Sections

Disseminated Intravascular Coagulation (DIC)

Sections Disseminated Intravascular Coagulation (DIC)
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
Media Gallery
Tables
References

DDx

Diagnostic Considerations

The differential diagnosis of disseminated intravascular coagulation (DIC) is broad and can include other causes of consumptive coagulopathies, such as trauma and major surgery. In addition, severe liver disease can result in markedly reduced production of coagulation factors and inhibitors. Thrombocytopenia may also occur in this setting secondary to splenic sequestration, resulting in an overall clinical picture quite similar to DIC.

Thrombotic thrombocytopenic purpura (TTP) – hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy superficially like DIC, but distinctly different; in contrast to DIC, the mechanism of thrombosis is not via the tissue factor (TF)/factor VIIa pathway. Results of blood coagulation assays in TTP-HUS are normal. Rather, in TTP-HUS, thrombosis arises from direct platelet activation, usually as a result of widespread endothelial damage or an inherited or acquired impairment of ADAMTS13, a protease that normally cleaves von Willebrand factor (vWF), which results in an ultralarge vWF (ULVWF) that agglutinates/activates platelets, leading to thrombosis and shearing of red blood cells on the ULVWF.^[51]

TTP-HUS and DIC can usually be distinguished on the basis of their occurrence in different clinical settings (ie, trauma or sepsis for DIC and fever associated with thrombocytopenia and a microangiopathic hemolytic anemia for TTP-HUS). Patients with TTP-HUS do not demonstrate the laboratory abnormalities frequently encountered in DIC (see Workup).^[52]

Other thrombotic microangiopathies include chemotherapy-induced or stem cell transplant–associated microangiopathy and HIV-induced TTP.^[53]

Thrombocytopenia is present in both DIC and immune thrombocytopenia (ITP). However, ITP is distinct from DIC in terms of its pathophysiologic mechanism and does not involve coagulation activation or microangiopathic hemolytic anemia.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is another clinical entity with a presentation similar to that of DIC. A subpopulation of patients who have received heparin develop antibodies against platelet antigens (PF4), and a diminution of platelet number can result. If the antibody is particularly reactive with platelets, its direct activation of platelets leads to thrombosis. In HITTS, although the platelet count is decreased, the plasma prothrombin time (PT), the activated partial thromboplastin time (aPTT), and the fibrinogen levels are normal. Thrombosis is observed, but, typically, HITTS does not produce the consumptive coagulopathy of DIC.

Severe COVID-19 often features a coagulation/fibrolytic abnormality that is marked by an increase in plasma D-dimer levels, and that may progress to DIC. However, the pathophysiology of coagulopathy with COVID-19 is very different from that of septic DIC^[8]; the coagulopathy is more localized and has distinct differences from classical DIC or thrombotic microangiopathy syndromes.^[54]The clinical presentation in COVID-19 coagulopathy is mostly prothrombotic, with venous and even arterial thromboembolism; hemorrhagic complications are uncommon.^[54]

On laboratory testing, the combination of increased D-dimer, thrombocytopenia, and prolonged global coagulation tests in COVID-19 coagulopathy mimics the pattern seen in DIC. However, compared with patients with typical DIC, patients with COVID-19 tend to have a relatively mild thrombocytopenia. Furthermore, in patients with the most severe COVID-19, the prothrombin time is only mildly prolonged; in up to 30% of patients with COVID-19, shortening of PT has been reported.^[55] Most patients with COVID-19 coagulopathy will not meet the International Society on Thrombosis and Haemostasis diagnostic criteria for overt DIC.^[54]

Differential Diagnoses

Dysfibrinogenemia
Hemolytic-Uremic Syndrome
Heparin-Induced Thrombocytopenia
Immune Thrombocytopenia (ITP) in Emergency Medicine
Thrombotic Thrombocytopenic Purpura (TTP)

