Disseminated Intravascular Coagulation (DIC) Treatment & Management

Updated: Aug 23, 2022
  • Author: Marcel M Levi, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Treatment

Approach Considerations

Treatment of disseminated intravascular coagulation (DIC) is controversial, but treatment guidelines have been published and offer broadly similar recommendations. [42, 72, 73] Treatment should primarily focus on addressing the underlying disorder. DIC can result from numerous clinical conditions, including sepsis, trauma, obstetric emergencies, and malignancy. Surgical management is limited to primary treatment of certain underlying disorders.

Management of the DIC itself has the following basic features:

  • Monitor vital signs
  • Assess and document the extent of hemorrhage and thrombosis
  • Correct hypovolemia
  • Administer basic hemostatic procedures when indicated

Platelet and factor replacement should be directed not at simply correcting laboratory abnormalities but at addressing clinically relevant bleeding or meeting procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage; it is usually reserved for cases of chronic DIC. Heparin is appropriate to treat the thrombosis that occurs with DIC. It also has a limited use in acute hemorrhagic DIC in a patient with a self-limited condition of acral cyanosis and digital ischemia.

In general, antifibrinolytic agents (eg, tranexamic acid, ε-aminocaproic acid) should be avoided in DIC because they are known to produce thrombotic complications, such as myocardial infarction and renal artery thrombosis when there is systemic clotting. However, in patients with trauma and massive blood loss, tranexamic acid has been shown to be effective in reducing blood loss and improving survival. [74]  Similarly, in massive postpartum hemorrhage, high-dose tranexamic acid has been shown to be effective. [75]  Antifibrinolytics also may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer when alpha-2-antiplasmin is uniquely decreased. These agents should always be administered with heparin to arrest their prothrombotic effects. [19]

Patients with DIC should be treated at hospitals with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgery. Patients who present to hospitals without those capabilities and who are stable enough for transfer should be referred expeditiously to a hospital that has those resources.

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Management of Underlying Disease

The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder. [76] Often, the DIC component will resolve on its own once the underlying disorder is addressed.

For example, if infection is the underlying etiology, the appropriate administration of antibiotics and source control is the first line of therapy. As another example, in case of an obstetric catastrophe, the primary approach is to deliver appropriate obstetric care, in which case the DIC will rapidly subside. If the underlying condition causing DIC is not known, a diagnostic workup should be initiated. Most patients with acute DIC require critical care treatment appropriate for the primary diagnosis, occasionally including emergency surgery.

A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities. [2] Clinical and laboratory parameters are measured with regularity (every 8 hours).

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Administration of Blood Components and Coagulation Factors

Typically, DIC results in significant reductions in platelet count and increases in coagulation times (prothrombin time [PT] and activated partial thromboplastin time [aPTT]). However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

Platelets

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding (eg, in the early postoperative phase or if an invasive procedure is planned).

The threshold for transfusing platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 × 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patient’s clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings. [77] In actively bleeding patients, platelet levels from 20 × 109/L to 50 × 109/L are grounds for platelet transfusion (1 or 2 U/kg/day).

Coagulation factors

Previously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might “add fuel to the fire” of consumption; however, this has never been established in research studies. [78]

It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (eg, factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk. Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjuction with fresh frozen plasma (FFP) administration.

Data suggest that the consumption-induced deficiency of coagulation factors can be partially rectified by administering large quantities of FFP, particularly in patients with an international normalized ratio (INR) higher than 2.0, a 2-fold or greater prolongation of the aPTT, or a fibrinogen level below 100 mg/dL. [79] The suggested starting dose is 15 mg/kg. [42]

Repeated measurement of global clotting tests (eg, aPTT and PT) might be useful for monitoring the coagulation defect. In case of a (relative) vitamin K deficiency in the face of consumption, administration of vitamin K may be required. [18, 6, 19]

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Anticoagulation

Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC. [80] However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.

Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates (eg, purpura fulminans or acral ischemia). [81, 82, 83] The use of heparin in chronic DIC where there is preponderance of coagulation without consumption coagulopathy is well established. [84] In other patients with acryl cyanosis and digital ischemia and DIC, heparin can be safely administered at lower doses. A dose of 4-5 U/kg constant infusion without a 80-U/kg bolus is a safe means to deliver heparin to the DIC without increasing the bleeding risk.

The use of low-molecular-weight heparin (LMWH) has been studied in DIC. Enoxaparin has been used for treatment and prophylaxis of chronic DIC in specific clinical situations. In a multicenter, cooperative, double-blinded trial from Japan that compared dalteparin with unfractionated heparin, the former was associated with a decreased bleeding tendency and reduced organ failure. [82] One randomized clinical trial showed LMWH to be superior for reducing 28-day mortality in patients with severe sepsis. [85]

Patients with DIC may benefit from prophylaxis to prevent venous thromboembolism, which will not be achieved with standard low-dose subcutaneous heparin. Theoretically, the most logical anticoagulant agent to use in DIC is directed against tissue factor activity.

