eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Disseminated Intravascular Coagulation

Author: Joseph U Becker, MD, Fellow, Global Health and International Emergency Medicine, Stanford University
Coauthor(s): Charles R Wira, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine
Contributor Information and Disclosures

Updated: Sep 10, 2009

Introduction

Background

Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. The resultant clinical condition is characterized by intravascular coagulation and hemorrhage. 

The subcommittee on DIC of the International Society on Thrombosis and Haemostasis has suggested the following definition for DIC: "An acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction."1  

DIC is not an illness on its own but rather a complication or an effect of progression of other illnesses and is estimated to be present in up to 1% of hospitalized patients.2    
DIC is always secondary to an underlying disorder and is associated with a number of clinical conditions (see List below), generally involving activation of systemic inflammation. DIC has several consistent components including activation of intravascular coagulation, depletion of clotting factors, and end-organ damage (see Components of DIC). DIC is most commonly observed in severe sepsis and septic shock. Indeed the development and severity of DIC correlates with mortality in severe sepsis.3,4 Although bacteremia, including both gram-positive and gram-negative organisms, is most commonly associated with DIC, other organisms including viruses, fungi, and parasites may cause DIC. 

Trauma, especially neurotrauma, is also frequently associated with DIC. DIC is more frequently observed in those patients with trauma who develop the systemic inflammatory response syndrome.5 Evidence indicates that inflammatory cytokines play a central role in DIC in both trauma patients and septic patients. In fact, systemic cytokine profiles in both septic patients and trauma patients are nearly identical.6    

Conditions associated with disseminated intravascular coagulation include the following7 :

  • Sepsis/severe infection
  • Trauma (neurotrauma)
  • Organ destruction
  • Malignancy (solid and myeloproliferative malignancies)
  • Severe transfusion reactions
  • Rheumatologic illness
    • Adult Stills disease
    • Lupus
  • Obstetric complications
  • Vascular abnormalities
  • Severe hepatic failure
  • Severe toxic reactions

Acute DIC versus chronic DIC

DIC exists in both acute and chronic forms. DIC develops acutely when sudden exposure of blood to procoagulants occurs, including tissue factor (tissue thromboplastin), generating intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, a severe consumptive coagulopathy leading to hemorrhage develops. Abnormalities of blood coagulation parameters are readily identified, and organ failure frequently occurs in acute DIC.

In contrast, chronic DIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of tissue factor. Compensatory mechanisms in the liver and bone marrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC. Chronic DIC is more frequently observed in solid tumors and in large aortic aneurysms.8

Pathophysiology

DIC is caused by widespread and ongoing activation of coagulation, leading to vascular or microvascular fibrin deposition, thereby compromising an adequate blood supply to various organs. Four different mechanisms are primarily responsible for the hematologic derangements seen in DIC: increased thrombin generation, a suppression of anticoagulant pathways, impaired fibrinolysis, and inflammatory activation.9 Activation of intravascular coagulation is mediated almost entirely by the intrinsic clotting pathway. 

Exposure to tissue factor in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue factor activates coagulation by the extrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate any effect on clotting.10,11 The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting.12   

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis. First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly, production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and microvascular coagulation.8,13 Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis.4   

Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin.8 Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa. However, the cytokines (tumor necrosis factor α [TNF-a], interleukin 1 [IL-1]) produced in sepsis and other generalized inflammatory states largely incapacitate the protein C pathway. Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cell surface.14 Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S.  

Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPI inhibits the tissue factor-VIIa complex. Although levels of TFPI are normal in patients with sepsis, a relative insufficiency in DIC is evident. TFPI depletion in animal models predisposes to DIC, and TFPI blocks the procoagulant effect of endotoxin in humans.15 The intravascular fibrin produced by thrombin is normally eliminated via a process termed fibrinolysis. The initial response to inflammation appears to be augmentation of fibrinolytic action; however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1 [PAI-1], TAFI) of fibrinolysis are released.16 Indeed, high levels of PAI-1 precede DIC and predict poor outcomes.17 Fibrinolysis cannot keep pace with increased fibrin formation, eventually resulting in under-opposed fibrin deposition in the vasculature.  

Inflammatory and coagulation pathways interact in substantial ways. Many of the activated coagulation factors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cell release of proinflammatory cytokines. Factor Xa, thrombin, and the tissue factor-VIIa complex have each been demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action of activated protein C and AT, their impairment in DIC contributes to further dysregulation of inflammation.7,18,19

Components of DIC include the following9 :
  • Exposure of blood to procoagulant substances
  • Fibrin deposition in the microvasculature
  • Impaired fibrinolysis
  • Depletion of coagulation factors and platelets (consumptive coagulopathy)
  • Organ damage and failure

Frequency

United States

Approximately 18,000 cases of DIC occurred in 1994. DIC may occur in 30-50% of patients with sepsis. DIC occurs in an estimated 1% of all hospitalized patients.2