Workup

Costello RA, Nehring SM. Disseminated Intravascular Coagulation. 2020 Jan. [QxMD MEDLINE Link]. [Full Text].
Vincent JL, De Backer D. Does disseminated intravascular coagulation lead to multiple organ failure?. Crit Care Clin. 2005 Jul. 21(3):469-77. [QxMD MEDLINE Link].
Papageorgiou C, Jourdi G, Adjambri E, Walborn A, Patel P, Fareed J, et al. Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies. Clin Appl Thromb Hemost. 2018 Oct 8. 1076029618806424. [QxMD MEDLINE Link].
[Guideline] 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 Nov. 86(5):1327-30. [QxMD MEDLINE Link].
Matsuda T. Clinical aspects of DIC--disseminated intravascular coagulation. Pol J Pharmacol. 1996 Jan-Feb. 48(1):73-5. [QxMD MEDLINE Link].
Levi M, de Jonge E, van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med. 2004. 36(1):41-9. [QxMD MEDLINE Link].
Iba T, Levi M, Levy JH. Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation. Semin Thromb Hemost. 2020 Feb. 46 (1):89-95. [QxMD MEDLINE Link].
Asakura H, Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol. 2020 Nov 7. [QxMD MEDLINE Link]. [Full Text].
Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet. 1983 Nov 19. 2(8360):1165-8. [QxMD MEDLINE Link].
Yuen P, Cheung A, Lin HJ, Ho F, Mimuro J, Yoshida N, et al. Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics. 1986 May. 77(5):670-6. [QxMD MEDLINE Link].
Asherson RA, Espinosa G, Cervera R, Gómez-Puerta JA, Musuruana J, Bucciarelli S, et al. Disseminated intravascular coagulation in catastrophic antiphospholipid syndrome: clinical and haematological characteristics of 23 patients. Ann Rheum Dis. 2005 Jun. 64(6):943-6. [QxMD MEDLINE Link]. [Full Text].
Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. Expert Rev Hematol. 2018 Aug. 11 (8):663-672. [QxMD MEDLINE Link].
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 Mar. 101(3):816-23. [QxMD MEDLINE Link].
Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost. 2001 Dec. 27(6):585-92. [QxMD MEDLINE Link].
Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med. 1995 Nov. 23(11):1835-42. [QxMD MEDLINE Link].
Jackson Chornenki NL, Dwivedi DJ, Kwong AC, Zamir N, Fox-Robichaud AE, Liaw PC, et al. Identification of hemostatic markers that define the pre-DIC state: A multi-center observational study. J Thromb Haemost. 2020 Oct. 18 (10):2524-2531. [QxMD MEDLINE Link]. [Full Text].
Omidkhoda N, Abedi F, Ghavami V, Rahimi H, Samadi S, Arasteh O, et al. The Effect of Heparin and Its Preparations on Disseminated Intravascular Coagulation Mortality and Hospitalization: A Systematic Review. Int J Clin Pract. 2022. 2022:2226761. [QxMD MEDLINE Link]. [Full Text].
Levi M. Disseminated intravascular coagulation: What's new?. Crit Care Clin. 2005 Jul. 21(3):449-67. [QxMD MEDLINE Link].
Franchini M, Lippi G, Manzato F. Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation. Thromb J. 2006 Feb 21. 4:4. [QxMD MEDLINE Link]. [Full Text].
Levi M. Pathogenesis and diagnosis of disseminated intravascular coagulation. Int J Lab Hematol. 2018 May. 40 Suppl 1:15-20. [QxMD MEDLINE Link].
Levi M. The coagulant response in sepsis. Clin Chest Med. 2008 Dec. 29(4):627-42, viii. [QxMD MEDLINE Link].
Leblebisatan G, Sasmaz I, Antmen B, Yildizdas D, Kilinc Y. Management of life-threatening hemorrhages and unsafe interventions in nonhemophiliac children by recombinant factor VIIa. Clin Appl Thromb Hemost. 2010 Feb. 16(1):77-82. [QxMD MEDLINE Link].
Maczewski M, Duda M, Pawlak W, Beresewicz A. Endothelial protection from reperfusion injury by ischemic preconditioning and diazoxide involves a SOD-like anti-O2- mechanism. J Physiol Pharmacol. 2004 Sep. 55(3):537-50. [QxMD MEDLINE Link].
Levi M. Keep in contact: the role of the contact system in infection and sepsis. Crit Care Med. 2000 Nov. 28(11):3765-6. [QxMD MEDLINE Link].
Sower LE, Froelich CJ, Carney DH, Fenton JW 2nd, Klimpel GR. Thrombin induces IL-6 production in fibroblasts and epithelial cells. Evidence for the involvement of the seven-transmembrane domain (STD) receptor for alpha-thrombin. J Immunol. 1995 Jul 15. 155(2):895-901. [QxMD MEDLINE Link].
Taylor FB Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock. 1991 Mar. 33(3):127-34. [QxMD MEDLINE Link].
Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Büller HR, et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest. 1994 Jan. 93(1):114-20. [QxMD MEDLINE Link]. [Full Text].
Carey MJ, Rodgers GM. Disseminated intravascular coagulation: clinical and laboratory aspects. Am J Hematol. 1998 Sep. 59(1):65-73. [QxMD MEDLINE Link].
Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood. 1996 Aug 1. 88(3):881-6. [QxMD MEDLINE Link].
Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1. 163(3):740-5. [QxMD MEDLINE Link]. [Full Text].
Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze GJ Jr. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood. 1991 Jul 15. 78(2):387-93. [QxMD MEDLINE Link].
Biemond BJ, Levi M, Ten Cate H, Van der Poll T, Büller HR, Hack CE, et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond). 1995 May. 88(5):587-94. [QxMD MEDLINE Link].
