyamoto K, Nakao S. Marked difference in pathophysiology between tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats. Crit Care Med. 2002;30(1):161–4.

    Article  CAS  PubMed  Google Scholar 

  45. Scarpelini S, Rhind SG, Nascimento B, Tien H, Shek PN, Peng HT, Huang H, Pinto R, Speers V, Reis M, Rizoli SB. Normal range values for thromboelastography in healthy adult volunteers. Braz J Med Biol Res. 2009;42(12):1210–7.

    Article  CAS  PubMed  Google Scholar 

  46. Sillesen M, Johansson PI, Rasmussen LS, Jin G, Jepsen CH, Imam AM, et al. Platelet activation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage. J Trauma Acute Care Surg. 2013;74(5):1252–9.

    Article  CAS  PubMed  Google Scholar 

  47. Zhao T, Li Y, Liu B, Wu E, Sillesen M, Velmahos GC, Halaweish I, Alam HB. Histone deacetylase inhibitor treatment attenuates coagulation imbalance in a lethal murine model of sepsis. Surgery. 2014;156(2):214–20.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Gentry PA. Comparative aspects of blood coagulation. Vet J. 2004;168(3):238–51.

    Article  CAS  PubMed  Google Scholar 

  49. Connolly TM, Condra C, Feng DM, Cook JJ, Stranieri MT, Reilly CF, Nutt RF, Gould RJ. Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides. Thromb Haemost. 1994;72(4):627–33.

    CAS  PubMed  Google Scholar 

  50. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao G, Hennessy L, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Osuchowski MF, Remick DG, Lederer JA, Land CH, Aasen AO, Aibiki M, Azevedo LC, Bahrami S, Boros M, Cooney R, et al. Abandon the mouse research ship? Not just yet! Shock. 2014;41(6):463–75.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hatch Q, Debarros M, Eckert M, Satterly S, Nelson D, Porta R, Lesperance R, Long W, Martin M. Acute coagulopathy in a porcine venous hemorrhage and ischemia reperfusion model. Am J Surg. 2014;207(5):637–41.

    Article  PubMed  Google Scholar 

  53. Letson HL, Pecheniuk NM, Mhango LP, Dobson GP. Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock. Crit Care Med. 2012;40(8):2417–22.

    Article  CAS  PubMed  Google Scholar 

  54. Gierer P, Hoffmann JN, Mahr F, Menger MD, Mittlmeier T, Gradl G, Vollmar B. Sublethal trauma model with systemic endotoxemia for the study of microcirculatory disorders after the second hit. J Surg Res. 2008;147(1):68–74.

    Article  PubMed  Google Scholar 

  55. Tsai HJ, Tsao CM, Liao MH, Ka SM, Liaw WJ, Wu CC. Application of thrombelastography in liver injury induced by endotoxin in rat. Blood Coagul Fibrinolysis. 2012;23(2):118–26.

    Article  PubMed  Google Scholar 

  56. Hardaway RM, Williams CH, Marvasti M, Farias M, Tseng A, Pinon I, Yanez D, Martinez M, Navar J. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med. 1990;18(12):1413–8.

    Article  CAS  PubMed  Google Scholar 

  57. Giannoudis PV, van Griensven M, Hildebrand F, Krettek C, Pape HC. Femoral nailing-related coagulopathy determined by first-hit magnitude: an animal study. Clin Orthop Relat Res. 2008;466(2):473–80.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Castellino FJ, Chapman MP, Donahue DL, Thomas S, Moore EE, Wohlauer MV, et al. Traumatic brain injury causes platelet adenosine diphosphate and arachidonic acid receptor inhibition independent of hemorrhagic shock in humans and rats. J Trauma Acute Care Surg. 2014;76(5):1169–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dekker SE, Sillesen M, Bambakidis T, Jin G, Liu B, Boer C, et al. Normal saline influences coagulation and endothelial function after traumatic brain injury and hemorrhagic shock in pigs. Surgery. 2014;156(3):556–63.

