Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is a disorder characterized by systemic activation of the clotting cascade with microthrombi formation, platelet consumption, and subsequent exhaustion of all clotting factors. Common causes of DIC include sepsis, trauma, and malignancy. Depending on the underlying pathophysiological processes and subtype, patients present with signs of bleeding (e.g., purpura, petechiae, ecchymoses) and/or multiorgan failure. Laboratory studies can be highly variable. However, typical findings in overt decompensated DIC include thrombocytopenia, prolonged PT and aPTT, decreased fibrinogen levels, and elevated D-dimer levels. Treatment involves identification of the underlying cause and supportive therapy with transfusions of blood products (pRBCs, platelet concentrates, FFP, and/or cryoprecipitate) and, in select cases, anticoagulants (e.g., heparin) or antifibrinolytic therapy (tranexamic acid). Close monitoring and specialist consultation (e.g., critical care and hematology) are typically required.

Definition ^[1]

• Disseminated intravascular coagulation (DIC): a syndrome characterized by thrombosis, hemorrhage, and organ dysfunction caused by systemic activation of the clotting cascade, which leads to platelet consumption and exhaustion of clotting factors
  • Latent DIC: no overt symptoms (little to no bleeding, increased risk of thrombotic events, laboratory abnormalities)
  • Overt DIC: clear signs and symptoms (e.g., bleeding, thrombosis) that depend on the balance of the deranged processes
• Consumption coagulopathy: hyperfibrinolysis, causing overt coagulopathy and bleeding, PLUS hypercoagulability, which causes consumption of platelets and clotting factors, resulting in even more blood loss.

Classification ^[2][3]

The 2014 International Society of Thrombosis and Haemostasis (ISTH) harmonized guidelines distinguish between DIC types based on clinical phenotype, characteristic laboratory abnormalities, and treatment targets.

• Infections
  • Viral infection
  • Rickettsial infections
  • Malaria
  • Sepsis (more commonly with gram-negative organisms)
• Trauma
  • Acute traumatic coagulopathy
  • Traumatic brain injury
  • Crush injuries
  • Burns
  • Fat embolism
  • Surgery
  • Rhabdomyolysis
• Obstetric complications
  • Amniotic fluid embolism
  • Preeclampsia
  • HELLP syndrome
  • Abruptio placenta
  • Retained products of conception (e.g., intrauterine death, placenta)
• Organ failure
  • Acute pancreatitis
  • Fulminant hepatitis
  • Liver cirrhosis
  • Acute hepatic necrosis
  • Acute respiratory distress syndrome (ARDS)
• Malignancies
  • Hematological, e.g., acute promyelocytic leukemia (APL), acute myelocytic leukemia
  • Solid tumors, e.g.:
    • Pancreatic
    • Ovarian
    • Gastric
    • Non-small cell lung cancer
• Toxins
  • Snake bites
  • Amphetamine overdose
• Immunologic
  • Acute hemolytic transfusion reaction (AHTR)
  • Transplant reaction (e.g., graft-versus-host disease)
  • Extracorporeal procedures (e.g., dialysis)
• Vascular malformations
  • Aortic aneurysms
  • Vasculitis
• Dilution
  • Massive bleeding
  • Massive transfusion
  • Massive volume repletion/volume overload
• Drug reactions
• Other
  • Nephrotic syndrome
  • New thrombus formation
  • Hemolysis
  • Acidosis

The mnemonic “STOP Making Trouble!” helps to recall the etiology of DIC: S - Sepsis/Snakebites, T - Trauma (acute traumatic coagulopathy), O - Obstetric complications, P - Pancreatitis, M - Malignancy, T - Transfusion.

References:^[1][4][6]

The pathophysiology of DIC is variable and depends on the underlying processes (see “Hemostasis and bleeding disorders” and “Acquired thrombophilia”). ^[3][4]

• Nonsymptomatic type DIC: mild fibrinolysis and/or mild hypercoagulation
• Bleeding type DIC: hyperfibrinolysis (excessive plasmin activity → increased fibrin degradation → thrombi become unstable and dissolve shortly after forming)
• Massive bleeding type DIC: hypercoagulation and hyperfibrinolysis → consumption of platelets and all coagulation factors → bleeding diathesis
• Organ failure type DIC: ↑ cytokines → hypercoagulation with hypofibrinolysis → microthrombi → impaired perfusion and tissue necrosis

DIC is an acquired coagulopathy that is most frequently seen in hospitalized individuals.

