Massive transfusion and coagulopathy: pathophysiology and implications for clinical management

Jean-François Hardy, Philippe de Moerloose, Charles Marc Samama, Members of the Groupe d'Intérêt en Hémostase Périopératoire, Jean-François Hardy, Philippe de Moerloose, Charles Marc Samama, Members of the Groupe d'Intérêt en Hémostase Périopératoire

Abstract

Purpose: To review the pathophysiology of coagulopathy in massively transfused, adult and previously hemostatically competent patients in both elective surgical and trauma settings, and to recommend the most appropriate treatment strategies.

Methods: Medline was searched for articles on "massive transfusion," "transfusion," "trauma," "surgery," "coagulopathy" and "hemostatic defects." A group of experts reviewed the findings.

Principal findings: Coagulopathy will result from hemodilution, hypothermia, the use of fractionated blood products and disseminated intravascular coagulation. The clinical significance of the effects of hydroxyethyl starch solutions on hemostasis remains unclear. Maintaining a normal body temperature is a first-line, effective strategy to improve hemostasis during massive transfusion. Red cells play an important role in coagulation and hematocrits higher than 30% may be required to sustain hemostasis. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. In trauma patients, tissue trauma, shock, tissue anoxia and hypothermia contribute to the development of disseminated intravascular coagulation and microvascular bleeding. The use of platelets and/or fresh frozen plasma should depend on clinical judgment as well as the results of coagulation testing and should be used mainly to treat a clinical coagulopathy.

Conclusions: Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial and multicellular event. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding.

