Future Aspects of Hemophilia Research and Care

Abstract

Key issues in the management of patients with hemophilia include a thorough understanding of the mechanisms of blood coagulation and the complications that follow recurrent joint bleeding. Monoclonal antibodies are powerful tools for dissecting the intrinsic coagulation pathway and deriving reagents that could lead, on the long term, to the identification of molecules that enhance, or perhaps even replace factor (F) VIII concentrates in the management of hemophilia A. In recent in vitro experiments, it was demonstrated that plasmatic thrombin generation and intrinsic FX activation was enhanced by each of two FIXa-specific monoclonal antibodies, one of which had FIXa-agonistic activity only, whereas the other enhanced the activity of the intrinsic FX-activating complex (FVIIIa/FIXa) by at least two distinct mechanisms. Hemophilic synovitis, an inflammatory and proliferative disorder in patients with hemophilia, is the result of bleeding into joints and can lead to debilitating arthritis and chronic arthropathy. A major causative factor in the development of hemophilic synovitis is blood-derived iron deposited in joints. FVIII-deficient knockout mice with trauma-induced hemarthrosis serve as a model system for hemophilic synovitis, reproducing the histological features observed in patients. In addition, this animal model recapitulates the observations made in vitro with synovial cell cultures stimulated by iron. These in vitro experiments suggested a role for iron as an agent capable of inducing proliferation and oncogene expression by human and murine synovial fibroblasts. A better understanding of iron-regulated pathways and oncogene expression may lay the groundwork for targeted molecular interventions in hemophilic synovitis.