Clinical features are variable and depend on the predominant underlying mechanism. ^[7]

• Bleeding
  • Hematemesis, hematochezia
  • Hematuria
  • Oozing of blood from surgical wounds or intravenous lines
  • Petechiae, purpura, ecchymoses
• Massive hemorrhage: collection of blood in body cavities (hemoperitoneum, hemothorax)
• Organ failure: primarily due to hypercoagulation
  • Microangiopathic hemolytic anemia
  • Acute renal failure: oliguria
  • Hepatic dysfunction: jaundice
  • ARDS: dyspnea, rales
  • Pulmonary thromboembolism: dyspnea, chest pain, hemoptysis
  • Deep vein thrombosis: lower limb edema
  • Neurological dysfunction: altered mental status, stroke
  • Purpura fulminans: DIC with extensive skin necrosis
  • Waterhouse Friderichsen syndrome: adrenal infarcts → adrenal insufficiency
  • Signs of shock

The clinical features of DIC may appear acutely (e.g., following trauma, sepsis) or subacutely (e.g., DIC following malignancy).

Laboratory studies ^[3][5][9]

• Coagulation panel: Monitor frequently (e.g., every 6–8 hours or until stable or improving).
  • ↑ aPTT, ↑ PT
  • ↓ Fibrinogen: indicative of associated hyperfibrinolysis
  • Markers of fibrin breakdown: ↑ D-dimer or other FDPs
  • ↑ Bleeding time
  • Coagulation factors: ↓ factor V and ↓ factor VIII
• CBC and blood smear
  • ↓ Platelet count: due to consumption and/or bleeding
  • ↓ Hct: occurs with bleeding
  • Schistocytes: indicative of microangiopathic hemolytic anemia ^[10]
• Other tests of organ function (e.g., renal function tests, liver chemistries): Order depending on clinical picture and underlying conditions.

The diagnosis of DIC is not based on a single marker but on a combination of laboratory findings. Thrombocytopenia, elevated D-dimer, increased PT and aPTT, and low fibrinogen should immediately raise suspicion for DIC. ^[9]

Differential diagnoses by laboratory findings ^[13]

Differential diagnoses by underlying process

• Decreased production of platelets and clotting factors
  • Severe hepatic dysfunction
  • Vitamin K deficiency
  • Bone marrow suppression
  • Hemophilia
• Increased destruction of platelets and clotting factors ^[16]
  • Thrombotic thrombocytopenic purpura
  • Immune thrombocytopenic purpura
  • Heparin-induced thrombocytopenia
  • Acute hemolytic anemia
  • Hemolytic uremic syndrome
• Increased consumption of platelets and clotting factors
  • DVT/pulmonary embolism
  • Surgery
  • Infections
• Increased loss of platelets and clotting factors
  • Massive blood transfusion causing dilutional coagulopathy
  • Capillary leak syndrome

The differential diagnoses listed here are not exhaustive.

General principles ^[3][9]

• First-line: treatment of the underlying disease (see “Etiology”)
• Additional treatment depends on the subtype and is complicated (see “Overview of DIC types”). Involve specialists early.
  • Blood products as needed
  • Anticoagulation: if hypercoagulability is the leading problem (e.g., in organ failure type DIC)
  • Consider advanced treatment options (e.g., antithrombin) in consultation with a specialist.
• Supportive therapy
  • Avoid invasive procedures if possible
  • Vitamin K supplementation if deficiency is suspected ^[1]
• Initiate clinical and serial laboratory monitoring to assess response to treatment.

Treatment of the underlying disease is the cornerstone of management.

Blood products ^{[2][3][5][9][9]}

The decision to transfuse blood products should primarily be based on the presence or risk of bleeding. Laboratory parameters can be used as a treatment goal but should not be considered the sole rationale for transfusion. Involve specialists early.

• pRBCs: indicated for patients with active bleeding or Hb ≤ 7 mg/dL (see “Packed red blood cells” for specific transfusion thresholds and goals)
• Platelets: ^[17]
  • Indications
    • Active bleeding or high risk of bleeding (e.g, planned invasive procedure): platelet count < 50,000/mm³
    • No bleeding: platelet count < 10,000–20,000/mm³
  • Goals
    • Active bleeding or at high risk of bleeding: platelet count > 20–50,000/mm³.
    • If receiving massive transfusion: platelet count > 50,000/mm³.
• Fresh frozen plasma (FFP) ^[10][18]
  • Indications
    • PT or aPTT > 1.5 times the normal value if patient is bleeding or will undergo an invasive procedure
    • Consider if bleeding and fibrinogen < 150 mg/dL
    • As part of a massive transfusion protocol
  • Goals
    • PT < 3 seconds prolonged
    • Fibrinogen > 100–150 mg/dL
• Cryoprecipitate ^[19]
  • Indication: bleeding and fibrinogen levels < 150 mg/dL despite FFP or when FFP transfusion is not possible ^[2]
  • Goal: fibrinogen level of > 100–150 mg/dL
• Prothrombin complex concentrate (PCC) ^[2][10][18]
  • Individual decision in patients with active bleeding when FFP transfusion is not possible (e.g., due to volume overload)
  • Cautions ^[8]
    • May only partially correct coagulopathy
    • Can tip the procoagulant-anticoagulant balance towards thrombosis.
    • Monitoring of antithrombin activity and protein C levels is recommended.

