Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow‐up study

Unlabelled Box Essentials • Mild antithrombin deficiency may increase the risk of recurrent venous thromboembolism (VTE). • In a cohort study, we stratified patients with VTE to various cut‐off antithrombin levels. • A 1.6–3.7‐fold increased risk of recurrent VTE was observed in the lowest antithrombin categories. • Mild antithrombin deficiency (activity < 5th percentile of normal) increases recurrent VTE risk. Summary: Background Mild antithrombin deficiency (previously defined as antithrombin activity below 70% or 80%) has been associated with a 2.4–3.5‐fold increased risk of recurrent venous thromboembolism (VTE). This finding may have implications for duration of antithrombotic therapy in VTE patients with mild antithrombin deficiency. Objectives To externally validate whether mild antithrombin deficiency is a risk factor for recurrent VTE. Methods In a population‐based cohort study, patients with a first VTE (n = 2357) were stratified according to percentile cut‐off antithrombin levels (< 5th [< 87%], 5–10th [87–92%], > 10th percentile [> 92%]) and functional antithrombin levels (< 70%, 70–80%, > 80%). Results During a median follow‐up of 7.4 years, 361 recurrent events occurred (incidence rate, 2.5/100 patient‐years). We observed an increased risk of recurrent VTE in the lowest antithrombin activity category (< 5th percentile; < 87%) as compared with antithrombin activity that was > 10th percentile (> 92%), with an adjusted hazard ratio (HR) of 1.5 (95%CI, 1.0–2.3). When analyses were stratified to antithrombin cut‐off criteria of< 70% vs. patients with antithrombin activity > 80%, the adjusted HR for venous recurrence was 3.7 (95% CI, 1.4–9.9). Mild antithrombin deficiency was able to predict recurrent VTE over at least 8 years of follow‐up and the association remained present when the population was stratified to the presence or absence of thrombosis risk factors. Restriction analyses, where patients who used anticoagulation at time of blood draw and those who reported drinking ≥ 5 glasses alcohol daily were excluded, did not materially affect these outcomes. Conclusion This study confirms that mild antithrombin deficiency is a risk factor for recurrent VTE.