Antithrombin iii (at3) in covid-19: a pilot study defining at3 levels and safety of exogenous at3

Introduction: COVID pathogenesis involves a dysregulated inflammatory state and coagulopathy. Affected patients are at risk for thrombosis and bleeding as well as cytokine storming. Antithrombin 3 (AT3) has anti-inflammatory and anti-coagulant properties but its role in COVID is unknown. The incidence of AT3 deficiency (< 80% activity) in COVID is unknown. We hypothesize that AT3 supplementation is safe in patients with COVID and AT3 deficiency. Methods: Prospective randomized control trial of COVID, IRB approved at 2 centers from July 2021 to March 2022. Those with plasma AT3< 100% were randomized to either standard of care (SOC) or SOC+AT3 q48hr weight-based for a goal of 120% for up to 5 doses. An additional group with AT3>100% received SOC. Data are compared using ANOVA and Fisher’s exact test. Enrollment was concluded early due to reduced COVID cases and reduced length of stay. Results: In 531 subjects assessed for eligibility, 324 did not meet inclusion criteria, 151 did not consent, 4 withdrew consent, and 52 subjects completed the study. Enrollment AT3 (M±SD) was 96±12%. AT3 levels were < 100% in 40 (77%) and < 80% in 11(21%). SOC+AT3, SOC only, and AT3>100% had a Disseminated Intravascular Coagulation (DIC) score change (M±SD) of 0.4±1.5, -0.13±1.85 and 0±1.2, respectively, (p=0.63). Hospital length of stay was 13.9±14.9, 9.1±8.4, and 13±0.5 days respectively, (p=0.39). Mortality occurred in 2 (10%), 3 (15%), and 3 (25%), respectively, (p=0.56). There was 1 bleeding event in a subject with AT3>100% and no bleeding events were observed with exogenous AT3. There were no observed drug-related adverse events. Of the 18 subjects assigned to receive AT3, 15 received a median of 2 doses (IQR 2) for a total of 38 doses with a median dose of 1825.5 IU (IQR 794). Conclusions: COVID is associated with a relative AT3 deficiency and was observed in 21% of this cohort with reports of .02% to .2% in the general population. Exogenous AT3 supplementation was safe with no bleeding complications or drug-related adverse events. There was no significant change in outcomes, likely due to under-dosing and sample size. Further studies should evaluate higher doses of exogenous AT3 and focus on higher risk groups.