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Restoration of Anticoagulant Pathways

Strategies for restoring anticoagulant pathways have primarily involved administration of antithrombin concentrate or recombinant human APC (drotrecogin alfa); however, drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011. Tissue factor (TF) pathway inhibitor (TFPI) and recombinant thrombomodulin (rTM) have also been studied.

Antithrombin

The antithrombin pathway, an important inhibitor of coagulation in normal patients, is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function. [65, 86, 87, 88] To date, however, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.

Most of the randomized controlled trials involved patients with sepsis or septic shock. In the later clinical trials, very high doses of antithrombin concentrate were used to attain supraphysiologic plasma levels. A series of relatively small trials showed a modest reduction in mortality in antithrombin-treated patients. However, in none of the trials did the effect reach statistical significance.

A large-scale multicenter, randomized controlled trial to directly address this issue showed no significant reduction in mortality of septic patients who were treated with antithrombin concentrate. In this trial, 2114 patients with severe sepsis and associated organ failure were included. Surprisingly, subgroup analyses indicated some benefit in patients who did not receive concomitant heparin, but this observation needs prospective validation.

In another study that evaluated the effects of antithrombin in 23 patients with DIC diagnosed on the basis of the Japanese Association for Acute Medicine (JAAM) criteria (a newly developed diagnostic algorithm for critical illness), patients were treated with either high-dose (60 IU/kg/day; 12 patients) or low-dose (30 IU/kg/day; 11 patients) antithrombin concentrates for 3 days. [89]

On day 0, the patients’ backgrounds and antithrombin activity were identical in the 2 groups. [89] However, on day 7, the JAAM DIC score and PT ratio were significantly improved in comparison with those on day 0. However, mortality at 28 days and interaction within the administered antithrombin doses showed no differences. [89]

There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups. [89] The authors concluded that the effects of antithrombin on prognosis and coagulation and fibrinolytic parameters are independent of the doses administered in patients who have DIC associated with the systemic inflammatory response syndrome (SIRS) or sepsis.

A retrospective Japanese study in 1784 patients with severe sepsis and DIC, 715 of whom received treatment with antithrombin, found a statistically significant association between antithrombin supplementation and lower in-hospital all-cause mortality (odds ratio 0.748, P = 0.034). However, that association was not evident on quintile-stratified propensity score analysis or propensity score matching analysis. [90]

In this study, similar results were observed in DIC patients with or without concomitant heparin administration. In addition, although the number of transfusions needed was higher in the group that received antithrombin, the number of severe bleeding complications was not. [90]

A recombinant form of antithrombin, antithrombin gamma, is being developed as an alternative to antithrombin derived from human plasma. In a randomized, open-label trial in 222 patients with sepsis-induced DIC, the safety and efficacy of antithrombin gamma were comparable to that of plasms-derived antithrombin. [91]

Tissue factor pathway inhibitor

The TFPI mechanism of coagulation inhibition has 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. [92] However, a large phase III trial of TFPI in humans with DIC did not show any mortality benefit. [93]

Recombinant thrombomodulin

In Japan, rTM is widely used for treatment of DIC. Thrombomodulin binds with thrombin, and the resulting complex allows the conversion of protein C to APC. Additionally, thrombomodulin can also bind high-mobility group B (HBGM-1), which inhibits the inflammatory process. [79]

rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials. [94] It was evaluated in a randomized controlled study involving 234 subjects and was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis. [95]

However, a meta-analysis by Zhang et al found that in patients with infection complicated by DIC, treatment with rTM does not decrease short-term mortality: the risk ratio for 28- or 30-day mortality was 0.81 in randomized controlled trials and 0.96 in observational studies. [96]  In a systematic review and meta-analysis by Yamakawa et al of rTM for sepsis-induced DIC, pooled relative risk of 28-30 day mortality was 0.81 (95% CI, 0.62–1.06) in randomized controlled trials, indicating a non‐significant reduction in mortality, and 0.59 (95% CI, 0.45–0.77) in observational studies; results suggested that the probability of rTM therapy having a beneficial effect increases with increasing baseline risk. [97]

Inoue et al reported benefit with rTM treatment of DIC caused by noninfectious complications of allogeneic hematopoietic stem cell transplantation, such as acute graft-versus-host disease or thrombotic microangiopathy. In 12 episodes of DIC in 10 patients, the recovery rate was significantly higher than in historical controls. [98]

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Consultations

Consult a hematologist for assistance with diagnosis and management if the clinical picture is suggestive of DIC. 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.

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Long-Term Monitoring

Outpatient medications may include antiplatelet agents for those with low-grade DIC, antibiotics appropriate to the primary diagnosis, or both. 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. Chronic DIC in patients with cancer can be managed with subcutaneous heparin or low molecular weight heparin.

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