An update on the ‘danger theory’ in inhibitor development in hemophilia A

Abstract

Introduction: Nowadays, one of the most serious treatment complications in hemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe hemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negative impact on patients' health and quality of life and significantly increases hemophilia A treatment costs. The pathophysiology of inhibitor development is a complex and multi-causal process, in which both genetic factors as well as environmental factors participate. So-called 'danger signals' are considered contributors to inhibitor formation, and can be triggered by surgery, joint bleeds or infections. A pro-inflammatory tissue micro-environment is thereby established, which is characterized by the upregulation of costimulatory molecules on antigen-presenting cells (APCs), that can facilitate the alloimmunization to FVIII and thereby inhibitor formation. Here, the authors will discuss evidence from (pre)clinical studies about this theory in hemophilia A. Areas covered: In this review, the current knowledge regarding the 'danger theory' with regard to inhibitor development in hemophilia A is summarized. Expert opinion: Danger signals might contribute to inhibitor development; however, the evidence is scarce and not conclusive. Future studies, like multinational registries, are warranted but challenging. ARTICLE HISTORY

A study to determine the prevalence, clinical profile and incidence of formation of inhibitors in patients of hemophilia in north eastern part of India

“…The most serious complication of replacement therapy in hemophilia is the development of inhibitors. [4] An inhibitor is a polyclonal high-affinity immunoglobulin G (IgG) that is directed against the FVIII protein. These antibodies can be either inhibitory or non inhibitory.…”

New Inhibitors in the Ageing Population: A Retrospective, Observational, Cohort Study of New Inhibitors in Older People with Hemophilia

“…10 Although prophylaxis has been suggested to decrease inhibitor risk compared with on-demand treatment, the data to-date are inconclusive, 3,15 with studies to both support and refute the concept that inhibitor formation is lower in patients on regular prophylaxis compared with ondemand therapy. 3,16 The majority of patients that developed inhibitors in this study were treated with recombinant products, mainly standard half-life products, but our study was not designed to evaluate the type of concentrate as a risk factor for inhibitor development. Therefore, we were not able to confirm the findings by Fischer et al that reported no class-or brand-related differences in the EUHASS.…”

Advances in knowledge of inhibitor formation in severe haemophilia A

“…These factors impact the maturation of APCs, influencing expression of co‐stimulatory molecules and thus ultimately regulating the likelihood of anti‐self antibody production (Matzinger, ). However, there is conflicting evidence supporting an environmental signal‐driven inhibitor response towards FVIII which questions the Danger Theory’s clinical application in the context of haemophilia (Schep et al , ).…”