    Article  PubMed  Google Scholar 

  60. Jepsen CH, deMoya MA, Perner A, Sillesen M, Ostrowski SR, Alam HB, et al. Effect of valproic acid and injury on lesion size and endothelial glycocalyx shedding in a rodent model of isolated traumatic brain injury. J Trauma Acute Care Surg. 2014;77(2):292–7.

    Article  CAS  PubMed  Google Scholar 

  61. King DR, Cohn SM, Proctor KG. Changes in intracranial pressure, coagulation, and neurologic outcome after resuscitation from experimental traumatic brain injury with hetastarch. Surgery. 2004;136(2):355–63.

    Article  PubMed  Google Scholar 

  62. Patel MB, Feinstein AJ, Saenz AD, Majetschak M, Proctor KG. Prehospital HBOC-201 after traumatic brain injury and hemorrhagic shock in swine. J Trauma. 2006;61(1):46–56.

    Article  CAS  PubMed  Google Scholar 

  63. Ploplis VA, Donahue DL, Sandoval-Cooper MJ, MorenoCaffaro M, Sheets P, Thomas SG, et al. Systemic platelet dysfunction is the result of local dysregulated coagulation and platelet activation in the brain in a rat model of isolated traumatic brain injury. J Neurotrauma. 2014;31(19):1672–5.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sillesen M, Rasmussen LS, Jin G, Jepsen CH, Imam A, Hwabejire JO, et al. Assessment of coagulopathy, endothelial injury, and inflammation after traumatic brain injury and hemorrhage in a porcine model. J Trauma Acute Care Surg. 2014;76(1):12–20.

    Article  CAS  PubMed  Google Scholar 

  65. Imam AM, Jin G, Sillesen M, Duggan M, Jepsen CH, Hwabejire JO, et al. Early treatment with lyophilized plasma protects the brain in a large animal model of combined traumatic brain injury and hemorrhagic shock. J Trauma Acute Care Surg. 2013;75(6):976–83.

    Article  CAS  PubMed  Google Scholar 

  66. Chesebro BB, Rahn P, Carles M, Esmon CT, Xu J, Brohi K, Frith D, Pittet JF, Cohen MJ. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock. 2009;32(6):659–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Frith D, Goslings C, Gaarder C, Maegele M, Cohen MJ, Allard S, Johansson PI, Stanworth S, Thiemermann C, Brohi K. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost. 2010;8:1919–25.

    Article  CAS  PubMed  Google Scholar 

  68. Darlington DN, Craig T, Gonzales MD, Schwacha MG, Cap AP, Dubick MA. Acute coagulopathy of trauma in the rat. Shock. 2013;39(5):440–6.

    Article  CAS  PubMed  Google Scholar 

  69. White NJ, Martin EJ, Brophy DF, Ward KR. Coagulopathy and traumatic shock: characterizing hemostatic function during the critical period prior to fluid resuscitation. Resuscitation. 2010;81(1):111–6.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Mohr J, Ruchholtz S, Hildebrand F, Flohé S, Frink M, Witte I, Weuster M, Fröhlich M, van Griensven M, Keibl C, Mommsen P. Induced hypothermia does not impair coagulation system in a swine multiple trauma model. J Trauma Acute Care Surg. 2013;74(4):1014–20.

    Article  CAS  PubMed  Google Scholar 

  71. Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism. 2007;56(2):214–21.

    Article  CAS  PubMed  Google Scholar 

  72. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58(5):1002–9. Discussion 1009–10.

    Article  PubMed  Google Scholar 

  73. Martini WZ, Dubick MA, Wade CE, Holcomb JB. Evaluation of tris-hydroxymethylaminomethane on reversing coagulation abnormalities caused by acidosis in pigs. Crit Care Med. 2007;35(5):156.

    Google Scholar 

  74. Alam HB, Bice LM, Butt MU, Cho SD, Dubick MA, Duggan M, Englehart MS, Holcomb JB, Morris MS, Prince MD, Schreiber MA, Shults C, Sondeen JL, Tabbara M, Tieu BH, Underwood SA, Hemostatic Resuscitation Research Group. Testing of blood products in a polytrauma model: results of a multi-institutional randomized preclinical trial. J Trauma. 2009;67(4):856–64.