References

    1. Crosson JT. Massive transfusion. Clin Lab Med. 1996;16:873–82.
    1. Faringer PD, Mullins RJ, Johnson RL, Trunkey DD. Blood component supplementation during massive transfusion of AS-1 red cells in trauma patients. J Trauma. 1993;34:481–5.
    1. Murray DJ, Pennell BJ, Weinstein SL, Olson JD. Packed red cells in acute blood loss: dilutional coagu- lopathy as a cause of surgical bleeding. Anesth Analg. 1995;80:336–42.
    1. Reed RL, Ciavarella D, Heimbach DM, et al. Prophylactic platelet administration during massive transfusion. A prospective, randomized, double-blind clinical study. Ann Surg. 1986;203:40–8.
    1. Counts RB, Haisch C, Simon TL, Maxwell NG, Heimbach DM, Carrico CJ. Hemostasis in massively transfused trauma patients. Ann Surg. 1979;190:91–9.
    1. Hiippala S. Replacement of massive blood loss. Vox Sang. 1998;74(2):399–407.
    1. Simmons RL, Collins JA, Heisterkamp CA, Mills DE, Andren R, Phillips LL. Coagulation disorders in combat casualties. I. Acute changes after wounding. II. Effects of massive transfusion. III. Post-resuscita- tive changes. Ann Surg. 1969;169:455–82.
    1. Leslie SD, Toy PT. Laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid. Am J Clin Pathol. 1991;96:770–3.
    1. Stainsby D, MacLennan S, Hamilton PJ. Management of massive blood loss: a template guideline. Br J Anaesth. 2000;85:487–91.
    1. Guay J, Ozier Y, de Moerloose P, Samana CM, Belisle S, Hardy JF. Polytrauma and hemostatic anomalies (French) Can J Anaesth. 1998;45:683–91.
    1. Miller RD, Robbins TO, Tong MJ, Barton SL. Coagulation defects associated with massive blood transfusions. Ann Surg. 1971;174:794–801.
    1. Ng KF, Lam CC, Chan LC. In vivo effect of haemo- dilution with saline on coagulation: a randomized controlled trial. Br J Anaesth. 2002;88:475–80.
    1. Ruttmann TG, James MF, Finlayson J. Effects on coagulation of intravenous crystalloid or colloid in patients undergoing peripheral vascular surgery. Br J Anaesth. 2002;89:226–30.
    1. Ruttmann TG. Haemodilution enhances coagulation. Br J Anaesth. 2002;88:470–2.
    1. Mortelmans YJ, Vermaut G, Verbruggen AM, et al. Effects of 6% hydroxyethyl starch and 3% modified fluid gelatin on intravascular volume and coagulation during intraoperative hemodilution. Anesth Analg. 1995;81:1235–42.
    1. Samama CM. Traumatic emergencies and hemostasis (French) Cah Anesthesiol. 1995;43:479–82.
    1. Mardel SN, Saunders FM, Allen H, et al. quality of clot formation with gelatin-based plasma substitutes. Br J Anaesth. 1998;80:204–7.
    1. de Jonge E, Levi M, Berends F, van der Ende AE, ten Cate JW, Stoutenbeek CP. Impaired haemostasis by intravenous administration of a gelatin-based plasma expander in human subjects. Thromb Haemost. 1998;79:286–90.
    1. Strauss RG. Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion. 1981;21:299–302.
    1. Traylor RJ, Pearl RG. Crystalloid versus colloid versus colloid: all colloids are not created equal. Anesth Analg. 1996;83:209–12.
    1. de Jonge E, Levi M. Effects of different plasma sub- stitutes on blood coagulation: a comparative review. Crit Care Med. 2001;29:1261–7.
    1. Boldt J, Muller M, Heesen M, Heyn O, Hempelmann G. Influence of different volume therapies on platelet function in the critically ill. Intensive Care Med. 1996;22:1075–81.
    1. Boldt J, Haisch G, Suttner S, Kumle B, Schellhaass A. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) on measures of coagulation. Br J Anaesth. 2002;89:722–8.
    1. Strauss RG, Pennell BJ, Stump DC. A randomized, blinded trial comparing the hemostatic effects of pentastarch versus hetastarch. Transfusion. 2002;42:27–36.
    1. Langeron O, Doelberg M, Ang ET, Bonnet F, Capdevila X, Coriat P. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92:855–62.
    1. Innerhofer P, Fries D, Margreiter J, et al. The effects of perioperatively administered colloids and crystalloids on primary platelet-mediated hemostasis and clot formation. Anesth Analg. 2002;95:858–65.
    1. Knutson JE, Deering JA, Hall FW, et al. Does intra- operative hetastarch administration increase blood loss and transfusion requirements after cardiac surgery. Anesth Analg. 2000;90:801–7.
