Characterization and risk factors of anticoagulation-related bleeding in patients with thrombotic antiphospholipid syndrome: An analysis using a synthetic real-world data platform Free

Introduction: Antiphospholipid Syndrome (APS) is a systemic autoimmune condition associated with an elevated risk of both arterial and venous thrombosis. Patients with APS also experience bleeding frequently for which several hypotheses have been presented {Orsi 2024}, and anticoagulant therapy (AT) for secondary thromboprophylaxis is a major predisposing factor. However, the burden and predictive factors of bleeding in thrombotic APS are not well-defined. Leveraging a synthetic data platform, we aimed to characterize bleeding event demographics and risk factors in persons with APS and history of VTE receiving AT.

Methods: Using the MDClone platform, we identified persons diagnosed with APS between 2018-2025 with a history of acute venous thromboembolism (VTE) using appropriate ICD-10 codes. The MDClone platform produces privacy-maintained synthetic data based on real health system data from the Washington University in St Louis/Barnes-Jewish Hospital system and contains information that links several hospital information systems. Inclusion required the presence of (1) ≥1 outpatient anticoagulant prescriptions (per year of follow-up) and (2) ≥ 6 months of follow-up (calculated from anticoagulation initiation until the last database update (June 2025) or death). We defined bleeding using the ISTH definitions of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) using a validated administrative algorithm based on type and specific positions of ICD-10 codes and event verification with the presence/absence of blood transfusion codes and hemoglobin (Hb) drop > 2 g/dL. The primary outcomes of interest included clinically relevant bleeding (CRB), defined as composite of any MB or CRNMB event.

Multivariate logistic regression models identified risk factors for both CRB and MB. For CRB, the analysis was adjusted for age, sex, race, warfarin use (versus alternate anticoagulant therapy), anemia (Hb <10 g/dL), thrombocytopenia (platelets <100 x10⁹/L), uncontrolled hypertension (systolic blood pressure >140 mmHg), estimated glomerular filtration rate (GFR) <30mL/min/1.73m², chronic liver disease, and alcohol use.

Results: A total of 451 APS patients with acute VTE were analyzed (median follow-up: 4.1 years, IQR 2.0–5.9). The cohort was predominantly female (64.7%) and White (67.0%), with a median age at AT initiation of 54 years (IQR 40–65). AT consistent of warfarin in 59% and direct oral anticoagulants (DOACs) in 33.5%. Among patients with any available antiphospholipid antibody (aPL) laboratory data (n=349), 176 (50.4%) had at least one positive aPL. Among 105 patients with complete aPL profiles, 15.3% (n=23) were triple positive, 8.7% (n=13) double positive, and 46% (n=69) single positive. Patients with triple positive disease were more likely to receive warfarin (87.0%) compared to double positive (52.2%) and single positive (46%). Moderate-to-high IgG antibody titers (>40) occurred in 57 (19.7%) of the 289 patients with IgG titers available.

Within the full cohort, CRB events occurred in 32.4% (n=146), of which, MB occurred in 9.5% (n=43) and CRNMB occurred in 28.8% (n=130). MB consisted of critical-site bleeding in 3.5% and overt bleeding in 6.2%. Median time to the first MB event was 12.1 months (IQR 5.0–32.7). In the subgroup of patients with at least 1 positive aPL (n=176), rates of MB, CRNMB, and CRB were similar at 11.4%, 29.5%, and 33.5%, respectively.

For the composite CRB outcome, female sex (OR 2.28; 95% CI, 1.37–3.79; p=0.001), warfarin use (OR 1.68; 95% CI, 1.05–2.70; p=0.032), liver disease (OR 1.89; 95% CI, 1.00–3.57; p=0.049), and anemia (OR 2.72; 95% CI, 1.47–5.02; p=0.001) emerged as independent risk factors. Multivariate analysis revealed warfarin use (OR 2.67; 95% CI, 1.22–5.82; p=0.014) and anemia (OR 3.37; 95% CI, 1.66–6.82; p=0.001) as significant predictors of MB. In a subgroup analysis by patients with complete aPL profiles, neither double/triple aPL positivity nor moderate-to-high IgG titers correlated with increased bleeding risk.Conclusions: In this study of patients with thrombotic APS with VTE on AT, rates of MB and CRNMB were high, with MB occurring in 9.5% of patients. Warfarin therapy, anemia, female sex, and liver disease significantly increased the risk of bleeding in our cohort. Future studies should further investigate bleeding risks compared to patients without APS and explore additional immunomodulatory approaches to potentially mitigate bleeding complications.