The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors.

Introduction: Patients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development.

Aim: To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors.

Methods: A working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage -omics, existing phenotypic data, and in silico modelling to study inhibitors.

Results: An antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at-risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other -omics studies. Data can inform in silico prediction and mathematical models.

Conclusion: A longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in -omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement.