Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial

Abstract

Background Normal levels of plasma antithrombin (AT) activity might decrease heparin requirements to achieve an adequate level of anticoagulation during treatment with extracorporeal membrane oxygenation (ECMO). Acquired AT deficiency during ECMO is common, but formal recommendations on target, timing, and rate of AT supplementation are lacking. Thus, we conceived a pilot trial to evaluate the feasibility and safety of prolonged AT supplementation in patients requiring veno-venous ECMO for respiratory failure. Methods Grifols Antithrombin Research Awards (GATRA) is a prospective, randomized, single blinded, multicenter, controlled two-arm trial. Patients undergoing veno-venous ECMO will be randomized to either receive AT supplementation to maintain a functional AT level between 80 and 120% (AT supplementation group) or not (control group) for the entire ECMO course. In both study groups, anticoagulation will be provided with unfractionated heparin following a standardized protocol. The primary endpoint will be the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. Secondary endpoints will be the adequacy of anticoagulation and the incidence of hemorrhagic and thrombotic complications. Discussion GATRA is a pilot trial that will test the efficacy of a protocol of AT supplementation in decreasing the heparin dose and improving anticoagulation adequacy during ECMO. If positive, it might provide the basis for a future larger trial aimed at verifying the impact of AT supplementation on a composite outcome endpoint including hemorrhagic events, transfusion requirements, and mortality. Trial registration ClinicalTrials.gov, NCT03208270 . Registered on 5 July 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3386-4) contains supplementary material, which is available to authorized users.

Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study

“…The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients 39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation 40 . Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.…”

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO

“…Furthermore, we would recommend population pharmacokinetic and pharmacodynamic modeling, as well as prospective trials, to delineate the superior means of adjusting heparin therapy and AT supplementation to prevent adverse clinical outcomes. There is currently an ongoing pilot prospective randomized controlled, single-blinded, multicenter study that is evaluating the efficacy of a protocol of AT supplementation in decreasing heparin dose and improving anticoagulation adequacy in adult patients supported on ECMO for respiratory failure [89]. Such studies should also be performed in both children and neonates.…”

Outcomes With Direct and Indirect Thrombin Inhibition During Extracorporeal Membrane Oxygenation for COVID-19

“…18 This acquired AT deficiency is related to numerous factors including consumption of coagulation factors, reduced synthesis, elevated degradation by elastase generated in activated neutrophils, and in some cases disseminated intravascular coagulation. 19 Reduced levels of AT lead to heparin resistance and lack of therapeutic and stable anticoagulation. Thus, administration of UFH during ECMO can be cumbersome as it may require monitoring and supplementation of AT.…”