van Hinsbergh VW, Kooistra T, van den Berg EA, Princen HM, Fiers W, Emeis JJ. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood. 1988 Nov. 72(5):1467-73. [QxMD MEDLINE Link].
Mesters RM, Flörke N, Ostermann H, Kienast J. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost. 1996 Jun. 75(6):902-7. [QxMD MEDLINE Link].
Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Kumabashiri I, 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 Jun. 29(6):1164-8. [QxMD MEDLINE Link].
Levi M. Disseminated intravascular coagulation in cancer patients. Best Pract Res Clin Haematol. 2009 Mar. 22(1):129-36. [QxMD MEDLINE Link].
Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004 Jun 8. 109(22):2698-704. [QxMD MEDLINE Link].
Altieri DC. Molecular cloning of effector cell protease receptor-1, a novel cell surface receptor for the protease factor Xa. J Biol Chem. 1994 Feb 4. 269(5):3139-42. [QxMD MEDLINE Link].
Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A. 2000 May 9. 97(10):5255-60. [QxMD MEDLINE Link]. [Full Text].
Erez O, Mastrolia SA, Thachil J. Disseminated intravascular coagulation in pregnancy: insights in pathophysiology, diagnosis and management. Am J Obstet Gynecol. 2015 Oct. 213 (4):452-463. [QxMD MEDLINE Link].
Menakuru SR, Priscu A, Salih A, Dhillon V. Disseminated Intravascular Coagulation Due to Drinking Tonic Water. Cureus. 2021 Dec. 13 (12):e20512. [QxMD MEDLINE Link]. [Full Text].
[Guideline] 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 Apr. 145(1):24-33. [QxMD MEDLINE Link]. [Full Text].
Sohn CH, Kim SR, Kim YJ, Seo DW, Ahn S, Lee YS, et al. Disseminated Intravascular Coagulation in Emergency Department Patients With Primary Postpartum Hemorrhage. Shock. 2017 Sep. 48 (3):329-332. [QxMD MEDLINE Link].
Umemura Y, Yamakawa K, Kiguchi T, Yoshikawa Y, Ogura H, et al. Design and Evaluation of New Unified Criteria for Disseminated Intravascular Coagulation Based on the Japanese Association for Acute Medicine Criteria. Clin Appl Thromb Hemost. 2015 Jun 13. [QxMD MEDLINE Link].
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009 Nov. 124(5):608-13. [QxMD MEDLINE Link].
Sivula M, Pettilä V, Niemi TT, Varpula M, Kuitunen AH. Thromboelastometry in patients with severe sepsis and disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 2009 Sep. 20(6):419-26. [QxMD MEDLINE Link].
Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma. Thromb Res. 2009 Dec. 124(6):706-10. [QxMD MEDLINE Link].
Zhu YJ, Huang XK. Relationship between disseminated intravascular coagulation and levels of plasma thrombinogen segment 1+2, D-dimer, and thrombomodulin in patients with multiple injuries. Chin J Traumatol. 2009 Aug. 12(4):203-9. [QxMD MEDLINE Link].
Duchesne JC, Islam TM, Stuke L, Timmer JR, Barbeau JM, Marr AB, et al. Hemostatic resuscitation during surgery improves survival in patients with traumatic-induced coagulopathy. J Trauma. 2009 Jul. 67(1):33-7; discussion 37-9. [QxMD MEDLINE Link].
Siegal T, Seligsohn U, Aghai E, Modan M. Clinical and laboratory aspects of disseminated intravascular coagulation (DIC): a study of 118 cases. Thromb Haemost. 1978 Feb 28. 39(1):122-34. [QxMD MEDLINE Link].
Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, et al. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J. 2018. 16:14. [QxMD MEDLINE Link]. [Full Text].
Wada H, Mori Y, Shimura M, Hiyoyama K, Ioka M, Nakasaki T, et al. Poor outcome in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with severe vascular endothelial cell injuries. Am J Hematol. 1998 Jul. 58(3):189-94. [QxMD MEDLINE Link].
Takashima A, Shirao K, Hirashima Y, Takahari D, Okita NT, Nakajima TE, et al. Sequential chemotherapy with methotrexate and 5-fluorouracil for chemotherapy-naive advanced gastric cancer with disseminated intravascular coagulation at initial diagnosis. J Cancer Res Clin Oncol. 2010 Feb. 136(2):243-8. [QxMD MEDLINE Link].
Levi M. COVID-19 coagulopathy vs disseminated intravascular coagulation. Blood Adv. 2020 Jun 23. 4 (12):2850. [QxMD MEDLINE Link].
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15. 395 (10223):507-513. [QxMD MEDLINE Link]. [Full Text].
Bick RL. Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemost. 1996. 22(1):69-88. [QxMD MEDLINE Link].
Horan JT, Francis CW. Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation. Semin Thromb Hemost. 2001 Dec. 27(6):657-66. [QxMD MEDLINE Link].
Leung L. Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults. UpToDate [serial online]. Available at . Available at http://www.utdol.com.
Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haemost. 1980 Feb 29. 43(1):28-33. [QxMD MEDLINE Link].
Olson JD, Kaufman HH, Moake J, O'Gorman TW, Hoots K, Wagner K, et al. The incidence and significance of hemostatic abnormalities in patients with head injuries. Neurosurgery. 1989 Jun. 24(6):825-32. [QxMD MEDLINE Link].
Conway EM, Rosenberg RD. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol. 1988 Dec. 8(12):5588-92. [QxMD MEDLINE Link]. [Full Text].
Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001 Aug 9. 345(6):408-16. [QxMD MEDLINE Link].
Downey C, Kazmi R, Toh CH. Novel and diagnostically applicable information from optical waveform analysis of blood coagulation in disseminated intravascular coagulation. Br J Haematol. 1997 Jul. 98(1):68-73. [QxMD MEDLINE Link].
Dempfle CE. The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost. 1999 Aug. 82(2):673-83. [QxMD MEDLINE Link].
Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost. 1999 Aug. 82(2):695-705. [QxMD MEDLINE Link].
Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravascular coagulation. Role of D-dimer. Am J Clin Pathol. 1989 Mar. 91(3):280-7. [QxMD MEDLINE Link].
Levi M, Meijers JC. DIC: which laboratory tests are most useful. Blood Rev. 2011 Jan. 25(1):33-7. [QxMD MEDLINE Link].
Lin SM, Wang YM, Lin HC, Lee KY, Huang CD, Liu CY, et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med. 2008 Mar. 36(3):683-9. [QxMD MEDLINE Link].
Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med. 2004 Dec. 32(12):2416-21. [QxMD MEDLINE Link].
Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med. 2008 Jan. 36(1):145-50. [QxMD MEDLINE Link].
[Guideline] Wada H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2017. 15:17. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014. 2 (1):15. [QxMD MEDLINE Link]. [Full Text].
Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018 Feb 22. 131 (8):845-854. [QxMD MEDLINE Link].
Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3. 376(9734):23-32. [QxMD MEDLINE Link].
Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011. 15(2):R117. [QxMD MEDLINE Link].
[Guideline] 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 May. 129 (5):e177-84. [QxMD MEDLINE Link].
Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006. 10(4):222. [QxMD MEDLINE Link]. [Full Text].
Alving B, Spivak J, Deloughery T. Consultative hematology: Hemostasis and transfusion issues in surgery and critical care medicine. Hematology. 1998. 320-42.
[Guideline] 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 Jan. 125(1):6-11. [QxMD MEDLINE Link].
Pernerstorfer T, Jilma B, Eichler HG, Aull S, Handler S, Speiser W. Heparin lowers plasma levels of activated factor VII. Br J Haematol. 1999 Jun. 105(4):1127-9. [QxMD MEDLINE Link].
Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood. 1982 Aug. 60(2):284-7. [QxMD MEDLINE Link].
Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)--a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res. 1993 Dec 15. 72(6):475-500. [QxMD MEDLINE Link].
Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, et al. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999 Dec 21-28. 100(25):2485-90. [QxMD MEDLINE Link].
Majumdar G. Idiopathic chronic DIC controlled with low-molecular-weight heparin. Blood Coagul Fibrinolysis. 1996 Jan. 7(1):97-8. [QxMD MEDLINE Link].
Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007 Sep 1. 176(5):483-90. [QxMD MEDLINE Link].
Baudo F, Caimi TM, de Cataldo F, Ravizza A, Arlati S, Casella G, et al. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Intensive Care Med. 1998 Apr. 24(4):336-42. [QxMD MEDLINE Link].
Fourrier F, Jourdain M, Tournoys A. Clinical trial results with antithrombin III in sepsis. Crit Care Med. 2000 Sep. 28(9 Suppl):S38-43. [QxMD MEDLINE Link].
Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med. 1998 Jul. 24(7):663-72. [QxMD MEDLINE Link].
Sawamura A, Gando S, Hayakawa M, Hoshino H, Kubota N, Sugano M. Effects of antithrombin III in patients with disseminated intravascular coagulation diagnosed by newly developed diagnostic criteria for critical illness. Clin Appl Thromb Hemost. 2009 Oct. 15(5):561-6. [QxMD MEDLINE Link].
Hayakawa M, Kudo D, Saito S, et al. Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study. Shock. 2016 Aug 19. [QxMD MEDLINE Link].
Endo S, Shimazaki R, Antithrombin Gamma Study Group. An open-label, randomized, phase 3 study of the efficacy and safety of antithrombin gamma in patients with sepsis-induced disseminated intravascular coagulation syndrome. J Intensive Care. 2018. 6:75. [QxMD MEDLINE Link]. [Full Text].
Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med. 2000 Sep. 28(9 Suppl):S31-3. [QxMD MEDLINE Link].
Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003 Jul 9. 290(2):238-47. [QxMD MEDLINE Link].
Yamakawa K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care. 2011. 15(3):R123. [QxMD MEDLINE Link]. [Full Text].
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 Jan. 5(1):31-41. [QxMD MEDLINE Link].
Zhang C, Wang H, Yang H, Tong Z. Recombinant human soluble thrombomodulin and short-term mortality of infection patients with DIC: a meta-analysis. Am J Emerg Med. 2016 Sep. 34 (9):1876-82. [QxMD MEDLINE Link].
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 Apr. 13 (4):508-19. [QxMD MEDLINE Link]. [Full Text].
Inoue Y, Matsunawa M, Sano F, Miura I. Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation. Acta Haematol. 2018 Sep 18. 140 (2):121-127. [QxMD MEDLINE Link].