    Article  PubMed  Google Scholar 

  75. Dickneite G, Dorr B, Kaspereit F, Tanaka KA. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of hemodilutional coagulopathy in a porcine trauma model. J Trauma. 2010;68(5):1151–7.

    Article  CAS  PubMed  Google Scholar 

  76. Doran CM, Doran CA, Woolley T, Carter A, Male K, Midwinter MJ, et al. Targeted resuscitation improves coagulation and outcome. J Trauma Acute Care Surg. 2012;72(4):835–43.

    Article  CAS  PubMed  Google Scholar 

  77. Harr JN, Moore EE, Wohlauer MV, Droz N, Fragoso M, Banerjee A, Silliman CC. 2011. The acute coagulopathy of trauma is due to impaired initial thrombin generation but not clot formation or clot strength. J Surg Res 2011;170(2): 319–24.

    Google Scholar 

  78. Haas T, Fries D, Holz C, Innerhofer P, Streif W, Klingler A, et al. Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution. Anesth Analg. 2008;106(4):1078–86.

    Article  CAS  PubMed  Google Scholar 

  79. Kheirabadi BS, Crissey JM, Deguzman R, Perez MR, Cox AB, Dubick MA, et al. Effects of synthetic versus natural colloid resuscitation on inducing dilutional coagulopathy and increasing hemorrhage in rabbits. J Trauma. 2008;64(5):1218–28.

    Article  PubMed  Google Scholar 

  80. Martini WZ, Chinkes DL, Sondeen J, Dubick MA. Effects of hemorrhage and lactated Ringer’s resuscitation on coagulation and fibrinogen metabolism in swine. Shock. 2006;26(4):396–401.

    Article  CAS  PubMed  Google Scholar 

  81. Martini J, Cabrales P, Fries D, Intaglietta M, Tsai AG. Effects of fibrinogen concentrate after shock/resuscitation: a comparison between in vivo microvascular clot formation and thromboelastometry*. Crit Care Med. 2013;41(11):e301–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Martini WZ, Cortez DS, Dubick MA, Blackbourne LH. Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs. J Trauma Acute Care Surg. 2012;73(3):640–7.

    Article  CAS  PubMed  Google Scholar 

  83. Nielsen VG. Resuscitation with Hextend decreases endogenous circulating heparin activity and accelerates clot initiation after hemorrhage in the rabbit. Anesth Analg. 2001;93:1106–10.

    Article  CAS  PubMed  Google Scholar 

  84. Nishi K, Takasu A, Shinozaki H, Yamamoto Y, Sakamoto T. Hemodilution as a result of aggressive fluid resuscitation aggravates coagulopathy in a rat model of uncontrolled hemorrhagic shock. J Trauma Acute Care Surg. 2013;74(3):808–12.

    Article  CAS  PubMed  Google Scholar 

  85. Pragst I, Kaspereit F, Dorr B, Dickneite G. Prothrombin complex concentrate (Beriplex P/N) for control of bleeding after kidney trauma in a rabbit dilutional coagulopathy model. Thromb Res. 2010;125(3):272–7.

    Article  CAS  PubMed  Google Scholar 

  86. Riha GM, Kunio NR, Van PY, Kremenevskiy I, Anderson R, Hamilton GJ, et al. Uncontrolled hemorrhagic shock results in a hypercoagulable state modulated by initial fluid resuscitation regimens. J Trauma Acute Care Surg. 2013;75(1):129.

    Article  CAS  PubMed  Google Scholar 

  87. Shuja F, Shults C, Duggan M, Tabbara M, Butt MU, Fischer TH, et al. Development and testing of freeze-dried plasma for the treatment of trauma-associated coagulopathy. J Trauma. 2008;65(5):975–85.

    Article  PubMed  Google Scholar 

  88. Spoerke N, Zink K, Cho SD, Differding J, Muller P, Karahan A, et al. Lyophilized plasma for resuscitation in a swine model of severe injury. Arch Surg. 2009;144(9):829–34.

