eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Disseminated Intravascular Coagulation

Joseph U Becker, MD, Fellow, Global Health and International Emergency Medicine, Stanford University
Charles R Wira, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale School of Medicine

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 following^{[7 ]}:

• Sepsis/severe infection
• Trauma (neurotrauma)
• Organ destruction
• Malignancy (solid and myeloproliferative malignancies)
• Severe transfusion reactions
• Rheumatologic illness
  • Adult Stills disease
  • Lupus
• Obstetric complications
  • Amniotic fluid embolism
  • Abruptio placentae
  • Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome/eclampsia
  • Retained dead fetus syndrome
• Vascular abnormalities
  • Kasabach-Merritt syndrome
  • Large vascular aneurysms
• Severe hepatic failure
• Severe toxic reactions
  • Envenomations
  • Transfusion reactions
  • Transplant rejection

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 ]}

• 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 Patients^{[20 ]}

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

Differential Diagnoses

Acute or chronic liver failure
Hemolytic Uremic Syndrome
Heparin-induced thrombocytopenia
Other consumptive coagulopathy
Thrombocytopenic Purpura

Other Problems to Be Considered

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

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a thrombotic microangiopathy, similar to DIC; however, contrary to DIC, the mechanism of coagulation is not via the tissue factor-VIIa pathway. Rather, in TTP-HUS, activation of coagulation stems from direct platelet activation usually from widespread endothelial damage or via an inherited or acquired impairment of ADAMTS13, a protease that normally cleaves von Willebrand factor. However, TTP-HUS and DIC are usually distinguished by their occurrence in different clinical settings (trauma or sepsis in DIC and fever and neurologic symptoms in TTP-HUS). Furthermore, TTP-HUS does not demonstrate the laboratory abnormalities frequently encountered in DIC (see Lab Studies below).^{[21 ]} 

Idiopathic thrombocytopenic purpura (ITP) additionally, while also distinct mechanistically, can have clinical components similar to DIC, that is thrombocytopenia and thrombus formation. Heparin-induced thrombocytopenia (HIT) is another clinical entity similar in presentation to DIC. A subpopulation of patients who have received heparin will develop antibodies against platelet antigens and can result in diminution of platelet number. Although thrombosis may be observed, HIT does not typically produce the consumptive coagulopathy of DIC.

Workup

Laboratory Studies

No one test is sensitive and specific enough to diagnose disseminated intravascular coagulation (DIC). Rather, the diagnosis is made based on the clinical picture in combination with laboratory studies, best evaluated serially. Most individual laboratory tests demonstrate high sensitivity but very low specificity for DIC.^{[22 ]}Furthermore, while acute DIC typically overwhelms compensatory anticoagulation mechanisms resulting in depletion of factors and laboratory derangements, chronic or localized DIC may produce only minimal abnormalities in laboratory tests.^{[23 ]} 

Given that acute DIC entails massive thrombin activation and fibrin deposition with consumption of coagulation factors, many laboratory abnormalities are manifest. Because fibrin activation is a central component of DIC, evidence suggests that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence.^{[24 ]}However, soluble fibrin levels are not available to most clinicians in a relevant time frame. Likewise, laboratory assays aimed at differentiating between cross-linked fibrin, fibrinogen, and soluble fibrin have been developed but are not routinely available to the clinician. However, other commonly available laboratory tests often are frequently deranged in DIC. Typically, moderate-to-severe thrombocytopenia is present in DIC. Furthermore, the peripheral blood smear can demonstrate evidence of microangiopathic pathology (schistocytes). 

Fibrinolysis is an important component of DIC. As such, there is evidence of fibrin breakdown such as elevated D-dimer and fibrin degradation products (FDPs).

However, both of these assays may be elevated in other conditions such as venous thromboembolism, trauma, or recent surgery, limiting the specificity of these tests.^{[8,25 ]}Given the massive fibrin deposition in DIC, fibrinogen levels would seem to be decreased. However, this is not the case. Fibrinogen, as a positive acute-phase reactant is increased in inflammation, and while values may decrease as the illness progresses, they are rarely low.^{[8,26 ]}Given ongoing consumption of coagulation factors and impaired hepatic synthesis secondary to hypoperfusion or organ damage, typically global clotting times (aPTT and PT) are elevated. Antithrombin levels as well as other individual factors (V and VII) may also be diminished in acute DIC.

