Major bleeding and stroke in patients with hemophilia and atrial fibrillation

Abstract Background Congenital hemophilias affect about 30,000 US individuals (0.01% of the population) and atrial fibrillation (AF) about 10.5 million US individuals (4.5% of the population). Stroke prevention in this population is limited to expert opinion with formal guideline development hindered by a lack of clinical trials. Herein, we correlate outcomes of major bleeding and ischemic stroke with CV risk factors and antithrombotic management in our patient cohort. Methods This is a retrospective review (minimal risk study) of patients with hemophilia A, B, or C and concomitant AF diagnosed between 2000 and 2025. Patients were identified through a Mayo Clinic Rochester database using key terms. All cases were manually reviewed in the electronic medical record for appropriateness. Major bleeding was defined per International Society on Thrombosis and Haemostasis (ISTH) criteria. Stroke and bleeding risk were based on CHA₂DS₂-VASc and HAS-BLED scores. Analyses were performed using BlueSky Statistics software, with chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables. Results A total of 21 patients were identified. Of these, 18 (86%) were male. Common comorbidities included type 2 diabetes (T2DM) in 14 (67%), hyperlipidemia in 18 (86%), hypertension in 18 (86%), and coronary artery disease in 12 (57%). Fifteen (71%) were never smokers. One patient (5%) had HIV on antiretroviral therapy, and five (24%) had a history of localized, resected cancer. Congenital hemophilia A was present in 12 patients (57%), hemophilia B in 5 (24%), and hemophilia C in 5 (24%). The median age at hemophilia diagnosis was 55.3 years. Hemophilia severity was mild in 17 (81%) and moderate in 4 (19%). Median factor level was 33% (SD=12.77%). Most were diagnosed with hemophilia from accumulation of minor bleeding events and family history. Six (29%) had major bleeds prior to AF diagnosis. The median age at AF diagnosis was 65.6 years. Paroxysmal AF was the most common subtype (11 patients; 52%), followed by permanent (5; 24%) and persistent (5; 24%). Median CHA₂DS₂-VASc and HAS-BLED scores at AF diagnosis were 2 and 1, respectively. At AF diagnosis, 2 patients (10%) were already on antithrombotic therapy (aspirin 81 mg [ASA]), both for recent transcatheter aortic valve replacement (TAVR). For AF-related stroke prevention, 5 patients (24%) were started on ASA and 5 others (24%) were started on apixaban. Cardioversion was performed in 5 patients (24%) and ablation in 2 (10%)). Five (24%) underwent procedural interventions (3 Watchman devices, 2 Maze procedures). Three patients (14%) had at least one major bleed following AF diagnosis. Bleed locations included traumatic intracranial, severe epistaxis, and spontaneous intracranial (one each). At the time of bleed, one patient was on ASA and two were on no antithrombotic or anticoagulation. One patient (5%) had a second major bleed – a muscle hematoma. He was not on antithrombotic or anticoagulation at the time. Two bleeds were fatal. Patient 1 was an 83-year-old male with moderate hemophilia A, a history of major GI bleed prior to AF diagnosis, a CHA₂DS₂-VASc score of 7 on ASA (taken for 11.5 years), and a HAS-BLED score of 3 who died of complications from severe epistaxis.Patient 2 was a 56-year-old male with moderate hemophilia B, a CHA₂DS₂-VASc score of 1, and a HAS-BLED score of 1 that died from a spontaneous intracranial bleed. One patient experienced an ischemic stroke: a 71 year old male with moderate Hemophilia A, a CHA₂DS₂-VASc score of 7, and a HAS-BLED score of 5 who was anticoagulated on apixaban. Conclusion: Despite the relatively low use of anticoagulation and antithrombotic, nearly 15% of this cohort experienced major bleeding after AF diagnosis, including two fatal events. Ischemic stroke was rare but occurred in a high-risk patient that was anticoagulated with apixaban. These findings demonstrate limitations of existing risk-stratification tools in this unique population, and support the need for larger studies and evidence based guidelines for patients with bleeding disorders and AF.