Media Gallery

Diagnostic algorithm for the diagnosis of overt disseminated intravascular coagulation.
Coagulation pathway.

of 2

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation

Type	Cause
Infectious	Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial) Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus) Fungal (eg, Histoplasma) Parasitic (eg, malaria)
Malignancy	Hematologic (eg, acute myelocytic leukemia) Metastatic (eg, mucin-secreting adenocarcinoma)
Obstetric	Amniotic fluid embolism Abruptio placentae Acute peripartum hemorrhage Preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome Retained stillbirth Septic abortion and intrauterine infection Acute fatty liver of pregnancy^[40]
Trauma	Burns Motor vehicle accidents Snake envenomation
Transfusion	Hemolytic reactions Transfusion
Other	Liver disease/acute hepatic failure* Prosthetic devices Shunts (Denver or LeVeen) Ventricular assist devices
*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.

Table 2. Causes of Chronic Disseminated Intravascular Coagulation

Type	Cause
Malignancies	Solid tumors Leukemia
Obstetric	Retained dead fetus syndrome Retained products of conception
Hematologic	Myeloproliferative syndromes
Vascular	Rheumatoid arthritis Raynaud disease
Cardiovascular	Myocardial infarction
Inflammatory	Ulcerative colitis Crohn disease Sarcoidosis
Localized DIC	Aortic aneurysms Giant hemangioma (Kasabach-Merritt syndrome) Acute renal allograft rejection

Table 3. Main Features of Disseminated Intravascular Coagulation in Series of 118 Patients

Features	Affected Patients, %
Bleeding	64%
Renal dysfunction	25%
Hepatic dysfunction	19%
Respiratory dysfunction	16%
Shock	14%
Central nervous system dysfunction	2%