Imaging Studies

• Base diagnostic imaging on the underlying pathologic process as well as on areas suggestive of thrombosis and hemorrhage.
• Perform a bilateral perihilar soft-density chest radiograph if pulmonary injury is present.

Other Tests

• Base other tests on the underlying pathologic process as well as on areas suggestive of thrombosis and hemorrhage.

Procedures

• Base procedures on the underlying pathologic process as well as on areas suggestive of thrombosis and hemorrhage.
• Conduct invasive procedures with care because of bleeding complications. Procedures should follow the administration of clotting factor and platelet repletion.

Treatment

Prehospital Care

Monitor vital signs, assess and document extent of hemorrhage and thrombosis, correct hypovolemia, and administer basic hemostatic procedures when indicated.

Emergency Department Care

The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder. Typically, DIC results in significant reductions in platelet count and increases in coagulation times (PT and aPTT). Despite these abnormalities, routine platelet and coagulation factor replacement is not indicated in acute DIC unless ongoing bleeding is present or invasive procedures are planned. 

Most clinicians will provide platelet replacement if platelet counts drop below 20 X 10⁶/mL. Previously, concern has been raised regarding "fueling the fire" of consumption by providing replacement therapy; however, this has never been established in research studies.^{[30 ]}Cryoprecipitates should not routinely be used as replacement therapy in DIC as they lack several specific factors (factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Provision of vitamin K to correct relative deficiencies in the face of consumption may be required.^{[8,7,9 ]} 

Anticoagulation in DIC has recently received much attention. However, the beneficial effect of high- or low-dose heparin therapy in patients with acute DIC has never been convincingly established. Moreover, antithrombin (AT), the primary target of heparin activity is markedly decreased in DIC, limiting the effectiveness of heparin therapy without concomitant replacement of AT. Furthermore, well-founded concern exists in anticoagulating patients already at high risk for hemorrhagic complications. It is generally agreed that heparin is indicated in cases with obvious thromboembolic disease or where fibrin deposition predominates.^{[31,32,33 ]}The use of heparin in chronic DIC where there is preponderance of coagulation without consumption coagulopathy is well established.^{[34 ]}Lovenox (Enoxaparin) has also seen use in the treatment and prophylaxis of chronic DIC in specific clinical situations.  

As stated above, the AT pathway is an important inhibitor of coagulation in normal patients. This system is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of AT replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function.^{[26,35,36,37 ]}However, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with AT concentrate.  

The tissue factor pathway inhibitor (TFPI) mechanism of coagulation inhibition has likewise received attention as a potential therapy in sepsis-associated DIC. Indeed, initial results from animal studies have been very promising in demonstrating the ability of TFPI to arrest DIC and to prevent the mortality and end-organ damage witnessed in untreated animals.^{[38 ]}However, a large, phase III human trial of TFPI in DIC did not show any mortality benefit.^{[39 ]}

As with TFPI and AT, activated protein C (APC) is an important regulator of coagulation. In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function.   The PROWESS study (Human Recombinant Activated Protein C Worldwide Evaluation in Sepsis) documented reductions in 28-day mortality and improved organ function in APC-treated patients, despite an increase in the overall number of bleeding complications.^{[40,41 ]}These results were confirmed by the ENHANCE trial, which also suggested that APC might be more effective when administered earlier.^{[42 ]}

A retrospective, subgroup analysis of the PROWESS study demonstrated a lower mortality rate among patients treated with APC who met criteria for DIC with a modified DIC scoring system.^{[43 ]}Other studies of APC in patients with a low risk of death from sepsis have failed to show an effect, suggesting that APC may be most useful in severely ill patients.^{[44 ]}  

Future directions

As understanding of the inflammatory and coagulation derangements in DIC has improved in recent years, the range of therapeutic considerations has broadened. Treatment modalities focused on the TF-VIIa complex include inactivated factor VII and NAPc2, a member of the nematode family of anticoagulant proteins (NAPs) and an inhibitor of the complex between TF, factor VIIa, and factor Xa. NAPc2 has been observed to inhibit coagulation activation in a primate model of sepsis.^{[7,9 ]}Other research has used antibodies against tissue factor/factor VIIa in animal trials, with promising results.^{[9 ]}Hirudin, a direct inhibitor of thrombin has also been shown to be effective in treating DIC in animal studies.^{[9 ]}    