    1. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Hextend Study Group. Anesth Analg. 1999;88:992–8.
    1. Haynes GR, Bailey MK. Excessive use of hetastarch: an iatrogenic cause of bleeding and hypocalcemia. Anesth Analg. 2000;90:1455–6.
    1. American College of Surgeons . Advanced Trauma Life Support Course Manual. Chicago: American College of Surgeons; 1997. pp. 103–12.
    1. Yoshihara H, Yamamoto T, Mihara H. Changes in coagulation and fibrinolysis occurring in dogs during hypothermia. Thromb Res. 1985;37:503–12.
    1. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med. 1992;20:1402–5.
    1. Reed RL, Johnston TD, Hudson JD, Fischer RP. The disparity between hypothermic coagulopathy and clotting studies. J Trauma. 1992;33:465–70.
    1. Pina-Cabral JM, Ribeiro-da-Silva A, Almeida-Dias A. Platelet sequestration during hypothermia in dogs treated with sulphinpyrazone and ticlopidine - reversibility accelerated after intra-abdominal rewarming. Thromb Haemost. 1985;54:838–41.
    1. Oung CM, Li MS, Shum-Tim D, Chiu RC, Hinchey EJ. In vivo study of bleeding time and arterial hemorrhage in hypothermic versus normothermic animals. J Trauma. 1993;35:251–4.
    1. Valeri CR, Feingold H, Cassidy G, Ragno G, Khuri S, Altschule MD. Hypothermia-induced reversible platelet dysfunction. Ann Surg. 1987;205:175–81.
    1. Valeri CR, Khabbaz K, Khuri SF, et al. Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass. J Thorac Cardiovasc Surg. 1992;104:108–16.
    1. Michelson AD, MacGregor H, Barnard MR, Kestin AS, Rohrer MJ, Valeri CR. Reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. Thromb Haemost. 1994;71:633–40.
    1. Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A. Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet. 1996;347:289–92.
    1. Douning LK, Ramsay MA, Swygert TH, et al. Temperature corrected thrombelastography in hypothermic patients. Anesth Analg. 1995;81:608–11.
    1. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma. 1997;42:857–61.
    1. Ferrara A, MacArthur JD, Wright HK, Modlin IM, McMillen MA. Hypothermia and acidosis worsen coagulopathy in the patient requiring massive transfusion. Am J Surg. 1990;160:515–8.
    1. Valles J, Santos MT, Aznar J, et al. Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment. Blood. 1991;78:154–62.
    1. Santos MT, Valles J, Marcus AJ, et al. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. J Clin Invest. 1991;87:571–80.
    1. Valles J, Santos MT, Aznar J, et al. Platelet-erythro- cyte interactions enhance alpha(IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood. 2002;99:3978–84.
    1. Ouaknine-Orlando B, Samama CM, Riou B, et al. Role of the hematocrit in a rabbit model of arterial thrombosis and bleeding. Anesthesiology. 1999;90:1454–61.
    1. Peyrou V, Lormeau JC, Herault JP, Gaich C, Pfliegger AM, Herbert JM. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost. 1999;81:400–6.
    1. Valles J, Santos MT, Aznar J, Velert M, Barbera G, Carmena R. Modulatory effect of erythrocytes on the platelet reactivity to collagen in IDDM patients. Diabetes. 1997;46:1047–53.
    1. Valles J, Santos MT, Aznar J, et al. Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to pro- thrombotic effects of erythrocytes on platelet reactivity. Circulation. 1998;97:350–5.
    1. Santos MT, Valles J, Aznar J, Marcus AJ, Broekman MJ, Safier LB. Prothrombotic effects of erythro- cytes on platelet reactivity. Reduction by aspirin. Circulation. 1997;95:63–8.
    1. Eberst ME, Berkowitz LR. Hemostasis in renal disease: pathophysiology and management. Am J Med. 1994;96:168–79.
    1. Tangelder GJ, Teirlinck HC, Slaaf DW, Reneman RS. Distribution of blood platelets flowing in arterioles. Am J Physiol. 1985;248(3):H318–23.
    1. Teirlinck HC, Tangelder GJ, Slaaf DW, Muijtjens AM, Arts T, Reneman RS. Orientation and diameter distribution of rabbit blood platelets flowing in small arterioles. Biorheology. 1984;21:317–31.
    1. Uijttewaal WS, Nijhof EJ, Bronkhorst PJ, Den Hartog E, Heethaar RM. Near-wall excess of platelets induced by lateral migration of erythrocytes in flowing blood. Am J Physiol. 1993;264(4):H1239–44.
