What is the role of antithrombin replacement in the treatment of disseminated intravascular coagulation (DIC)?

Updated: Dec 06, 2020
  • Author: Marcel M Levi, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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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. [62, 84, 85, 86] 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. [87]

On day 0, the patients’ backgrounds and antithrombin activity were identical in the 2 groups. [87] 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. [87]

There were also no differences in the time course of the platelet counts, coagulation and fibrinolytic markers, and DIC scores in the 2 groups. [87] 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. [88]

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. [88]

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. [89]

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