Recombinant factor VIIa has also been demonstrated to be useful in cases of severe bleeding as can be seen in DIC.^{[9 ]}However, given the procoagulant effect of rVIIa, a careful consideration of the risks and benefits in patients with DIC should be undertaken before administration. Further, antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, can also be considered in patients with DIC in which bleeding predominates. These agents should always be administered with heparin to arrest their prothrombotic effects.^{[9,45 ]}   

Recognition of the importance of inflammation in both sepsis and DIC has led to further investigation of inhibitors of inflammation. In a murine model, researchers have shown antiselectin antibodies and heparin to block leukocyte and platelet adhesion.^{[46 ]}Similarly, focus has been placed on interleukin 10 (IL-10), an anti-inflammatory cytokine that may have effects on coagulation activation. Initial studies of IL-10 have shown promise in preventing coagulation activation associated with endotoxemia.^{[47 ]}

Other researchers have targeted p38 mitogen activated protein kinase (MAPK), an important element in intracellular signaling responsible for inflammatory responses. Inhibition of MAPK has been shown to reduce coagulation activation, fibrinolysis, and endothelial activation in endotoxemia.^{[48 ]}

Consultations

• Consult a hematologist for assistance with diagnosis and management.
• Consult a transfusion specialist or a blood bank; determine the availability of general and specialized blood products that may be necessary for the acute management of fulminant DIC.
• Consult a critical care specialist if multiple organ failure is present.
• Early consultation is indicated for this complicated, life-threatening condition. Obtain other subspecialty consultations as indicated by the patient's primary diagnosis.
  

Medication

Therapy should be based on etiology and aimed at eliminating the underlying disease. Therapy should be appropriately aggressive for the patient's age, disease, and severity and location of hemorrhage/thrombosis. Treatment for acute disseminated intravascular coagulation (DIC) includes anticoagulants, blood components, and antifibrinolytics.

Hemostatic and coagulation parameters should be monitored continuously during treatment. Base therapeutic decisions on clinical and laboratory evaluation of hemostasis. In cases of low-grade DIC, therapy other than supportive care may not be warranted or may include antiplatelet agents or subcutaneous heparin; treatment decisions should be based on clinical and laboratory evaluation of hemostasis. Activated human protein C has been shown to reduce the rate of mortality in the setting of severe sepsis for patients at high risk for death; this should be used cautiously and appropriately, following guidelines for administration.

Anticoagulant agents

These agents are used in the treatment of clinically evident intravascular thrombosis when the patient continues to bleed or clot 4-6 h after initiation of primary and supportive therapy. Thrombosis can present as purpura fulminans or acral ischemia. Take special precaution in obstetric emergencies or massive liver failure. The anti-inflammatory properties of antithrombin III may be particularly useful in DIC secondary to sepsis.

Heparin

Use and dose of heparin is based on severity of DIC, underlying cause, and extent of thrombosis. Monitoring results of therapy is mandatory. Heparin augments antithrombin III activity and prevents conversion of fibrinogen to fibrin. Does not actively lyse but inhibits further thrombogenesis. Prevents reaccumulation of a clot after spontaneous fibrinolysis.

Dosing

Adult

80-100 U/kg SC q4-6h or 20,000-30,000 U/d IV continuous infusion

Pediatric

Not established

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity

Contraindications

Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for localized bleeding or hematoma; may aggravate hemorrhage; in neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock

Antithrombin III (ATnativ, Thrombate III)

Used for moderately severe–to– severe DIC or when levels are depressed markedly. Alpha 2-globulin that inactivates thrombin, plasmin, and other serine proteases of coagulation, including factors IXa, Xa, XIa, XIIa, and VIIa. These effects inhibit coagulation.

Dosing

Adult

Total Units = (Desired Level - Initial Level) (0.6 X Total Body Weight kg) IV q8h with a desired level >125% or loading dose of 100 U/kg IV over 3 h; followed by continuous infusion of 100 U/kg/d

Pediatric

Not established

Interactions

Increases anticoagulation effects of heparin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypotension; despite measures taken to delete infectious agents from human product, potentially still can transmit disease or contain unknown infectious agents

Recombinant human activated protein C

These agents inhibit factors Va and VIIIa of the coagulation cascade. They may also inhibit plasminogen activator inhibitor-1 (PAI-1).

