Inhibitors and immune tolerance induction in hemophilia A: A balancing act

Abstract

The development of neutralizing antibodies against factor VIII (FVIII), so called ‘inhibitors’, is one of the most important and challenging complications in the treatment of hemophilia A. This thesis was aimed at exploring issues regarding the pathophysiology of inhibitor formation and the working mechanism of Immune Tolerance Induction (ITI). The pathophysiology of inhibitor formation involves a complex interplay of both genetic and environmental factors. We reviewed whether ‘danger signals’ during FVIII administration are involved in the process of inhibitor development. According to the ‘danger theory’, certain ‘danger signals’, such a joint bleeds or surgery, result in the upregulation of costimulatory signals, which, together with presentation of FVIII, are essential to fully activate naïve CD4+ T-cells. Although the ‘danger model’ provides a plausible theoretical background, the data to support this hypothesis in hemophilia A are limited and not conclusive. Another opposed risk factor of inhibitor development is switching to a different FVIII product. In a combined prospective and retrospective cohort study we showed that switching FVIII products was not associated with the risk of inhibitor development, nor with changes in the frequency of several immunoregulatory cells and markers. The only effective therapy to eliminate inhibitors is ITI, in which repeated and long-term administration of FVIII ultimately results in downregulation of the anti-FVIII immune response. After summarizing current evidence regarding mechanisms of tolerance induction, we studied the role of a set of immunoregulatory cells and markers in ITI. It was shown that inhibitor patients express significantly lower frequencies of regulatory B-cells (Bregs) and regulatory T-cell markers, such as CTLA4 and PD1, which are restored by successful ITI. Our findings suggest that an existing anti-FVIII immune response is associated with deficits in peripheral tolerance mechanisms and that Bregs and changes in immunoregulatory properties of CD4+ T-cells likely contribute to immune tolerance induction in hemophilia A patients with inhibitors. Next to congenital hemophilia A, this thesis describes the clinical presentation, treatment and outcome of acquired hemophilia A (AHA). AHA is a severe auto-immune bleeding disorder caused by (auto-) antibodies to FVIII that develop in previous healthy, i.e. non-hemophilia, patients. Our cohort study emphasized that AHA is a serious bleeding disorder, which affects mostly elderly and frail patients. It is associated with significant morbidity and mortality, not only bleeding-, but especially also treatment-related. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower complete remission rate. The higher efficacy of steroid combined with cyclophosphamide or rituximab however, was overshadowed by higher infection rates and infections represented the most important cause of death. Therefore the delicate balance between treatment efficacy and safety is one of the most important challenges in the management of the typically old and frail AHA patient. In summary, this thesis describes different aspects of mechanisms involved in anti-FVIII antibodies in both congenital and acquired hemophilia A. It mostly emphasizes the complexity of our immune system and the sophisticated interplay of all factors involved in controlling the delicate balance between attacking ‘non-self’ and tolerating ‘self’.