Table 4. Japanese Association for Acute Medicine (JAAM) Scoring System for DIC

Clinical conditions that should be ruled out
Thrombocytopenia Dilution and abnormal distribution Massive blood loss, massive infusion ITP, TTP-HUS, HIT, HELLP syndrome Disorders of hematopoiesis Liver disease Hypothermia Spurious laboratory results
Diagnostic algorithm for SIRS
Temperature >38°C or < 36°C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO₂< 32 mm Hg (< 4.3 kPa) WBC count >12,000 cells/µL, < 4000 cells/ µL, or 10% immature (band) forms
Diagnostic algorithm SIRS criteria	Score
>3	1
0-2	0
Platelet count (× 10⁹/L)
< 80 or >50 % decrease within 24 hours	3
>80 and < 120 or >30% decrease within 24 hours	1
>120	0
Prothrombin time (value of patient/normal value)
>1.2	1
< 1.2	0
Fibrin/FDPs (mg/L)
>25	3
>10 and < 25	1
< 10	0
Diagnosis 4 points or more	DIC
DIC = disseminated intravascular coagulation; FDP = fibrin degradation product; HELLP = hemolysis, elevated liver enzymes, low platelet count; HIT = heparin-induced thrombocytopenia; HUS = hemolytic uremic syndrome; ITP = idiopathic thrombocytopenic purpura; PaCO₂ = partial pressure of carbon dioxide in arterial blood; SIRS = systemic inflammatory response syndrome; TTP = thrombotic thrombocytopenic purpura; WBC = white blood cell.

Table 5. Japanese Society on Thrombosis and Hemostasis (JSTH) Diagnostic Criteria for DIC

Test Results		Points
Platelet count (×10³/μl)*	80-120	1
	51-80	2
	≤50	3
Fibrin degradation products (FDP; μg/ml)**	10-19	1
	20-39	2
	≥40	3
Fibrinogen (mg/dl)	101-150	1
Fibrinogen (mg/dl)	≤100	2
Prothrombin time ratio	1.25-1.66	1
Prothrombin time ratio	≥1.67	2
Antithrombin (%)	≤70	1
TAT, SF, or F₁₊₂	≥2-fold upper limit of normal	1
Liver failure	Acute: Prothrombin time activity 40% or International Normalized Ratio ≥1.5) Chronic: Cirrhosis with Child-Pugh B or C (≥7 points)	-3
F₁₊₂= prothrombin fragment 1 + 2; SF=soluble fibrin; TAT=thrombin-antithrombin complex For a platelet count of >50 × 10³/μL, add 1 point if the count decreases ≥30% within 24 h. The maximum score for the platelet count is 3 points. *For institutions that do not measure FDP, a D-dimer increase of ≥2-fold the upper limit of normal scores 1 point.

Back to List

Author

Marcel M Levi, MD Dean, Academic Medical Center, University of Amsterdam, The Netherlands

Marcel M Levi, MD is a member of the following medical societies: American Society of Hematology, International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Coauthor(s)

Alvin H Schmaier, MD Robert W Kellermeyer Professor of Hematology/Oncology, Case Western Reserve University School of Medicine; Chief, Division of Hematology/Oncology, University Hospitals Case Medical Center

Alvin H Schmaier, MD is a member of the following medical societies: American Federation for Medical Research, American Heart Association, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Central Society for Clinical and Translational Research, International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Acknowledgements

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Joseph U Becker, MD Fellow, Global Health and International Emergency Medicine, Stanford University School of Medicine

Joseph U Becker, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Steven A Conrad, MD, PhD Chief, Department of Emergency Medicine; Chief, Multidisciplinary Critical Care Service, Professor, Department of Emergency and Internal Medicine, Louisiana State University Health Sciences Center

Steven A Conrad, MD, PhD is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American College of Emergency Physicians, American College of Physicians, International Society for Heart and Lung Transplantation, Louisiana State Medical Society, Shock Society, Society for Academic Emergency Medicine, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital

Disclosure: Nothing to disclose.

Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Avishek Kumar, MD Resident Physician, Department of Internal Medicine, St Michael's Medical Center, Seton Hall University School of Health and Medical Sciences

Avishek Kumar, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Hamid Salim Shaaban MD, Fellow in Hematology/ Oncology, Department of Internal Medicine, Seton Hall University School of Health and Medical Sciences

Hamid Salim Shaaban is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Charles R Wira, MD Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine

Charles R Wira, MD is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.