Epidemiological aspects and complications of congenital hemophilia A in Brazil

Abstract

This thesis investigates mortality, inhibitor development, and predictive factors in hemophilia, focusing on Brazilian and Dutch cohorts. A nationwide registry study in Brazil showed that while overall survival has improved and HIV-related mortality has declined, intracranial hemorrhage remains a leading cause of death, emphasizing the need for early prophylaxis. The prospective HEMFIL study demonstrated a high incidence of inhibitors (36%) in previously untreated Brazilian patients with severe hemophilia A, consistent with international cohorts. Genetic analysis confirmed the strong influence of high-risk F8 mutations, while clinical data highlighted intensive early exposure as a trigger. Two immunological studies identified biomarker profiles associated with inhibitor risk, suggesting that both pro-inflammatory and regulatory signals contribute to loss of tolerance. A machine learning–-based network model (HemfilNET) integrated genetic, clinical, and biomarker data, showing promising predictive performance, though external validation is required. Finally, a Dutch study demonstrated that although joint problems remain common among elderly people with hemophilia A, outcomes were not significantly different between those with and without past inhibitors. Together, these studies underscore that inhibitor development remains the most critical treatment-related challenge in hemophilia. Despite advances in therapeutic access, there is still a pressing need for targeted interventions, as the mechanisms leading to inhibitor development are not yet fully understood.