Antithrombin Replacement and Extracorporeal Membrane Oxygenation: The time is ripe for a Simpler Solution

The use of extracorporeal membrane oxygenation (ECMO) circuit obligates the administration of systemic anticoagulation to avoid patient and circuit thrombosis. Identifying an optimal approach for achievement of target pharmacologic anticoagulation remains elusive with controversy existing between the ideal agent employed, dosing protocols, monitoring approaches, and supplemental therapies including antithrombin (AT) administration in the context of unfractionated heparin (UFH) therapy.1 With this in mind, we read with great interest the salient study by Liviskie et al. investigating the effectiveness of AT dosing equations to predict postdose AT levels in a cohort of 41 pediatric patients under 1 year of age.2 Important findings included a low baseline mean AT level of 43% (±13%) and mean postdose AT level of 52.6% (±14.2%) with poor correlation using weight-based dosing equations (R2 = 0.082) that improved with integration of desired change in AT level from baseline augmented with adjustments of the patients’ weight supplemented with an adaptation utilizing the estimated weight from the volume of the ECMO circuit (R2 = 0.427). We applaud the authors for providing highly granular detail on AT dosing on a relatively large number of infant ECMO patients along with the concurrent analysis leveraging a robust quantity of prediction equations that included commonly accepted as well as manufacturer recommended and institutional adjusted calculations. Although intriguing data, the clinical appropriateness of AT replacement or its broader implications into the broader context of systemic anticoagulant administration during ECMO support remain unclear. Anticoagulation effect of UFH is generated by the marked upregulation of AT activity after complexing with endogenous or exogenous heparinoids. The indirect action of UFH is problematic because of the need for AT. This warrants consideration for replacement of AT in settings of congenital or acquired AT deficiency. Exogenous AT has been demonstrated to reduce the amount of UFH required to achieve the desired clinical response but does so in a highly variable manner with a fundamentally unpredictable effect size. The target AT levels to achieve optimal anticoagulation is loosely defined (60–120%) and is further bewildered by pharmacokinetic differences between available formulations.3 Despite these arbitrary goals, evidence suggests that AT levels as low as 30–50% are satisfactory to attain adequate anticoagulation targets.4 Taken together, in ECMO patients, AT replacement remains controversial with noteworthy absence of superior outcomes and perhaps more concerning trend toward increased mortality and a higher incidence of thrombotic and hemorrhagic events.1,5,6 On the grounds of this framework, it is useful to consider alternatives that offer simplification of management approaches for the achievement of harmony between hemostatic and thromboembolic concerns. The contemporary administration of UFH relies on a battery of laboratory testing and the inherent reliance upon endogenous levels of an essential circulating secondary protein; AT. In stark contrast, direct thrombin inhibitors (DTIs) produce transient inhibition of thrombin to downregulate the cleavage of fibrinogen into its active form and is, in a clinically relevant fashion, accomplished entirely without the requirement of a cofactor, such as AT.7 DTIs offer additional potential advantages as they are capable of binding to soluble and clot-bound thrombin thereby facilitating abatement of existing thrombus propagation.8 Over the past decade, an expanding body of evidence has emergence demonstrating the safety and potential superiority of bivalirudin, a member of the DTI class, in realizing the delicate balance between hemorrhage and thrombosis in adult and pediatric ECMO patients.9,10 Titration of DTIs remains reliant primarily upon aPTT and, importantly, does not require consideration of AT level or replacement in settings of quantitative deficiencies of AT. As a consequence, leveraging DTIs offer the potential for improvement in cost effectiveness derived in part from reduction in AT assay obtainment and the expensive administration of exogenous AT replacement.10 Our center established bivalirudin as the first-line anticoagulant therapy in adult and pediatric ECMO in 2017 and since then we have demonstrated a dramatic reduction in AT assays and AT replacement per ECMO hour as compared to a historic cohort (Figure 1). Equally impactful is a large reduction in the dose of AT administered per ECMO day achieved through the migration to bivalirudin as our first-line anticoagulant with a decrease of 86% in the infant ECMO population (28.3 vs. 9.2 units per ECMO day) and 67% reduction in the aggregated adult plus pediatric ECMO population (68.5 vs. 9.5 units per ECMO day). Consequently, it is plausible that transition to a DTI-based anticoagulation approach may offer at least comparable clinical outcomes while accomplishing this with a streamlined, and simplified, dosing titration approach obviates the need to consider circulating levels of AT.Figure 1.: Antithrombin Labs per ECMO day (plot, scale on left Y-axis) overlaid with percentage of ECMO runs maintained on bivalirudin (bar graph, right Y-axis) by year of ECMO run (X-axis). The vertical dashed line in 2017 denotes the year of transition at our center to bivalirudin as first line for systemic anticoagulation in adult and pediatric ECMO. This figure represents an aggregate of all adult and pediatric ECMO runs in the included years.Hemostatic management on ECMO continues to be among the most vexing aspects of ECMO support and is contingent upon a myriad of competing variables with management complexity exacerbated by a multitude of available laboratory assays and pharmacologic therapies. For those centers relying upon UFH, further clarification is needed as to the role of AT as it relates to thresholds triggering replacement, target AT level, and AT dosing calculations. Although Liviskei et al. accomplished the admirable task of analyzing a variety of AT equations effectiveness, it is rather telling that the postreplacement AT level remained below that recommended by ELSO with a vast majority failing to achieve the desired therapeutic effect. Given the developing evidence in support of DTI along with its inherent advantages with regard to laboratory monitoring and ease of agent titration, it may offer a simplified, and cost-effective, strategy for the maintenance of systemic anticoagulation of ECMO patient.