    Article  CAS  PubMed  Google Scholar 

  89. Todd SR, Malinoski D, Muller PJ, Schreiber MA. Hextend attenuates hypercoagulability after severe liver injury in swine. J Trauma. 2005;59(3):589–93. Discussion 93–4.

    PubMed  Google Scholar 

  90. Torres LN, Sondeen JL, Ji L, Dubick MA, Torres FI. Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats. J Trauma Acute Care Surg. 2013;75(5):759–66.

    Article  CAS  PubMed  Google Scholar 

  91. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289–95.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Via D, Kaufmann C, Anderson D, Stanton K, Rhee P. Effect of hydroxyethyl starch on coagulopathy in a swine model of hemorrhagic shock resuscitation. J Trauma. 2001;50(6):1076–82.

    Article  CAS  PubMed  Google Scholar 

  93. Watters JM, Tieu BH, Differding JA, Muller PJ, Schreiber MA. A single bolus of 3% hypertonic saline with 6% dextran provides optimal initial resuscitation after uncontrolled hemorrhagic shock. J Trauma. 2006;61(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  94. Wohlauer MV, Moore EE, Droz NM, Harr J, Gonzalez E, Fragoso M, et al. Hemodilution is not critical in the pathogenesis of the acute coagulopathy of trauma. J Surg Res. 2012;173(1):26–30.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Sillesen M, Johansson PI, Rasmussen LS, Jin G, Jepsen CH, Imam A, et al. Fresh frozen plasma resuscitation attenuates platelet dysfunction compared with normal saline in a large animal model of multisystem trauma. J Trauma Acute Care Surg. 2014;76(4):998–1007.

    Article  CAS  PubMed  Google Scholar 

  96. Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg. 2007;246(5):831–5.

    Article  PubMed  Google Scholar 

  97. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127–30.

    Article  PubMed  Google Scholar 

  98. Floccard B, Rugeri L, Faure A, Saint Denis M, Boyle EM, Peguet O, Levrat A, Guillaume C, Marcotte G, Vulliez A, Hautin E, David JS, Négrier C, Allaouchiche B. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26–32.

    Article  PubMed  Google Scholar 

  99. Branco BC, Inaba K, Ives C, Okoye O, Shulman I, David JS, Schöchl H, Rhee P, Demetriades D. Thromboelastogram evaluation of the impact of hypercoagulability in trauma patients. Shock. 2014;41(3):200–7.

    Article  PubMed  Google Scholar 

  100. Wolberg AS, Meng ZH, Monroe 3rd DM, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56(6):1221–8.

    Article  CAS  PubMed  Google Scholar 

  101. Hess JR, Hiippala S. Optimizing the use of blood products in trauma care. Crit Care. 2005;9 Suppl 5:S10–4.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Alam HB, Bowyer MW, Koustova E, Gushchin V, Anderson D, Stanton K, et al. Learning and memory is preserved after induced asanguineous hyperkalemic hypothermic arrest in a swine model of traumatic exsanguination. Surgery. 2002;132(2):278–88.

    Article  PubMed  Google Scholar 

  103. Cohen MJ, Brohi K, Ganter MT, Manley GT, Mackersie RC, Pittet JF. Early coagulopathy after traumatic brain injury: the role of hypoperfusion and the protein C pathway. J Trauma. 2007;63(6):1254–61. Discussion 61–2.

    Article  CAS  PubMed  Google Scholar 

  104. Laroche M, Kutcher ME, Huang MC, Cohen MJ, Manley GT. Coagulopathy after traumatic brain injury. Neurosurgery. 2012;70(6):1334–45.

    Article  PubMed  Google Scholar 

  105. Windelov NA, Sorensen AM, Perner A, Wanscher M, Larsen CF, Ostrowski SR, et al. Platelet aggregation following trauma: a prospective study. Blood Coagul Fibrinolysis. 2014;25(1):67–73.

