Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is a disorder characterized by systemic activation of the extrinsic 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.

Disseminated intravascular coagulation (DIC)

• Definition: 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

According to disease onset ^[1]

• Acute DIC
  • Excess thrombin generation leading to the formation of microthrombi and, eventually, microangiopathic hemolytic anemia (MAHA)
  • Rapid consumption of coagulation factors and platelets
  • Common causes include septic shock, acute pancreatitis, burns, snake bites, transplant rejection
  • Often starts as a hypercoagulable state (organ failure type DIC)
• Chronic DIC
  • Small thrombin generation over prolonged periods of time
  • Slower consumption of coagulation factors and platelets
  • Common causes include malignancies, aneurysms, retroperitoneal hematomas, intrauterine fetal death
  • Often manifests as nonsymptomatic type DIC
  • Thrombosis is more common in symptomatic chronic DIC.

Consumption coagulopathy

• Definition: Hyperfibrinolysis, causing overt coagulopathy and bleeding, PLUS hypercoagulability, which causes consumption of platelets and clotting factors, resulting in even more blood loss.

• 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:^[2][3][4]

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.

Overview ^[3][4][5]

• The pathophysiology of DIC is variable and depends on the underlying processes (see “Hemostasis and bleeding disorders” and “Acquired thrombophilia”).
• There are 4 concurrent events involved:
  • Initiation and propagation of coagulation (loss of localized activation of coagulation)
  • A systemic inflammatory activation → impairment of physiological anticoagulant pathways (e.g., depression of antithrombin and impairment of protein C system) and endogenous fibrinolysis (due to a consistent rise in PAI-1)
  • Activation of tissue factor pathway → factor Xa and IXa generation → increased thrombin production
  • Impaired fibrin removal due to depression of the fibrinolytic system → microthrombi production and possible obstruction of the microvasculature

Mechanisms

• Underlying disease → ↑ release of procoagulants (e.g., tissue factor) → ↑ activation of the extrinsic coagulation cascade and platelets → ↑ activation of thrombin → ↑ generation of fibrin → ↑ generation of microthrombi rich in fibrin and platelets → ↑ activation of fibrinolysis and other anticoagulant pathways that break down thrombi → ↑ fibrin degradation and consumption of natural anticoagulants → further clinical course and resulting type of DIC is determined by the dominance of hyperfibrinolysis and/or hypercoagulopathy
  • Nonsymptomatic type DIC: low-grade fibrinolysis and/or hypercoagulation
  • Bleeding type DIC: hyperfibrinolysis due to excessive plasmin activity → increased fibrin degradation → thrombi becoming unstable and dissolving shortly after formation
  • Massive bleeding type DIC: hypercoagulation and hyperfibrinolysis → consumption of platelets and all coagulation factors → bleeding diathesis
  • Organ failure type DIC: ↑ cytokines → ↑ plasminogen activator inhibitor-I (PAI-I) and ↑ neutrophil extracellular traps (NETs) → hypercoagulation with suppressed fibrinolysis → platelet and fibrin-rich microthrombi → impaired perfusion and tissue necrosis

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).

General principles ^[6][8]

• Suspect DIC based on clinical features and typical underlying diseases; especially in patients with clinical deterioration.
• Laboratory studies vary depending on the subtype, underlying disorders, and stage of DIC.
• Challenges
  • No single test can reliably rule out DIC.
  • Nonsymptomatic DIC may only become apparent after specific laboratory screening.
  • DIC may already be irreversibly decompensated by the time diagnosis is made using scoring systems.
  • Many conditions can manifest with similar laboratory abnormalities (see “Differential diagnoses of DIC by laboratory findings”).

Laboratory studies ^[5][6][9]

Routine laboratory tests

• 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]

Specialized tests ^[5]

The following tests should be considered on a case-by-case basis in consultation with a specialist (e.g., intensivist, hematologist).

• Monitoring treatment: Anti-Xa activity can be used to monitor the anticoagulant effect of heparin. ^[6]
• Classifying DIC subtype: may be helpful in cases in which the subtype is uncertain ^[2][5]
  • Soluble fibrin (SF)
  • Thrombin-antithrombin complex (TAT)
  • Plasminogen activator inhibitor-1 (PAI-1)
  • Plasmin-plasmin inhibitor complex (PPIC)
  • Other procoagulants and anticoagulants that may be consumed
    • Coagulation factors: ↓ factor V and ↓ factor VIII ^[10]
    • Coagulation inhibitors: ↓ protein C and ↓ antithrombin

International Society of Thrombosis and Haemostasis (ISTH) DIC score ^[5][9][11]

• Multiple scoring systems exist, each with advantages and disadvantages that depend on the underlying cause of DIC. ^[2]
• The ISTH DIC score identifies patients with a high likelihood of overt DIC. It can only be used in patients with a known predisposing disease.

Differential diagnoses by laboratory findings ^[1]

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 ^[15]
  • 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 ^[5][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 ^[3]
• Initiate clinical and serial laboratory monitoring to assess response to treatment.

Treatment of the underlying disease is the cornerstone of management.

Blood products ^{[5][6][9][9][16]}

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 gr/dL (see “Packed red blood cells” for specific transfusion thresholds and goals and “Massive transfusion” in case of massive hemorrhage)
• 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 ^[16]
  • Goal: fibrinogen level of > 100–150 mg/dL
• Prothrombin complex concentrate (PCC) ^[10][16][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 ^[5][16]

• Tranexamic acid : not routinely recommended ^[9]
  • Indication: Consider in patients with severe bleeding and hyperfibrinolysis (especially after trauma). ^[16]
  • Contraindications ^[5]
    • 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 ^{[5][9][11][16][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 ^[16]
  • 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. ^[5][16]
  • Antithrombin (AT): Not routinely recommended due to a lack of supporting evidence.
  • Plasma-derived activated protein C (APC)
  • Recombinant human thrombomodulin (rhTM) ^[8][16]
  • 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. ^[3][5]

All patients ^[5][16]

• 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.