Abstract
In sepsis, the coagulation system is often systemically activated in combination with the simultaneous impairment of fibrinolysis and anticoagulant systems. Since this hypercoagulable state often leads to disseminated intravascular coagulation (DIC), an independent predictor of mortality in critically ill patients, the appropriate management of DIC itself is a crucial part of treatment strategies for severe sepsis. In this context, the Japanese Association of Acute Medicine (JAAM) scoring system for DIC has been proposed as a valid test for diagnosing DIC; this system is also expected to aid in devising specifically tailored management strategies. Anticoagulant therapy is commonly given to septic patients with DIC as part of the standard care in Japan. More recently, antithrombin concentrate and recombinant thrombomodulin have become the two major anticoagulant agents of choice. In relation to the use of antithrombin, recent studies have indicated that the recovery of antithrombin activity to within the normal range (>70 %) is necessary if supplementation therapy is to provide a favorable outcome. Recombinant thrombomodulin is slightly more controversial, with favorable results being greater among severe cases of DIC. In the present review, we summarize recent clinical advances in anticoagulant therapy for sepsis-associated DIC.
Similar content being viewed by others
References
Morrissey JH. Tissue factor: a key molecule in hemostatic and nonhemostatic systems. Int J Hematol. 2004;79:103–8.
Madoiwa S, Nunomiya S, Ono T, Shintani Y, Ohmori T, Mimuro J, et al. Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation. Int J Hematol. 2006;84:398–405.
Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13:34–45.
van der Poll T, Herwald H. The coagulation system and its function in early immune defense. Thromb Haemost. 2014;112:640–8.
Levi M, van der Poll T. A short contemporary history of disseminated intravascular coagulation. Semin Thromb Hemost. 2014;40:874–80.
Ogura H, Gando S, Saitoh D, Takeyama N, Kushimoto S, Fujishima S, et al. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J Infect Chemother. 2014;20:157–62.
Fujishima S, Gando S, Saitoh D, Mayumi T, Kushimoto S, Shiraishi S, et al. A multicenter, prospective evaluation of quality of care and mortality in Japan based on the Surviving Sepsis Campaign guidelines. J Infect Chemother. 2014;20:115–20.
Iba T, Gando S, Thachil J. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost. 2014;12:1010–9.
Di Nisio M, Baudo F, Cosmi B, D’Angelo A, De Gasperi A, Malato A, et al. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2012;129:e177–84.
Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol. 1983;49:265–75.
Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–30.
Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31.
Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;2:20.
Levi M. Another step in improving the diagnosis of disseminated intravascular coagulation in sepsis. Crit Care. 2013;17:448.
Gando S, Saitoh D, Ogura H, Fujishima S, Mayumi T, Araki T, et al. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care. 2013;17:R111.
Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586–92.
Oda S, Aibiki M, Ikeda T, Imaizumi H, Endo S, Ochiai R, Kotani J, et al. The Japanese guidelines for the management of sepsis. Sepsis Registry Committee of the Japanese Society of Intensive Care Medicine. J Intensive Care. 2014;2:55.
Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.
Murata A, Okamoto K, Mayumi T, Muramatsu K, Matsuda S. Recent change in treatment of disseminated intravascular coagulation in japan: an epidemiological study based on a national administrative database. Clin Appl Thromb Hemost. 2015. (pii:1076029615575072).
Gando S, Saitoh D, Ishikura H, Ueyama M, Otomo Y, Oda S, et al. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care. 2013;17:R297.
Iba T, Nagaoka I, Boulat M. The anticoagulant therapy for sepsis-associated disseminated intravascular coagulation. Thromb Res. 2013;131:383–9.
Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al. The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11:761–7.
Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125:6–11.
Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145:24–33.
Murata A, Okamoto K, Mayumi T, Muramatsu K, Matsuda S. The recent time trend of outcomes of disseminated intravascular coagulation in Japan: an observational study based on a national administrative database. J Thromb Thrombolysis. 2014;38:364–71.
Wada H, Okamoto K, Iba T, Kushimoto S, Kawasugi K, Gando S, et al. Addition of recommendations for the use of recombinant human thrombomodulin to the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan”. Thromb Res. 2014;134:924–5.
Singh B, Hanson AC, Alhurani R, Wang S, Herasevich V, Cartin-Ceba R, et al. Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004–2010): a population-based study. Chest. 2013;143:1235–42.
Liumbruno GM, Franchini M, Lanzoni M, Candura F, Vaglio S, Profili S, et al. Clinical use and the Italian demand for antithrombin. Blood Transfus. 2013;11(Suppl 4):86–93.
