“Management strategies for anticoagulating adult ECMO patients and optimal management continue to be a work in progress.”
In their study, Mansour et al. analyzed 50 venoarterial ECMO patients (42% postcardiotomy shock) who had antithrombin activity measured serially for 7 days with 11 total measurements per patient. Heparin responsiveness was assessed based on anti-Xa level, daily heparin dose, and a derived heparin sensitivity index, which was calculated by dividing hourly per kilogram heparin dose by anti-Xa level. Antithrombin supplementation was performed in select patients with heparin resistance, but patients were censored in the analysis at the time of antithrombin supplementation. The main study findings related to antithrombin were (1) median antithrombin activity was low at ECMO cannulation (median activity = 51%), (2) antithrombin activity increased significantly by 6 h after cannulation (median activity = 55%, P = 0.04), (3) 64% of patients had a time-weighted average antithrombin activity less than 70% during ECMO, and (4) 71% of patient time on ECMO was spent with antithrombin activity less than 70%. In addition, antithrombin activity was not related to the heparin responsiveness index or anti-Xa activity and was only weakly correlated with daily heparin dose. Patients who experienced bleeding had a significantly higher time-weighted average antithrombin activity (69% vs. 57%, P = 0.004), but there was no apparent relationship between antithrombin activity and clinical thrombosis. The study’s conclusion was that routine measurement of antithrombin activity during ECMO and antithrombin supplementation to improve heparin responsiveness are not indicated. In addition, typical antithrombin deficiency has no apparent impact on the ability to anticoagulate patients into their target anticoagulation range.
ECMO is a life-saving therapy that can provide respiratory support or combined cardiopulmonary support, depending on cannula configuration. An ECMO circuit exposes patients’ blood to an extracorporeal, nonendothelial surface that can exceed 2.5 m2, activating coagulation through the intrinsic (contact activation) pathway. Adult ECMO patients may also present with a hypercoagulable state, as noted during the COVID-19 pandemic, due to multiple factors that include increased levels of fibrinogen, factor VIII, and von Willebrand factor. Venoarterial ECMO patients are at high risk for thromboembolic complications with a reported thrombosis incidence of 20 to 30%. When thromboembolic complications occur during venoarterial ECMO, they can have devastating consequences, including stroke, limb ischemia, or even death.
Venoarterial ECMO patients frequently present with shock liver and rapidly changing procoagulant and anticoagulant factor levels, including antithrombin. Anticoagulation for adult ECMO patients is a critical component of management, with current best practice based on observational studies, expert opinion, and subspecialty society guidelines, all of which suggest that unfractionated heparin should be the first-line treatment. Despite the mainstay use of heparin because of its short half-life and titratability, it requires a cofactor antithrombin (also called antithrombin III) to inhibit thrombin and activated factor X, and there is also the potential for heparin induced thrombocytopenia and heparin resistance with the drug.
The study of Mansour et al. adds to a complex body of literature on antithrombin and its repletion in critical illness. In contrast to the findings of Mansour et al., a 2021 cohort study that included 17 venoarterial ECMO and 22 venovenous ECMO patients reported that heparin dose correlated significantly with anti-Xa activity, and low anti-Xa activity was associated with residual thrombin generation in vitro. These findings suggest that low antithrombin activity and heparin resistance during ECMO could increase thrombotic risk; however, antithrombin activity was significantly lower for venoarterial ECMO patients in this study (30 to 50%) compared to the Mansour study. Although Mansour et al. found low antithrombin activity (less than 70%) to be common, only 16% of patients in the cohort had antithrombin activity less than 30%, and 4% had antithrombin activity less than 20%. As a result, drawing generalized conclusions about heparin responsiveness, also defined as heparin resistance, may not be appropriate because the relationship between antithrombin, heparin, and anti-Xa may not be monotonic. Further, with the relatively small size of the cohort in the study of Mansour et al. meaningful subgroup analysis among patients with only severe antithrombin deficiency was not possible. As a result, the clinical significance of mild antithrombin deficiency should not be applied to all cases of antithrombin deficiency.
Other insights from the study of Mansour et al. include the fact that most patients had lower antithrombin activity during venoarterial ECMO cannulation; however, median antithrombin activity increased to near normal (median value = 71%, P < 0.001) by 4 days. Although antithrombin supplementation is commonly used to treat heparin resistance in ECMO patients, determining a critical level for supplementation remains to be determined. Management strategies for anticoagulating adult ECMO patients and optimal management continue to be a work in progress. Some ECMO centers have switched to bivalirudin or argatroban, direct thrombin inhibitors that do not require antithrombin for their anticoagulant effect as first-line anticoagulants. Use of direct thrombin inhibitors allows for greater time in the therapeutic range, but potential downsides include higher cost and the lack of a rapid reversal agent.
Measuring antithrombin activity during ECMO and supplementing when antithrombin reaches a critically low value may help to optimize heparin anticoagulation and potentially reduce bleeding and thrombotic complications, but patients’ underlying disease state and the high morbidity and mortality associated with ECMO are likely to confound outcomes in nonrandomized studies. In addition, accurately measuring hemostatic outcomes such as bleeding and thrombosis in critically ill ECMO patients is challenging, as noted in a recent National Heart Lung Blood Institute symposium, which recently attempted to standardize definitions for clinically meaningful outcomes.
Based on currently available evidence, a “less is more” approach may provide the most clinically relevant perspective. The data of Mansour et al. provide evidence that the commonly occurring decrease in antithrombin activity that occurs in venoarterial ECMO patients is of minimal clinical significance vis-à-vis the overall complexity of managing a critically ill ECMO patient. Routine monitoring of antithrombin activity does not appear warranted, and antithrombin supplementation is probably only appropriate in cases of severe antithrombin deficiency when target anticoagulation levels cannot be achieved with a high dose of heparin. In these situations, switching to a direct thrombin inhibitor is also a reasonable alternative. One randomized trial showed no benefit to antithrombin supplementation in venovenous ECMO patients with mild antithrombin deficiency. Notably, one busy adult ECMO center has reported good clinical outcomes for venoarterial ECMO patients who received no systemic anticoagulation during ECMO.
Despite the potentially challenging aspects of studying critically ill intensive care unit patients, pragmatic randomized clinical trials are needed in adult ECMO patients to evaluate optimal anticoagulation practice and its clinical implications. These trials should limit patient heterogeneity based on disease state, utilize recommended definitions for bleeding outcomes, and be sufficiently powered to detect clinically meaningful differences in outcomes. At least one randomized clinical trial in Australia, BivaLirudin versUS Heparin in Extracorporeal Membrane Oxygenation (BLUSH) appears near commencement and should add valuable information to the ECMO anticoagulation literature in the next few years.
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