    Article  PubMed  Google Scholar 

  106. Harr JN, Moore EE, Wohlauer MV, Fragoso M, Gamboni F, Liang X, Banerjee A, Silliman CC. Activated platelets in heparinized shed blood: the “second hit” of acute lung injury in trauma/hemorrhagic shock models. Shock. 2011;36(6):595–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Frith D, Cohen MJ, Brohi K. Animal models of trauma-induced coagulopathy. Thromb Res. 2012;129(5):551–6.

    Article  CAS  PubMed  Google Scholar 

  108. Brohi K, Cohen MJ, Ganter MT, Shultz MJ, Levi M, Mackersie RC, Pittet JF. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64:1211–7.

    Article  PubMed  Google Scholar 

  109. Kasotakis G, Sideris A, Yang Y, de Moya M, Alam H, King DR, et al. Aggressive early crystalloid resuscitation adversely affects outcomes in adult blunt trauma patients: an analysis of the Glue Grant database. J Trauma Acute Care Surg. 2013;74(5):1215–21.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Caballo C, Escolar G, Diaz-Ricart M, Lopez-Vilchez I, Lozano M, Cid J, et al. Impact of experimental haemodilution on platelet function, thrombin generation and clot firmness: effects of different coagulation factor concentrates. Blood Transfus. 2013;11(3):391–9.

    PubMed  PubMed Central  Google Scholar 

  111. Brown LM, Aro SO, Cohen MJ, Trauma Outcomes G, Holcomb JB, Wade CE, et al. A high fresh frozen plasma: packed red blood cell transfusion ratio decreases mortality in all massively transfused trauma patients regardless of admission international normalized ratio. J Trauma. 2011;71(2 Suppl 3):S358.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73(1):13–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194–200.

    Article  PubMed  Google Scholar 

  114. Martini WZ. Fibrinogen availability and coagulation function after hemorrhage and resuscitation in pigs. Mol Med. 2011;17(7-8):757–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Moore HB, Moore EE, Gonzalez E, Chapman MP, Chin TL, Silliman CC, Banerjee A, Sauala A. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg. 2014;77(6):811–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors C, Khan S, De’Ath HD, Allard S, Hart DP, Pasi KJ, Hunt BJ, Stanworth S, MacCallum PK, Brohi K. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost. 2013;11(2):307–14.

    Article  CAS  PubMed  Google Scholar 

  117. Cotton BA, Harvin JA, Kostousouv V, Minei KM, Badwan ZA, Schochl H, Wade CE, Holcomb JB, Matlievic N. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73(2):365–70.

    Article  CAS  PubMed  Google Scholar 

  118. Viersen VA, Greuters S, Korfage AR, Van der Rijst C, Van Bochove V, Nanayakkara PW, Vandewalle E, Boer C. Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion. Resuscitation. 2012;83(12):1451–5.

    Article  CAS  PubMed  Google Scholar 

  119. Hayakawa M, Gando S, Ieko M, Honma Y, Homma T, Yanagida Y, Kubota N, Uegaki S, Sawamura A, Asakura H. Massive amounts of tissue factor induce fibringenolysis without tissue hypoperfusion in rats. Shock. 2013;39(6):514–9.

    Article  CAS  PubMed  Google Scholar 

  120. DeBarros M, Hatch Q, Porta CR, Salgar S, Izenberg S, DuBose J, Eckert M, Martin M. Tranexamic acid corrects fibrinolysis in the presence of acidemia in a swine model of severe ischemic reperfusion. J Trauma Acute Care Surg. 2014;76(3):625–32.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

Dr. Alam would like to acknowledge research support provided by numerous grants by the Office of Naval Research (including N000140910378, and N000141310071), US Army Medical Research and Materiel Command (W81XWH-09-1-0520), Defense Advanced Research Projects Agency (W911NF-06-1-0220), and National Institutes of Health (R01GM084127). The authors would like to thank Simone E. Dekker for her insightful comments on earlier versions of this chapter.

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Bambakidis, T., Sillesen, M., Alam, H.B. (2016). Animal Models of Trauma Induced Coagulopathy. In: Gonzalez, E., Moore, H., Moore, E. (eds) Trauma Induced Coagulopathy. Springer, Cham. https://doi.org/10.1007/978-3-319-28308-1_34

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