Antifibrinolytic therapy ^[2][3]

• Tranexamic acid: : not routinely recommended ^[9]
  • Indication: Consider in patients with severe bleeding and hyperfibrinolysis (especially after trauma). ^[2]
  • Contraindications ^[3]
    • Not recommended in patients with nonsymptomatic type DIC or organ failure type DIC
    • Avoid in patients with APL undergoing ATRA treatment.
  • If indicated, administer early.

Aminocaproic acid is generally contraindicated in DIC.

Anticoagulation ^{[2][3][9][11][20]}

• Prophylactic heparin: indicated as DVT prophylaxis in critically ill patients in the absence of bleeding ^[21]
  • LMWH (e.g., enoxaparin )
  • UFH
• Therapeutic heparin: indicated for clinically overt thromboembolic events
  • LMWH (e.g., enoxaparin) : sometimes preferred over UFH ^[2]
  • UFH : Consider in patients with high bleeding risk due to its short half-life and reversibility.
• Other coagulation inhibitors: Consider in individual cases in consultation with a specialist. ^[2][3]
  • Antithrombin (AT): Not routinely recommended due to a lack of supporting evidence.
  • Plasma-derived activated protein C (APC)
  • Recombinant human thrombomodulin (rhTM) ^[2][8]
  • Synthetic inhibitors of serine proteases ^[20]

Patients receiving anticoagulants require careful monitoring of bleeding events and dosage adjustment for BMI and kidney function.

Warfarin is ineffective and possibly harmful in DIC, as it inhibits production of protein C and protein S, which can worsen coagulopathy. ^[22][23]

Fibrinolytic therapy (e.g., tPA) should be avoided in all types of DIC. ^[1][3]

All patients ^[2][3]

• Consider DIC in patients with an associated underlying condition and clinical deterioration.
• Order CBC and serial coagulation tests (including PT, aPTT, fibrinogen, D-dimer and other FDPs).
• Consider calculating the ISTH DIC score to support the diagnosis.
• Rule out differential diagnoses.
• Consult hematology and intensive care as needed.
• Consider ordering specialized tests according to DIC type.
• Identify and treat the underlying cause.
• Monitor coagulation parameters frequently.
• Avoid invasive procedures if possible.
• Supplement vitamin K if there is a suspected deficiency.

Bleeding type DIC or massive bleeding type DIC

• Transfusion of blood products as needed (e.g., pRBCs, FFP, platelets, cryoprecipitate)
• Consider massive transfusion.
• Consider tranexamic acid.

Nonsymptomatic type DIC and organ failure type DIC

• Transfusion of blood products as needed (e.g., FFP, platelets)
• VTE prophylaxis unless contraindicated
• Provide therapeutic anticoagulation for thromboembolic events.

1. Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014; 2 (1): p.20. doi: 10.1186/2052-0492-2-20 . | Open in Read by QxMD
2. Asakura H, et al. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2016; 14 (1). doi: 10.1186/s12959-016-0117-x . | Open in Read by QxMD
3. Papageorgiou C, et al. Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies. Clinical and Applied Thrombosis/Hemostasis. 2018; 24 (9_suppl): p.8S-28S. doi: 10.1177/1076029618806424 . | Open in Read by QxMD
4. 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): p.15. doi: 10.1186/2052-0492-2-15 . | Open in Read by QxMD
5. Levi M, et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology.. Br J Haematol. 2009; 145 (1): p.24-33. doi: 10.1111/j.1365-2141.2009.07600.x . | Open in Read by QxMD
6. Wada H, et al. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines. Journal of Thrombosis and Haemostasis. 2013; 11 (4): p.761-767. doi: 10.1111/jth.12155 . | Open in Read by QxMD
7. Thachil J. Disseminated Intravascular Coagulation. Anesthesiology. 2016; 125 (1): p.230-236. doi: 10.1097/aln.0000000000001123 . | Open in Read by QxMD
8. Salyer SW. Hematologic Emergencies. Elsevier ; 2007 : p. 555-574
9. Levi M, Scully M. How I treat disseminated intravascular coagulation. Blood. 2018; 131 (8): p.845-854. doi: 10.1182/blood-2017-10-804096 . | Open in Read by QxMD
10. Szczepiorkowski ZM, Dunbar NM. Transfusion guidelines: when to transfuse. Hematology Am Soc Hematol Educ Program. 2013; 2013 (1): p.638-644. doi: 10.1182/asheducation-2013.1.638 . | Open in Read by QxMD
11. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth. 2014; 113 (6): p.922-934. doi: 10.1093/bja/aeu158 . | Open in Read by QxMD
12. Gando S, Levi M, Toh C-H. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016; 2 (1). doi: 10.1038/nrdp.2016.37 . | Open in Read by QxMD
13. Di Nisio M, et al. Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2012; 129 (5): p.e177-e184. doi: 10.1016/j.thromres.2011.08.028 . | Open in Read by QxMD
14. Wada H, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010; 125 (1). doi: 10.1016/j.thromres.2009.08.017 . | Open in Read by QxMD
15. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in Nonsurgical Patients. Chest. 2012; 141 (2): p.e195S-e226S. doi: 10.1378/chest.11-2296 . | Open in Read by QxMD
16. Koba S, Yamaguchi T, Miki K, Makihara H, Imashuku S. Management of Chronic Disseminated Intravascular Coagulation Associated with Aortic Aneurysm/Dissection. Case Rep Hematol. 2019; 2019 : p.1-6. doi: 10.1155/2019/6204652 . | Open in Read by QxMD
17. Rubin RN, Colman RW. Disseminated Intravascular Coagulation. Drugs. 1992; 44 (6): p.963-971. doi: 10.2165/00003495-199244060-00005 . | Open in Read by QxMD
18. Müller MC, Meijers JC, Vroom MB, et al. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review. Crit Care. 2014; 18 (1): p.R30. doi: 10.1186/cc13721 . | Open in Read by QxMD
19. Müller MCA, Meijers JC, van Meenen DM, Thachil J, et al. Thromboelastometry in critically ill patients with disseminated intravascular coagulation.. Blood Coagul Fibrinolysis. 2019; 30 (5): p.181-187. doi: 10.1097/MBC.0000000000000808 . | Open in Read by QxMD
20. Whiting P, Al M, Westwood M, et al. Viscoelastic point-of-care testing to assist with the diagnosis, management and monitoring of haemostasis: a systematic review and cost-effectiveness analysis. Health Technol Assess (Rockv). 2015; 19 (58): p.1-228. doi: 10.3310/hta19580 . | Open in Read by QxMD
21. Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta-analysis and trial sequential analysis. Anaesthesia. 2017; 72 (4): p.519-531. doi: 10.1111/anae.13765 . | Open in Read by QxMD
22. Fahrendorff M, Oliveri RS, Johansson PI. The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products – A systematic review and meta-analysis. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2017; 25 (1). doi: 10.1186/s13049-017-0378-9 . | Open in Read by QxMD
23. Whiting D, DiNardo JA. TEG and ROTEM: Technology and clinical applications. Am J Hematol. 2014; 89 (2): p.228-232. doi: 10.1002/ajh.23599 . | Open in Read by QxMD
24. Taylor FB Jr, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation.. Thromb Haemost. 2001; 86 (5): p.1327-30. doi: 10.1055/s-0037-1616068 . | Open in Read by QxMD
25. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
26. Boral BM, Williams DJ, Boral LI. Disseminated Intravascular Coagulation. Am J Clin Pathol. 2016; 146 (6): p.670-680. doi: 10.1093/ajcp/aqw195 . | Open in Read by QxMD
27. Hunt BJ. Bleeding and Coagulopathies in Critical Care. N Engl J Med. 2014; 370 (9): p.847-859. doi: 10.1056/nejmra1208626 . | Open in Read by QxMD
28. Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. Expert Rev. Hematol. 2018; 11 (8): p.663-672. doi: 10.1080/17474086.2018.1500173 . | Open in Read by QxMD
29. Wada H, et al. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J. 2018; 16 (1). doi: 10.1186/s12959-018-0168-2 . | Open in Read by QxMD
30. Shah PB. Intention-to-treat and per-protocol analysis. Can Med Assoc J. 2011; 183 (6): p.696-696. doi: 10.1503/cmaj.111-2033 . | Open in Read by QxMD