The efficacy of antithrombin administration in the acute phase of burn injury

Summary

Severe burn injury is characterized by the activation of coagulation, decreased fibrinolytic activity and decreased natural anticoagulant activity. The aim of our study was to investigate the effect of antithrombin (AT) administration on coagulation status and on organ function in the early post-burn period. Thirty-one patients were admitted to the burn intensive care unit and were then randomised into two groups (AT- treated and non-AT-treated) for four consecutive days after thermal injury. The clinical data, coagulation and fibrinolysis parameters were compared and the adverse effects were monitored. Significant differences in the time course of coagulation markers (thrombin/AT complexes, tissue plasminogen activator, D-dimer) were observed between AT-treated and non-AT treated groups. According to the International Society onThrombosis and Haemostasis criteria, disseminated intravascular coagulation (DIC) diagnosis was made in 28 of 31 patients. The presence of overt DIC was associated with mortality (p<0.001).The Sequential Organ Failure As-sessment (SOFA) score time trend differed significantly between the two investigation groups (decreased in the treated group and did not change in the non-AT-treated group). AT-treated patients had an absolute reduction in a 28-day mortality of 25% as compared to the non-AT-treated group (p=0.004). No treatment related side effects were observed. Treatment withAT seems to affect the coagulation status and reduce multiple organ failure incidence and mortality in the early post-burn period.

Keywords

Antithrombin - burn injury - coagulation markers - disseminated in-travascular coagulation - sequential organ failure assessment score

• References

• 1 Aoki K, Aikawa N, Sekine K. et al. Elevation of plasma free PAI-1 levels as an integrated endothelial response to severe burns. Burns 2001; 27: 569-575.
• 2 Niedermayr M, Schramm W, Kamolz L. et al. Antithrombin deficiency and its relationship to severe burns. Burns 2007; 33: 173-178.
• 3 Garcia-Avello A, Lorente JA, Cesar-Perez J. et al. Degree of hypercoagulability and hyperfibrinolysis is related to organ failure and prognosis after burn trauma. Thromb Res 1998; 89: 59-64.
• 4 Barret JP, Gomez PA. Disseminated intravascular coagulation: a rare entity in burn injury. Burns 2005; 31: 354-357.
• 5 Soejima K, Schmalstieg FC, Sakurai H. et al. Pathophysiological analysis of combined burn and smoke inhalation injuries in sheep. Am J Physiol Lung Cell Mol Physiol 2001; 280: L1233-1241.
• 6 Kowal-Vern A, Gamelli RL, Walenga JM. et al. The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. J Trauma 1992; 33: 50-57.
• 7 Wells S, Sissons M, Hasleton PS. Quantitation of pulmonary megakaryocytes and fibrin thrombi in patients dying from burns. Histopathology 1984; 08: 517-527.
• 8 Murakami K, McGuire R, Cox RA. et al. Recombinant antithrombin attenuates pulmonary inflammation following smoke inhalation and pneumonia in sheep. Crit Care Med 2003; 31: 577-583.
• 9 Kowal-Vern A, Walenga JM, McGill V. et al. The impact of antithrombin (H) concentrate infusions on pulmonary function in the acute phase of thermal injury. Burns 2001; 27: 52-60.
• 10 Kowal-Vern A, Latenser BA. Antithrombin (human) concentrate infusion in pediatric patients with >50% TBSA burns. Burns 2003; 29: 615-618.
• 11 Eisele B, Lamy M. Clinical experience with anti-thrombin III concentrates in critically ill patients with sepsis and multiple organ failure. Semin Thromb Hemost 1998; 24: 71-80.
• 12 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-592.
• 13 Uchiba M, Okajima K, Murakami K. Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats. Thromb Res 1998; 89: 233-241.
• 14 Hoffmann JN, Vollmar B, Romisch J. et al. Antithrombin effects on endotoxin-induced microcirculatory disorders are mediated mainly by its interaction with microvascular endothelium. Crit Care Med 2002; 30: 218-225.
• 15 Pulletz S, Lehmann C, Volk T. et al. Influence of heparin and hirudin on endothelial binding of antithrombin in experimental thrombinemia. Crit Care Med 2000; 28: 2881-2886.
• 16 Roemisch J, Gray E, Hoffmann JN. et al. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13: 657-670.
• 17 Niessen RW, Lamping RJ, Jansen PM. et al. Anti-thrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons. Thromb Haemost 1997; 78: 1088-1092.
• 18 Taylor Jr FB, Toh CH, Hoots WK. et al. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327-1330.
• 19 Smith GW, Gamelli RL, Shankar R. Hematologic, Hematopoetic, and Acute Phase Response. In: Total Burn Care. 3rd edition. W. B. Saunders: Harcourt Publishers Ltd; 2006: 325-342.
• 20 Enkhbaatar P, Traber LD, Traber DL. Antithrombin in burn trauma. In: Yearbook of Intensive Care and Imergency Medicine. Springer: 2007: 791-796.
• 21 Mavrommatis AC, Theodoridis T, Economou M. et al. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 2001; 27: 1853-1859.
• 22 Roman J, Velasco F, Fernandez F. et al. Coagulation, fibrinolytic and kallikrein systems in neonates with uncomplicated sepsis and septic shock. Haemostasis 1993; 23: 142-148.
• 23 Lorente JA, Garcia-Frade LJ, Landin L. et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-1542.
• 24 Kowal-Vern A, Walenga JM, Levi M. et al. Significance of the PAP complex in thermal injury. Clinical Appl Thromb Hemost 1995; 01: 210-214.
• 25 Asakura H, Ontachi Y, Mizutani T. et al. An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation. Crit Care Med 2001; 29: 1164-1168.
• 26 Aoki K, Nishino N, Baba S. et al. Postoperative changes in plasma tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. Surg Today 1994; 24: 1039-1043.
• 27 Watanabe R, Wada H, Watanabe Y. et al. Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. Thromb Res 2001; 104: 1-6.
• 28 Okabayashi K, Wada H, Ohta S. et al. Hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit. Am J Hematol 2004; 76: 225-229.
• 29 Kountchev J, Bijuklic K, Bellmann R. et al. Reduction of D-dimer levels after therapeutic administration of antithrombin in acquired antithrombin deficiency of severe sepsis. Crit Care 2005; 09: R596-600.
• 30 Fourrier F, Leclerc F, Aidan K. et al. Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 2003; 29: 1081-1087.
• 31 Ilias W, List W, Decruyenaere J. et al. Antithrombin III in patients with severe sepsis: a pharmacokinetic study. Intensive Care Med 2000; 26: 704-715.
• 32 Paternoster DM, Fantinato S, Manganelli F. et al. Efficacy of AT in pre-eclampsia: a casecontrol prospective trial. Thromb Haemost 2004; 91: 283-289.
• 33 Nishiyama T. Antithrombin can modulate coagulation, cytokine production, and expression of adhesion molecules in abdominal aortic aneurysm repair surgery. Anesth Analg 2006; 102: 1007-1011.
• 34 Warren BL, Eid A, Singer P. et al. KyberSept Trial Study G Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
• 35 Kienast J, Juers M, Wiedermann CJ. et al. Kyber-Sept investigators. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2006; 04: 90-97.