Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. DIC is always triggered by another (often serious) condition, including severe sepsis, trauma, malignancy, or obstetric complications. Acute DIC often presents dramatically, with rapid onset of spontaneous bleeding from multiple locations throughout the body simultaneously. A chronic form of DIC also exists, typically in patients with late-stage malignancies. Management involves stabilizing the patient, replacing consumed platelets and coagulation factors, and treating the triggering condition.

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Overview

Definition

Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade that results in both:

  • Widespread microvascular thrombi contributing to multiple organ dysfunction
  • Consumption of clotting factors and platelets leading to hemorrhage

Epidemiology

  • Incidence rates:
    • 1% of all hospitalized patients in tertiary care centers
    • 30%–50% of septic patients
    • Approximately 40% of severe trauma patients
    • 20% of pregnant patients with HELLP syndrome
    • 66% of pregnant patients with amniotic fluid embolism
  • Gender bias: none, equal incidence between sexes
  • Age bias: none, may develop at any age
  • Ethnic bias: none, occurs in all races
  • Prognosis: 
    • Depends on the severity of the coagulopathy and the underlying condition that led to the disease
    • Generally poor if untreated

Classification

Acute DIC:

  • Sudden overwhelming activation of systemic coagulation and subsequent fibrinolysis
  • Occurs in the setting of an acute process:
    • Trauma
    • Sepsis
    • Pregnancy complications
  • Frequently results in significant hemorrhage and end-organ damage

Chronic DIC:

  • Insidious presentation due to continuous exposure to systemic procoagulants
  • Typically occurs in late-stage malignancies
  • More likely to result in thrombotic (rather than hemorrhagic) complications

Etiology

Disseminated intravascular coagulation is always a complication of other conditions:

Table: Etiologies of disseminated intravascular coagulation
Infection
  • Bacterial:
    • Sepsis (both gram-positive and gram-negative species)
    • Escherichia coli
    • Neisseria meningitidis
  • Viral:
    • HIV
    • Cytomegalovirus
    • Varicella
    • Hepatitis
  • Parasitic: malaria
Inflammation
  • Pancreatitis
  • Fulminant liver failure
Malignancy
  • Acute promyelocytic leukemia
  • Metastatic adenocarcinomas, especially:
    • Pancreas
    • Stomach
    • Ovary
    • Prostate
Obstetric causes
  • Amniotic fluid embolism
  • Placental abruption
  • Postpartum hemorrhage
  • Preeclampsia/eclampsia/HELLP syndrome
  • Retained stillbirth
  • Septic abortion
  • Acute fatty liver of pregnancy
Trauma
  • Burns
  • Frostbite
  • Head injuries
  • Snake bites
Hematologic and vascular causes
  • Hemolytic transfusion reaction (e.g., ABO incompatibility)
  • Large hemangiomas (Kasabach–Merritt syndrome)
  • Abdominal aortic aneurysm/dissection (chronically exposed subendothelium)

Pathophysiology

In DIC, coagulation and subsequent fibrinolysis are activated systemically, which is abnormal and leads to microthrombi throughout the vasculature. These microthrombi consume large amounts of platelets and coagulation factors, leading to a severe coagulopathy and clinical bleeding.

Normal activation of coagulation

  • Platelets bind exposed von Willebrand factor (VWF) on injured endothelial cells:
    • Adherent platelets activate and express glycoprotein (Gp) IIb/IIIa receptors.
    • GpIIb/IIIa receptors bind fibrinogen.
    • Fibrinogen can bind one platelet on each side → platelet aggregation/formation of the platelet plug
    • Activated platelets secrete substances that augment further platelet aggregation and the coagulation cascade.
  • Tissue factor (TF) binds circulating factor VII and activates the extrinsic pathway (initial activation of the coagulation cascade):
    • Membrane-bound glycoprotein expressed on injured endothelial cells
    • Restricts activation of the cascade primarily to local sites of injury
  • The initial thrombin produced activates factor XI in the intrinsic pathway.
    • The intrinsic pathway significantly amplifies the local response.
    • Coagulation factors form multicomponent enzyme complexes, which are also bound to membrane surfaces.
    • Keeps coagulation localized
  • Thrombin converts fibrinogen to fibrin, forming a stable clot.
  • Plasmin is produced to break down fibrin.
  • Fibrin degradation products (FDPs):
    • Have anticoagulant properties
    • Are cleared by the liver

Activation of systemic coagulation (abnormal)