Drotrecogin alfa-activated (Xigris)

Indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.

Dosing

Adult

24 mcg/kg/h IV by continuous infusion over 96 h

Pediatric

Not established

Interactions

None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors)

Contraindications

Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, presence of epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Bleeding is most common serious adverse effect; caution with conditions that increase risk of bleeding including INR >3, concurrent therapeutic heparin (>15 U/kg/h), within 6 wk of GI bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors administration, within 3 mo of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs; caution with thrombocytopenia (<50 X 10⁹/L); chronic severe hepatic disease and known bleeding diathesis not associated with the acute coagulopathy related to sepsis

Blood components

Blood components are used to correct abnormal hemostatic parameters. These products should be considered only after initial supportive and anticoagulant therapy. Washed PRBCs and platelet concentrates are considered safe in uncontrolled DIC. Specialized blood components (cryoprecipitate, FFP) may interfere with or improve DIC.

Packed red blood cells (PRBCs; washed)

Preferred to whole blood since they limit volume, immune, and storage complications. Obtain PRBCs after centrifugation of whole blood. Use washed or frozen PRBCs in individuals with hypersensitivity transfusion reactions.

Dosing

Adult

1 unit of PRBCs should raise hemoglobin by 1 g/dL or raise hematocrit by 3%

Pediatric

Not established

Interactions

None reported

Contraindications

Competent adult or legal guardian may refuse blood product; immediate consultation with hospital ethical and legal staff is mandated

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Use CMV-negative units or filtered ones; transfusion reactions and transmission of blood-borne pathogens are a concern; benefits should outweigh risks associated with such products

Platelet concentrates (Random or single donor, pheresis units)

Considered safe for use in acute DIC.

Dosing

Adult

Based on platelet count and clinical situation

Pediatric

Not established

Interactions

None reported

Contraindications

Competent adult or legal guardian may refuse blood product; immediate consultation with hospital ethical and legal staff mandated

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Platelets should be CMV-negative or the pheresis units from single donors filtered; benefits should outweigh risks associated with such products

Fresh frozen plasma (FFP)

This treatment entails removing blood from body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. Contains coagulation factors as well as protein C and protein S. Can be performed by using either 2 large-bore peripheral IV sites or multiple lumen central line. Recommended with active bleeding and fibrinogen <100 mg/dL.

Dosing

Adult

15-20 mL/kg IV or based on clinical situation

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Viral contamination and infection are remotely possible but unlikely

Cryoprecipitate or fibrinogen concentrates

Not commonly recommended except when fibrinogen is needed.

Dosing

Adult

Each bag contains 80-100 U of factor VIII; base administration on fibrinogen levels, antithrombin III levels, and coagulation parameters

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled DIC with abnormal antithrombin III levels

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Benefits should outweigh risks associated with transfusion therapy; viral contamination and infection are remotely possible, although unlikely because of prescreening

Antifibrinolytic agents

These agents are used only after all other therapeutic modalities have been tried and deemed unsuccessful. Increase in circulating plasmin and laboratory evidence of decreased plasminogen should be documented. Antifibrinolytics may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer.
 
Related to the use of activated protein C is the recent utilization of protein C concentrate to treat coagulation abnormalities in adult patients with sepsis. Protein C concentrate was found to be safe and useful in restoring coagulation and hematologic parameters. Further study is required and prospective evaluation of its safety and efficacy are indicated.^{[49 ]}

Aminocaproic acid (Amicar)

Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Main problem is that thrombi that form during treatment are not lysed, and clinical significance of reducing bleeding is uncertain.

Dosing

Adult

Load 5-10 g IV slowly; followed by 2-4 g/h IV; not to exceed 30 g/d

Pediatric

Not established

Interactions

Estrogens may cause increase in clotting factors, leading to hypercoagulable state

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with DIC, important to differentiate between hyperfibrinolysis and DIC

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer unless definite diagnosis of hyperfibrinolysis has been made; caution in cardiac, hepatic, or renal disease

Tranexamic acid (Cyklokapron)

Used as alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

Dosing

Adult

Nonstandardized dosing: 25 mg/kg PO tid/qid; 1-2 g IV q8-12h

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; ongoing DIC and CNS involvement

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include gastrointestinal and visual disturbances and hypotension; caution in renal impairment

Follow-up

Further Inpatient Care

• Most patients with acute disseminated intravascular coagulation (DIC) require critical care treatment appropriate for the primary diagnosis, occasionally including emergent surgery.
• Assessment of severity of DIC (DIC score)
  • A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.^{[50 ]}
  • Clinical and laboratory parameters are measured with regularity (every 8 h).