Afshari A, Wetterslev J, Brok J, Møller AM. Antithrombin III for critically ill patients. Cochrane Database Syst Rev. 2008;3:CD005370.
Iba T, Saitoh D. Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2014;2:66.
Iba T, Kidokoro A. High-dose antithrombin therapy for sepsis. J Trauma. 2000;49:979–80.
Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost. 2014;12:1470–9.
Tagami T, Matsui H, Fushimi K, Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis. Thromb Haemost. 2015;114:537–45.
Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis. 2002;13:657–70.
Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest. 1992;101:816–23.
Lauterbach R, Pawlik D, Radziszewska R, Wozniak J, Rytlewski K. Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newborns. Eur J Pediatr. 2006;165:585–9.
Aibiki M, Fukuoka N, Umakoshi K, Ohtsubo S, Kikuchi S. Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation. Shock. 2007;27:139–44.
Chappell D, Brettner F, Doerfler N, Jacob M, Rehm M, Bruegger D, et al. Protection of glycocalyx decreases platelet adhesion after ischaemia/reperfusion: an animal study. Eur J Anaesthesiol. 2014;31:474–81.
Mehta D, Ravindran K, Kuebler WM. Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol. 2014;307:L924–35.
Chappell D, Jacob M, Hofmann-Kiefer K, Rehm M, Welsch U, Conzen P, et al. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res. 2009;83:388–96.
Iba T, Saito S, Wada H, Asakura H. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a prospective multicenter survey. Thromb Res. 2012;130:e129–33.
Iba T, Saitoh D, Wada H, Asakura H. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a secondary survey. Crit Care. 2014;18:497.
Iba T, Saitoh D, Gando S, Thachi J. The usefulness of antithrombin activity monitoring during antithrombin supplementation in patients with sepsis-associated disseminated intravascular coagulation. Thromb Res. 2015;135:897–901.
Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78.
Iba T, Kidokoro A. High-dose antithrombin therapy for sepsis: mechanisms of action. Shock. 2002;18:389–94.
Hoppensteadt D, Tsuruta K, Cunanan J, Hirman J, Kaul I, Osawa Y, et al. Thrombin generation mediators and markers in sepsis-associated coagulopathy and their modulation by recombinant thrombomodulin. Clin Appl Thromb Hemost. 2014;20:129–35.
Ikezoe T. Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. J Intensive Care. 2015;3:1.
Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 2012;95:333–45.
Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem. 1982;257:7944–7.
Schuepbach RA, Madon J, Ender M, Galli P, Riewald M. Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects. J Thromb Haemost. 2012;10:1675–84.
Herzog C, Lorenz A, Gillmann HJ, Chowdhury A, Larmann J, Harendza T, et al. Thrombomodulin’s lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling. Cardiovasc Res. 2014;101:400–10.
Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost. 2015;13:31–40.
Tagami T, Matsui H, Fushimi K, Yasunaga H. Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation. Font Med. 2015;2:1–7.
Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost. 2015;13:508–19.
Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41:2069–79.
Yoshimura J, Yamakawa K, Ogura H, Umemura Y, Takahashi H, Morikawa M, et al. Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Crit Care. 2015;19:810.
Iba T. The obstacles that should be overcome to develop new anticoagulants for severe sepsis. Crit Care Med. 2014;42:e248–9.
Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924–33.
Tagami T, Matsui H, Yasunaga H. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: reply to two papers. J Thromb Haemost. 2015;13:686–8.
Iba T. Antithrombin or thrombomodulin administration in severe pneumonia patients with sepsis and disseminated intravascular coagulation: comment on two papers. J Thromb Haemost. 2015;13:682–3.
Murata A, Okamoto K, Mayumi T, Muramatsu K, Matsuda S. Observational study to compare antithrombin and thrombomodulin for disseminated intravascular coagulation. Int J Clin Pharm. 2015;37:139–47.
Zhang Z, Ni H, Xu X. Do the observational studies using propensity score analysis agree with randomized controlled trials in the area of sepsis? J Crit Care. 2014;886:e9–15.
Acknowledgments
T. Iba is a member of the JSTH/DIC subcommittee and J. Thachil is a chairperson of the ISTH/DIC subcommittee. A part of this review was presented at the 61st Annual Meeting of the Scientific and Standardization Committee/International Society on Thrombosis and Haemostasis
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
About this article
Cite this article
Iba, T., Thachil, J. Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a perspective from Japan. Int J Hematol 103, 253–261 (2016). https://doi.org/10.1007/s12185-015-1904-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-015-1904-z