  • Abnormal systemic activation of the coagulation cascade may occur owing to:
    • An overwhelming systemic inflammatory response (e.g., severe sepsis)
    • Sudden exposure of the blood to procoagulants, including:
      • TF
      • Thromboplastin
      • VWF
    • Examples of procoagulant exposure:
      • Sepsis: Bacterial endotoxins can trigger release of circulating TF.
      • Malignancy: Some cancers can produce circulating TF.
      • Trauma: Significant vascular endothelial damage results in ↑ amounts of TF.
      • Obstetric: The placenta can release a proteolytic enzyme capable of activating factor X.
  • Effects of systemic coagulation:
    • With systemic activation of the coagulation cascade, thrombi are formed throughout the vasculature.
    • Thrombi can affect both small and large vessels.
    • Extensive, systemwide coagulation consumes large amounts of platelets and coagulation factors.
  • Fibrinolysis:
    • Activated in conjunction with coagulation cascade
    • Plasmin cleaves fibrin polymers and produces FDPs.
    • ↑ Levels of FDPs interfere with new fibrin clot formation and platelet aggregation → impaired hemostasis
  • End-organ damage occurs by:
    • Widespread microthrombi formation
    • Hemorrhage
    • Ischemic effects from hemorrhagic hypovolemia
  • Organ dysfunction can include:
    • Change in mental status
    • Acute kidney injury
    • Respiratory dysfunction
    • Hepatic dysfunction
    • Cardiac tamponade
    • Hemothorax
    • Intracerebral hemorrhage
    • Gangrene and loss of digits

Acute versus chronic disseminated intravascular coagulation

Acute DIC is decompensated DIC:

  • Rapid systemic activation of coagulation 
  • Leads to rapid consumption of platelets and coagulation factors 
  • Consumption significantly outpaces production.
  • ↑ Number of thrombi → ↑ fibrinolysis → ↑ FDPs → pathologically prevents new clots and platelet aggregation
  • End result: severe clinical bleeding/hemorrhage plus thrombotic end-organ damage

Chronic DIC is compensated DIC:

  • Typically occurs in patients with:
    • Advanced malignancy 
    • Large aneurysms
  • Develops when blood is continuously (or intermittently) exposed to smaller amounts of procoagulants
  • Compensation mechanisms:
    • New production of platelets and coagulation factors
    • Liver is able to clear FDPs.
  • Compensation mechanisms are able to balance the ongoing consumption of products and production of FDPs.
  • Thrombotic complications are more common than bleeding.

Clinical Presentation

Acute disseminated intravascular coagulation

Acute DIC typically presents rapidly and dramatically, with acute and severe bleeding from multiple sites simultaneously throughout the body. Other manifestations are related to thrombotic end-organ dysfunction.

Table: Clinical manifestations of acute disseminated intravascular coagulation
Vital signs
  • Hypovolemic shock
  • Hypotension
  • Tachycardia
Skin
  • Petechiae
  • Ecchymosis
  • Bleeding from IV and drain sites
  • Surgical site bleeding
  • Purpura fulminans (life threatening):
    • Extensive tissue thrombosis
    • Skin necrosis
    • Retiform purpura
    • Associated with protein C deficiency
  • Gangrene
Mucosal
  • Gingival bleeding
  • Epistaxis
Renal
  • Hematuria
  • Oliguria
  • Azotemia
Pulmonary
  • Hemoptysis
  • Hemothorax
  • ARDS
GI
  • Hematochezia
  • Hematemesis
Neurologic
  • Altered mental status
  • Hemorrhagic stroke
  • Ischemic stroke
  • Focal neurologic deficits
  • Headache
  • Seizure

Skin manifestation of DIC:
Note the petechiae and purpura.

Image: “ Purpura” by George Henry Fox. License: Public Domain

Chronic disseminated intravascular coagulation

  • Frequently asymptomatic
  • Thrombotic sequelae are more common than bleeding complications.
  • Manifestations can include:
    • Venous thromboembolism
    • Petechiae and ecchymosis
    • Bleeding from IV lines, catheters, and mucosal surfaces

Diagnosis

The diagnosis is made on the basis of clinical history and laboratory findings, though no single test is diagnostic for DIC. Laboratory tests also aid in management.

Laboratory tests

In DIC, coagulation factors and platelets are rapidly consumed in the formation of systemwide microthrombi. Lab findings in DIC include:

  • CBC:
    • Mild-to-moderate thrombocytopenia (platelets are consumed)
    • Anemia (due to hemorrhage and hemolysis)
  • Peripheral blood smear:
    • Microangiopathic hemolytic anemia
    • Schistocytes: fragmented, jagged RBCs
  • PT: 
    • ↑ (prolonged) in DIC
    • Interpretation: Factors in the extrinsic and/or common pathways have been consumed.
  • aPTT: 
    • ↑ (prolonged) in DIC
    • Interpretation: Factors in the intrinsic and/or common pathways have been consumed.
  • Fibrinogen:
    • Usually ↓ owing to consumption
    • May be normal despite significant consumption if fibrinogen was originally ↑, which occurs in patients with:
      • Sepsis
      • Malignancy
      • Other inflammatory conditions
  • D-dimer: 
    • ↑↑ in DIC
    • An FDP, which indicates recent or ongoing thrombosis
    • Interpretation: A negative test for D-dimer essentially rules out DIC.
  • Findings in chronic DIC:
    • Thrombocytopenia (mild)
    • ↓ or normal PT and aPTT
    • ↑ D-dimer