    1. Blajchman MA, Bordin JO, Bardossy L, Heddle NM. The contribution of the haematocrit to thrombo- cytopenic bleeding in experimental animals. Br J Haematol. 1994;86:347–50.
    1. Escolar G, Garrido M, Mazzara R, Castillo R, Ordinas A. Experimental basis for the use of red cell transfusion in the management of anemic-thrombocy- topenic patients. Transfusion. 1988;28:406–11.
    1. Livio M, Benigni A, Remuzzi G. Coagulation abnormalities in uremia. Semin Nephrol. 1985;5:82–90.
    1. Small M, Lowe GD, Cameron E, Forbes CD. Contribution of the haematocrit to the bleeding time. Haemostasis. 1983;13:379–84.
    1. Ho CH. The hemostatic effect of packed red cell transfusion in patients with anemia. Transfusion. 1998;38:1011–4.
    1. Valeri CR, Cassidy G, Pivacek LE, et al. Anemia- induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion. 2001;41:977–83.
    1. Khuri SF, Wolfe JA, Josa M, et al. Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgi- cal blood loss. J Thorac Cardiovasc Surg. 1992;104:94–107.
    1. McLoughlin TM Jr, Fontana JL, Alving B, Mongan PD, Bunger R. Profound normovolemic hemodilu- tion: hemostatic effects in patients and in a porcine model. Anesth Analg. 1996;83:459–65.
    1. Friesen RH, Campbell DN, Clarke DR, Tornabene MA. Modified ultrafiltration attenuates dilutional coagulopathy in pediatric open heart operations. Ann Thorac Surg. 1997;64:1787–9.
    1. Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation. 1991;84(5):422–31.
    1. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg. 1995;81:360–5.
    1. Ciavarella D, Reed RL, Counts RB, et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol. 1987;67:365–8.
    1. Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem. 2000;46(8):1260–9.
    1. Fitzgerald DJ. Vascular biology of thrombosis: the role of platelet-vessel wall adhesion. Neurology. 2001;57(5):S1–4.
    1. Fuss C, Palmaz JC, Sprague EA. Fibrinogen: structure, function, and surface interactions. J Vasc Interv Radiol. 2001;12:677–82.
    1. Nurden AT, Nurden P. A review of the role of platelet membrane glycoproteins in the platelet-vessel wall interaction. Baillieres Clin Haematol. 1993;6:653–90.
    1. Calvete JJ. On the structure and function of platelet integrin alpha IIb beta 3, the fibrinogen receptor. Proc Soc Exp Biol Med. 1995;208:346–60.
    1. Hirshberg A, Dugas M, Banez EI, Scott BG, Wall MJ, Mattox KL. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a computer simulation. J Trauma. 2003;54:454–63.
    1. Murray DJ, Olson J, Strauss R, Tinker JH. Coagulation changes during packed red cell replacement of major blood loss. Anesthesiology. 1988;69:839–45.
    1. Harke H, Rahman S. Haemostatic disorders in massive transfusion. Bibl Haematol. 1980;46:179–88.
    1. Harvey MP, Greenfield TP, Sugrue ME, Rosenfeld D. Massive blood transfusion in a tertiary referral hospital. Clinical outcomes and haemostatic complications. Med J Aust. 1995;163:356–9.
    1. Hulka F, Mullins RJ, Frank EH. Blunt brain injury activates the coagulation process. Arch Surg. 1996;131:923–7.
    1. Mannucci PM, Federici AB, Sirchia G. Hemostasis testing during massive blood replacement. A study of 172 cases. Vox Sang. 1982;42:113–23.
    1. Harrigan C, Lucas CE, Ledgerwood AM, Mammen EF. Primary hemostasis after massive transfusion for injury. Am Surg. 1982;48:393–6.
    1. Harrigan C, Lucas CE, Ledgerwood AM, Walz DA, Mammen EF. Serial changes in primary hemostasis after massive transfusion. Surgery. 1985;98:836–44.
    1. Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost. 1990;16:1–20.
    1. Samama CM, Quezada R, Riou B, et al. Intraoperative measurement of activated partial thromboplastin time and prothrombin time with a new compact monitor. Acta Anaesthesiol Scand. 1994;38:232–7.
    1. Turi DC, Peerschke EI. Sensitivity of three activated partial thromboplastin time reagents to coagulation factor deficiencies. Am J Clin Pathol. 1986;85:43–9.
    1. Lucas CE, Ledgerwood AM. Clinical significance of altered coagulation tests after massive transfusion for trauma. Am Surg. 1981;47:125–30.
