Antithrombin Iii (At3) in Covid-19: A Pilot Study Defining At3 Levels and Safety of Exogenous At3

ABSTRACT

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 antiinflammatory 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. METHOD(S) 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. RESULT(S) 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). CONCLUSION(S) 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.