Peripheral blood smear showing schistocytes, which are indicative of intravascular hemolysis

Image: “Disseminated carcinomatosis with DIC” by Ed Uthman, MD. License: Public Domain

Imaging

No specific imaging study confirms the diagnosis of DIC. Specific imaging methods may be indicated to assist in:

  • The diagnosis of the underlying etiology (e.g., abdominal imaging for suspected malignancy)
  • Evaluation of end-organ damage (e.g., head CT in patients with evidence of stroke)

Management

The most important principles in management are to treat the underlying cause and stabilize the patient.

Acute disseminated intravascular coagulation

  • Emergency care: airway, breathing, circulation:
    • Ensure that the airway is secure and support ventilation.
    • Hemodynamic support:
      • Volume resuscitation with IV fluids
      • Vasopressors
      • Blood transfusion
  • Product replacement: coagulation factors and platelets (see Blood component replacement below)
  • Treat the underlying cause: treatment may include:
    • Antimicrobial agents
    • Delivery of fetus in obstetric cases

Blood component replacement

  • Platelets:
    • 1 pool of 5–6 units should ↑ platelet counts by approximately 30,000/µL 
    • Indications:
      • Active bleeding
      • Platelets < 50,000/µL with need for urgent surgery
      • Platelets < 10,000/µL
  • Fresh frozen plasma (FFP)
    • 1 unit = 200–300 mL
    • Contains all soluble plasma proteins and clotting factors 
    • Indications: 
      • Serious bleeding and ↑ PT or aPTT 
      • Serious bleeding and ↓ fibrinogen
  • Cryoprecipitate
    • 1 unit = 10–20 mL 
    • Contains:
      • Fibrinogen
      • Factors VIII and XIII
      • VWF
    • Indication: fibrinogen < 100 mg/dL
    • Used to help boost fibrinogen without significant extra volume

Chronic disseminated intravascular coagulation

  • Anticoagulation with heparins (for deep vein thrombosis (DVT) prophylaxis)
  • Treat the underlying cause (usually malignancy)

Differential Diagnosis

  • Cirrhosis: The liver is the primary site of synthesis for a majority of the clotting factors. In addition to impaired synthesis of clotting factors, cirrhosis also may independently result in thrombocytopenia owing to splenic sequestration of platelets and decreased thrombopoietin production. Platelets themselves may also be dysfunctional. Like DIC, cirrhosis can lead to both bleeding and thrombosis. A history of liver injury and abnormal liver function tests can help distinguish cirrhosis from DIC. Of note, fulminant liver failure may actually trigger DIC, as well.
  • Thrombotic thrombocytopenic purpura (TTP): a bleeding disorder marked by a pentad of microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic symptoms, and fever: Thrombotic thrombocytopenic purpura occurs because of a congenital or acquired deficiency of ADAMTS13, which is a metalloproteinase that cleaves VWF. Deficiencies of ADAMTS13 result in large VWF multimers that increase platelet aggregation, leading to microvascular thrombosis and consumption of platelets. Unlike DIC, in TTP, the PT and PTT are usually normal (or only mildly elevated) and fibrinogen is normal or even increased.
  • Immune thrombocytopenia (ITP): an autoimmune disorder characterized by anti-GpIIb/IIIa autoantibodies that lead to the destruction of platelets: Immune thrombocytopenia often occurs after GI or respiratory viral infections, though it can also be drug-induced. Clinically, it may present with prolonged bleeding, petechiae, easy bruising, and/or purpura. Unlike DIC, in ITP, there is no coagulation defect, so the PT and PTT are normal. 

References

  1. Marcel, M. (2020). Disseminated intravascular coagulation (DIC). Retrieved March 21, 2021, from https://emedicine.medscape.com/article/199627-overview
  2. Leng, L. (2021). Disseminated intravascular coagulation (DIC) in adults: Evaluation and management. Retrieved March 21, 2021, from https://www.uptodate.com/contents/disseminated-intravascular-coagulation-dic-in-adults-evaluation-and-management
  3. Longo, D., Fauci, A., Kasper, D., Hauser, S., Jameson, J., Loscalzo, J. (2012). Harrison’s Manual of Medicine, 18th ed. McGraw-Hill Professional, pages 2188–2191.

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