eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Disseminated Intravascular Coagulation: Treatment & Medication

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

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.

Adult

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

Pediatric

Not established

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

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

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.

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

Increases anticoagulation effects of heparin

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.

Adult

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

Pediatric

Not established

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

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)

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.

Adult

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

Pediatric

Not established

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

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.

Adult

Based on platelet count and clinical situation

Pediatric

Not established

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

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.

Adult

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

Pediatric

Administer as in adults

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.

Adult

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

Pediatric

Not established

Documented hypersensitivity; uncontrolled DIC with abnormal antithrombin III levels

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.

Adult

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

Pediatric

Not established

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

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

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.

Adult

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

Pediatric

Not established

Documented hypersensitivity; ongoing DIC and CNS involvement

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

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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