Advances in knowledge of inhibitor formation in severe haemophilia A

Abstract

Summary Anti‐drug antibody formation following factor VIII (FVIII) replacement therapy is the most important treatment‐related complication in patients with severe haemophilia A. A significant number of these antibodies show neutralising activity against FVIII and are referred to as FVIII inhibitors. Alloimmunity to FVIII, given the absence of endogenous circulating FVIII protein, may be predictable to some extent; however, only 30% of patients develop inhibitors. Genetic and environmental risk factors have been identified, contributing to the likelihood of inhibitor development. Multiple immunological theories have been proposed which in part explain the outcomes of many epidemiological studies. Significant differences exist among replacement therapies, including the source, FVIII sequence, glycosylation, formulation components, impurities and aggregation potential, which significantly complicate interpretation of the results from these studies. In this review, we present recent advances in the understanding of the cellular mechanisms of inhibitor formation and highlight some areas of uncertainty requiring further investigation.

Comparative glycosylation mapping of plasma-derived and recombinant human factor VIII

“…Specifically, different glycosylation patterns could be the primary factor. [39] For example, it was concluded that a mannose receptor is involved in immune recognition of FVIII by antigen-presenting cells (APC), e.g., dendritic cells. [40] Our work and previous studies showed that N2118 at the C1 domain is primarily attached with high-mannose N-glycans in both pdFVIII and rFVIII, [23,24] suggesting a mechanism for FVIII internalizations by APC via the mannose receptor.…”

Passive Immunity for Coronavirus Disease 2019: A Commentary on Therapeutic Aspects Including Convalescent Plasma

“…The International Severe Acute Respiratory and Emerging Infection Consortium is developing a clinical trial protocol to investigate passive immunotherapy for severe acute respiratory and emerging infection. 54,59 Viral load by quantitative viral nucleic acid testing and viral antibody titers were found to be useful in defining the virologic and immunological kinetics that lead to improved clinical outcomes. It will be important to define the optimal plasma volume, number of doses, and quantitative neutralizing antibody titers to determine the optimal amount of antibody that is needed to effectively inhibit virus replication.…”

“…Plasma collection 14 days after resolution of symptoms provides the best likelihood of having high titers of anti-SARS-CoV-2 antibodies. 59 Convalescent plasma may be provided to patients with SARS-CoV-2 infections through one of three approval pathways: (1) Passive Immunity for COVID- 19 Lindholm et al 801 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.…”

A previously treated severe haemophilia A patient developed high-titre inhibitor after vaccinations

“…The development of factor VIII (FVIII) neutralizing antibodies, known as inhibitor, is the most serious treatment-related complication for hemophilia A (HA) and is detected in 25%–30% of patients. 1 Inhibitor development is a multifactorial process involving genetic and non-genetic risk factors. Non-genetic risk factors include severe bleeding, infections, and vaccinations around the time of FVIII treatment based on the ‘danger theory’.…”