Further Outpatient Care

• Patients who recover from acute DIC should follow up with their primary care provider or a hematologist.
• Patients with low-grade or chronic DIC may be treated by a hematologist on an outpatient basis after initial assessment and stabilization.

Inpatient & Outpatient Medications

• Outpatient medications may include antiplatelet agents for those with low-grade DIC and/or antibiotics appropriate to the primary diagnosis. 
• DIC can result from several clinical conditions including sepsis, trauma, obstetric emergencies, and malignancy. 
  • DIC results in intravascular coagulation mediated largely by exposure of blood to tissue factor via damage to the endothelium or by the expression of procoagulants by endothelial, malignant, and inflammatory cells. Ongoing coagulation in acute DIC quickly consumes coagulation factors and platelets producing a microangiopathic picture with simultaneous intravascular coagulation and hemorrhage. 
  • Diagnosis can be difficult, especially in cases of chronic, smoldering DIC, where clinical and laboratory abnormalities may be subtle. Treatment should primarily focus on addressing the underlying disorder. Platelet and factor replacement should be directed not at correcting laboratory abnormalities but to clinically relevant bleeding or procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage and is usually reserved for cases of chronic DIC. Subgroups of patients with sepsis who have DIC may benefit from activated protein C (APC), with consideration given to its anticoagulant effects. Recognition of the importance of inflammation in sepsis, coagulation, and DIC is vitally important in directing the development of novel therapeutic strategies.

Transfer

• Patients who are stable enough for transfer should be referred expeditiously to centers with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgical centers.

Complications

• Acute renal failure
• Life-threatening thrombosis and hemorrhage (in patients with moderately severe–to–severe DIC)
• Cardiac tamponade
• Hemothorax
• Intracerebral hematoma
• Gangrene and loss of digits
• Death

Prognosis

• The prognosis is influenced most by the underlying condition that led to DIC and the severity of the DIC.

Miscellaneous

Medicolegal Pitfalls

• Failure to establish early clinical suspicion and make a laboratory diagnosis, because the sequelae of DIC can be devastating
• Failure to focus on treating the underlying cause of DIC when the thromboembolic and bleeding complications of the process seem to be dominating the clinical picture

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Keywords

disseminated intravascular coagulation, DIC, thrombohemorrhagic disorder, sepsis, major trauma, abruptio placenta, fibrinolytic activation, endothelial injury, cytokines, tissue factors, thrombin, plasmin, coagulation cascade, acute DIC, chronic DIC, localized DIC, idiopathic purpura fulminans, septicabortion, deep venous thrombosis, DVT, hematemesis, hematochezia, azotemia, renal failure, hematuria, petechiae, purpura, hemorrhagic bullae, acral cyanosis, acute myelocytic leukemia, mucin-secreting adenocarcinomas, amniotic fluid embolism, eclampsia, retained dead fetus syndrome, myeloproliferative syndromes, paroxysmal nocturnal hemoglobinuria, Raynaud disease, giant hemangiomas

Kasabach-Merritt syndrome, hemolytic uremic syndrome, systemic DIC, procoagulant activation, inhibitor consumption, end-organdamage, end-organ failure, decreased platelet count, thrombosis, microvascular thrombosis, spontaneous hemorrhage, subacute bleeding, gram-negative sepsis, gram-positive infections, rickettsial, cytomegalovirus, CMV, varicella, hepatitis, histoplasma, malaria, mucin-secreting adenocarcinoma, placental abruption, acute fatty liver of pregnancy, transfusions, snakeenvenomation,liver disease, acute hepatic failure, leukemia, rheumatoid arthritis, Raynaud's disease, Raynaud disease, ulcerative colitis, Crohn disease, Crohn's disease, sarcoidosis, aortic aneurysms, acute renal allograft rejection

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
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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
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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
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The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Mary A Furlong, MD, and Brendan R Furlong, MD, to the development and writing of this article.

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