Nonneutralizing Antibodies in Haemophilia A Patients: To be Ignored or Not to be!

BACKGROUND: The existence of nonneutralizing antibodies (NNAs) to factor VIII (FVIII) unrecognized by the clot-based Bethesda assay has been widely accepted. They are reported both in haemophilia A (HA) patients without inhibitors and healthy controls, but are poorly studied. AIM: The article discusses the contradictory reports on the nature and clinical significance of NNAs. DISCUSSION AND CONCLUSION: Initially defined as antibodies to non-functional domains of FVIII, recent studies have provided evidence for multi-domain specificities. Subclass analysis and affinity studies have shown evidence for distinct immune regulatory pathways which lead to antibody responses against FVIII in different groups. Their role in pharmacokinetics of FVIII is the most frequently studied, while few studies also indicate their possible role as biomarkers for future development of neutralizing antibodies (inhibitors). The impact of NNAs on the clinical severity of HA is largely elusive; however, they can cause difficulties in the interpretation of immunological tests. There is a need for longitudinal comprehensive studies in HA patients on the natural history of NNAs and also for clear guidelines for accurate diagnosis. Present review summarizes the data available on the prevalence of NNAs, their clinical impact and discusses directions for future research.