Implementation of 2020 international guidelines in acquired hemophilia: Insights from a decade of national registry data in Spain

Abstract

Abstract Background: Acquired hemophilia A (AHA) is a rare but potentially life-threatening autoimmune bleeding disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). Due to its infrequent occurrence and heterogeneous presentation, diagnosis is often delayed, and treatment approaches vary widely across institutions. In 2014, the Spanish Society of Thrombosis and Hemostasis launched a national registry to document the clinical characteristics, management, and outcomes of AHA. The publication of international guideline in 2020 provided an opportunity to evaluate their real-world impact. Aims: To assess the effect of international guideline implementation on diagnostic efficiency, treatment patterns, clinical outcomes, and mortality in patients with acquired hemophilia in Spain. Methods: This is a retrospective, observational analysis of 257 patients diagnosed with AHA between January 2014 and March 2024 and included in the national registry. Patients were stratified into two cohorts: Group 1 (diagnosed between 2014 and 2020, pre-guideline) and Group 2 (diagnosed between 2021 and 2024, post-guideline). We compared demographic variables, bleeding characteristics, laboratory findings, immunosuppressive and hemostatic strategies, treatment outcomes, and causes of death. Statistical comparisons used chi-square and Mann-Whitney U tests, with significance set at p<0.05. Results: The median age of the cohort was 75 years (IQR 62–83), and 58% were male. Following guideline implementation, diagnostic timelines significantly improved, with the median time from first bleeding symptom to diagnosis reduced from 14.5 to 7 days (p<0.001). While baseline FVIII activity and inhibitor titers remained similar across cohorts (median FVIII 1 IU/dL, inhibitor 18 BU), the proportion of patients with underlying malignancy increased from 23.8% to 40% (p=0.012), reflecting a shift toward broader diagnostic awareness and inclusion. Hemostatic treatment patterns also evolved. The use of recombinant activated factor VII (rFVIIa) as first-line therapy increased significantly from 35.6% in the pre-guideline cohort to 43% post-guideline (p=0.014), with high response rates in both groups. Activated prothrombin complex concentrate (aPCC) use remained stable at around 25%. Notably, seven patients (8.8%) in the post-guideline group received off-label emicizumab prophylaxis for a median of 8 weeks, with no breakthrough bleeding or thrombotic events reported. Immunosuppressive strategies shifted in line with guideline recommendations. Corticosteroid monotherapy became more common (42% post-guideline vs. 20% pre-guideline, p=0.009), particularly in patients with favorable risk profiles (FVIII >1%, inhibitor <20 BU), who represented approximately 40% of the total cohort. Combination regimens with cyclophosphamide remained the most widely used (43%), and rituximab was employed in about 16% of cases. Median time to complete remission was 42 days (IQR 25–87), and similar across cohorts, indicating stable efficacy across evolving regimens. Despite these advances, infection remained the predominant cause of death, accounting for 58% of deaths in the post-guideline group compared to 49% previously. Bleeding-related mortality remained low overall (3.5%) but significantly higher among patients receiving corticosteroid monotherapy (8.1%) compared to those on combination regimens (1.2%, p=0.010), especially in patients with high inhibitor titers (>20 BU). No thrombotic complications related to bypassing agents or emicizumab were recorded. Cox multivariable analysis identified baseline inhibitor >20 BU (HR 2.9, 95% CI 1.4–6.1) and active malignancy (HR 2.4, 95% CI 1.1–5.3) as independent predictors of mortality. Conclusions: The implementation of international guidelines for AHA in Spain has significantly improved diagnostic timelines and measurable shifts in therapeutic practice. An increase in rFVIIa, cautious introduction of emicizumab, and expanded use of corticosteroid in monotherapy reflect growing alignment with evidence-based standards. However, persistent mortality due to infections and increased bleeding risk in high-risk patients receiving monotherapy underscore the ongoing need for improved risk stratification, standardized infection prevention, and individualized immunosuppressive strategies. National registry data remain critical in capturing real-world outcomes and guiding future research and policy in rare bleeding disorders.