    1. Hewson JR, Neame PB, Kumar N, et al. Coagulopathy related to dilution and hypotension during massive transfusion. Crit Care Med. 1985;13:387–91.
    1. Tuman KJ, Spiess BD, McCarthy RJ, Ivankovich AD. Effects of progressive blood loss on coagulation as measured by thrombelastography. Anesth Analg. 1987;66:856–63.
    1. Cammerer U, Dietrich W, Rampf T, Braun SL, Richter JA. The predictive value of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg. 2003;96:51–7.
    1. Forestier F, Coiffic A, Mouton C, Ekouevi D, Chene G, Janvier G. Platelet function point-of-care tests in post-bypass cardiac surgery: are they relevant. Br J Anaesth. 2002;89:715–21.
    1. Lasne D, Fiemeyer A, Chatellier G, Chammas C, Baron JF, Aiach M. A study of platelet functions with a new analyzer using high shear stress (PFA 100) in patients undergoing coronary artery bypass graft. Thromb Haemost. 2000;84:794–9.
    1. Kleinman S, Chan P, Robillard P. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev. 2003;17:120–62.
    1. Blumberg N, Laczin J, McMican A, Heal J, Arvan D. A critical survey of fresh-frozen plasma use. Transfusion. 1986;26:511–3.
    1. Anonymous. Guideline for the use of fresh-frozen plasma. Medical Directors Advisory Committee, National Blood Transfusion Council. S Afr Med J 1998; 88: 1344-7.
    1. Hellstern P, Haubelt H. Indications for plasma in massive transfusion. Thromb Res. 2002;107(1):S19–22.
    1. Horsey PJ. Multiple trauma and massive transfusion (Editorial) Anaesthesia. 1997;52:1027–9.
    1. Erber WN. Massive blood transfusion in the elective surgical setting. Transfus Apheresis Sci. 2002;27:83–92.
    1. Pantanowitz L, Kruskall MS, Uhl L. Cryoprecipitate. Patterns of use. Am J Clin Pathol. 2003;119:874–81.
    1. Cinat ME, Wallace WC, Nastanski F, et al. Improved survival following massive transfusion in patients who have undergone trauma. Arch Surg. 1999;134:964–8.
    1. Rivers E, Nguyen B, Havstad S, et al. Early goal- directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–77.
    1. Al Douri M, Shafi T, Al Khudairi D, et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis. 2000;11(1):S121–7.
    1. Hendriks HG, van der Maaten JM, de Wolf J, Waterbolk TW, Slooff MJ, van der Meer J. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII. Anesth Analg. 2001;93:287–9.
    1. Jeffers L, Chalasani N, Balart L, Pyrsopoulos N, Erhardtsen E. Safety and efficacy of recombinant factor VIIa in patients with liver disease undergoing laparoscopic liver biopsy. Gastroenterology. 2002;123:118–26.
    1. Arkin S, Blei F, Fetten J, et al. Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors. Blood Coagul Fibrinolysis. 2000;11:255–9.
    1. Poon MC, ďOiron R. Recombinant activated factor VII (NovoSeven) treatment of platelet-related bleeding disorders. International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders Group. Blood Coagul Fibrinolysis. 2000;11(1):S55–68.
    1. Martinowitz U, Holcomb JB, Pusateri AE, et al. Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma. 2001;50:721–9.
    1. Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 2001;51:431–8.
    1. Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology. 2002;96:1522–5.
    1. Martinowitz U, Kenet G, Lubetski A, Luboshitz J, Segal E. Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma. Can J Anesth. 2002;49:S15–20.
    1. Hedner U. NovoSeven as a universal haemostatic agent. Blood Coagul Fibrinolysis. 2000;11(1):S107–11.
    1. Allen GA, Hoffman M, Roberts HR, Monroe DM. Recombinant activated factor VII: its mechanism of action and role in the control of hemorrhage. Can J Anesth. 2002;49:S7–14.
    1. Roberts HR. Clinical experience with activated factor VII: focus on safety aspects. Blood Coagul Fibrinolysis. 1998;9(1):S115–8.
    1. Hardy JF. Managing uncontrolled hemorrhage in trauma and surgery: a novel and promising approach. Can J Anesth. 2002;49:S4–6.
    1. Murkin JM. A novel hemostatic agent: the potential role of recombinant activated factor VII (rFVIIa) in anesthetic practice. Can J Anesth. 2002;49:S21–6. doi: 10.1007/BF03017929.
    1. Koh MB, Hunt BJ. The management of perioperative bleeding. Blood Rev. 2003;17:179–85.

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