Mortality/Morbidity

Morbidity and mortality depend on both the underlying disease and the severity of coagulopathy. Assigning a numerical figure for DIC-specific morbidity and mortality is difficult. Below are examples of mortality rates in diseases complicated by DIC:

  • Idiopathic purpura fulminans associated with DIC has a mortality rate of 18%.
  • Septic abortion with clostridial infection and shock associated with severe DIC has a mortality rate of 50%.
  • In the setting of major trauma, the presence of DIC approximately doubles the mortality rate.3,4   
  • A recent study utilizing the Japanese Association for Acute Medicine (JAAM) diagnostic criteria for DIC showed that septic patients with DIC had higher mortality than trauma patients with DIC (34.7% vs 10.5%).20

Sex

Incidence is equal in males and females.

Age

No age predilection is known.

Clinical

History

In addition to the symptoms related to the underlying disease process, typically, a history of blood loss and hypovolemia, such as gastrointestinal bleeding, is present. Look for symptoms and signs of thrombosis in large vessels, such as deep venous thrombosis (DVT), and of microvascular thrombosis, such as renal failure. Bleeding from at least 3 unrelated sites is particularly suggestive of disseminated intravascular coagulation (DIC). 

  • Epistaxis
  • Gingival bleeding
  • Mucosal bleeding
  • Cough
  • Dyspnea
  • Confusion, disorientation
  • Fever
  • Bruising, petechiae

Table 1. Main Features of DIC in a Series of 118 Patients20

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Table
FeaturesAffected Patients, %
Bleeding64%
Renal dysfunction25%
Hepatic dysfunction19%
Respiratory dysfunction16%
Shock14%
Central nervous system dysfunction2%
FeaturesAffected Patients, %
Bleeding64%
Renal dysfunction25%
Hepatic dysfunction19%
Respiratory dysfunction16%
Shock14%
Central nervous system dysfunction2%


Physical

  • Circulation
    • Signs of spontaneous and life-threatening hemorrhage
    • Signs of subacute bleeding
    • Signs of diffuse or localized thrombosis
  • Central nervous system
    • Nonspecific altered consciousness/stupor
    • Focal deficits not usually present
  • Cardiovascular system
    • Hypotension
    • Tachycardia
    • Circulatory collapse
  • Respiratory system
    • Pleural friction rub
    • Signs of adult respiratory distress syndrome (ARDS)
  • Gastrointestinal system
    • Hematemesis
    • Hematochezia
  • Genitourinary system
    • Signs of azotemia and renal failure
    • Acidosis
    • Hematuria
    • Oliguria
    • Metrorrhagia
    • Uterine hemorrhage
  • Dermatologic system
    • Petechiae
    • Jaundice (liver dysfunction or hemolysis)
    • Purpura
    • Hemorrhagic bullae
    • Acral cyanosis
    • Skin necrosis of lower limbs (purpura fulminans)
    • Localized infarction and gangrene
    • Wound bleeding and deep subcutaneous hematomas
    • Thrombosis

Causes

Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result of a single or multiple conditions.

  • Acute DIC
    • Infectious
      • Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial)
      • Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis)
      • Fungal (eg, Histoplasma)
      • Parasitic (eg, malaria)
    • Malignancy
      • Hematologic (eg, acute myelocytic leukemias)
      • Metastatic (eg, mucin-secreting adenocarcinomas)
    • Obstetric
      • Placental abruption
      • Amniotic fluid embolism
      • Acute fatty liver of pregnancy
      • Eclampsia
    • Trauma
    • Burns
    • Motor vehicle accidents (MVAs)
    • Snake envenomation
    • Transfusion
    • Hemolytic reactions
    • Massive transfusion
    • Liver disease - Acute hepatic failure
    • Prosthetic devices
    • Shunts (Denver, LeVeen)
    • Ventricular assist devices
  • Chronic DIC
    • Malignancies
      • Solid tumors
      • Leukemia
    • Obstetric
      • Retained dead fetus syndrome
      • Retained products of conception
    • Hematologic
      • Myeloproliferative syndromes
      • Paroxysmal nocturnal hemoglobinuria
    • Vascular
      • Rheumatoid arthritis
      • Raynaud disease
    • Cardiovascular - Myocardial infarction
    • Inflammatory
      • Ulcerative colitis
      • Crohn disease
      • Sarcoidosis
  • Localized DIC
    • Aortic aneurysms
    • Giant hemangiomas (Kasabach-Merritt syndrome)
    • Acute renal allograft rejection
    • Hemolytic uremic syndrome

More on Disseminated Intravascular Coagulation

Overview: Disseminated Intravascular Coagulation
Differential Diagnoses & Workup: Disseminated Intravascular Coagulation
Treatment & Medication: Disseminated Intravascular Coagulation
Follow-up: Disseminated Intravascular Coagulation
References
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Further Reading

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Contributor Information and Disclosures

Author

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

Coauthor(s)

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.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

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

 
 
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