Abstract
People with hemophilia (PWH) have an increased tendency to bleed, often into their
joints, causing debilitating joint disease if left untreated. To reduce the incidence
of bleeding events, PWH receive prophylactic replacement therapy with recombinant
factor VIII (FVIII) or FIX. Bleeding events in PWH are typically proportional to their
plasma FVIII or IX levels; however, in many PWH, bleeding tendency and the likelihood
of developing arthropathy often varies independently of endogenous factor levels.
Consequently, many PWH suffer repeated bleeding events before correct dosing of replacement
factor can be established. Diagnostic approaches to define an individual's bleeding
tendency remain limited. Multiple modulators of bleeding phenotype in PWH have been
proposed, including the type of disease-causing variant, age of onset of bleeding
episodes, plasma modifiers of blood coagulation or clot fibrinolysis pathway activity,
interindividual differences in platelet reactivity, and endothelial anticoagulant
activity. In this review, we summarize current knowledge of established factors modulating
bleeding tendency and discuss emerging concepts of additional biological elements
that may contribute to variable bleeding tendency in PWH. Finally, we consider how
variance in responses to new gene therapies may also necessitate consideration of
patient-specific tailoring of treatment. Cumulatively, these studies highlight the
need to reconsider the current “one size fits all” approach to treatment regimens
for PWH and consider therapies guided by the bleeding phenotype of each individual
PWH at the onset of therapy. Further characterization of the biological bases of bleeding
heterogeneity in PWH, combined with the development of novel diagnostic assays to
identify those factors that modulate bleeding risk in PWH, will be required to meet
these aspirations.
Keywords
hemophilia - bleeding heterogeneity - coagulation - fibrinolysis - gene therapy
