Avaliação dos fatores clínicos, genéticos e imunológicos relacionados ao desenvolvimento de inibidores em hemofilia

Abstract

Congenital hemophilia A (HA) is an X-linked hemorrhagic disease characterized by deficiency of factor VIII (FVIII). Treatment is performed by infusion of FVIII concentrate for prophylaxis and/or treatment of hemorrhages. During treatment, approximately 10%-30% of patients with HA develop alloantibodies (inhibitors) that neutralize the procoagulant activity of the deficient factor, leading to ineffective replacement. Eradication of inhibitors can occur in up to 80% of cases with immunotolerance treatment. This thesis aimed to evaluate the epidemiological aspects of hemophilia and its complications, through the analysis of inhibitor incidence, mortality and causes of death of patients with hemophilia and the evaluation of the relationship of the rs3754689 polymorphism in the Lactase gene with the development of inhibitors in Brazilian patients with HA. To assess the incidence of inhibitors and genetic polymorphism, the prospective cohort of the HEMFIL study was used, in which previously untreated or minimally treated patients with hemophilia are followed up to 75 days of exposure (ED) to the factor or until the development of an inhibitor. To date, 82 patients with HA (FVIII:C < 2%) have been included in T0, of which 30 patients developed an inhibitor (T1/Inhibitor) and 41 patients completed 75 ED without positive inhibitor. The cumulative incidence for inhibitor development was 36.0% (95% CI, 25.2-48.5), of which 25.0% (95% CI, 15.6- 37.9) correspond to high-titer inhibitors. Allele frequency analysis showed no difference in the rs3754689 polymorphism between the groups of patients with positive and negative inhibitor (p = 0.931), nor between high and low inhibitor titers (p = 0.386). This thesis also analyzed the mortality rate and causes of death of patients with hemophilia in Brazil between 2000 and 2014, using the Mortality Information System (SIM) as a data source. A total of 784 deaths of patients with hemophilia were identified between 2000 and 2014, and mortality in this group was 13% higher when compared to the general male population (SMR 1.13, 95% CI, 1.01-1.16). The standardized mortality ratio decreased over the 15 years evaluated from 1.51 (95% CI, 1.29-1.74) in 2000 to 0.89 (95% CI, 0.74-1.04) in 2014. Intracranial hemorrhage remained an important cause of death in these patients.