title: Pathophysiology of hemophilic arthropathy and potential targets for therapy.
abstract: Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; Van Creveldkliniek, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Electronic address: a.e.pulles-3@umcutrecht.nl.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Pulles
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Mastbergen
authors.affiliation: Van Creveldkliniek, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Roger E G
authors.initials: RE
authors.lastname: Schutgens
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; Van Creveldkliniek, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Lize F D
authors.initials: LF
authors.lastname: van Vulpen
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D006395:Hemarthrosis / Q000473:pathology; D006467:Hemophilia A / Q000473:pathology*; D006470:Hemorrhage / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D013583:Synovial Membrane / Q000473:pathology; D013585:Synovitis / Q000473:pathology*
keywords: Hemophilic arthropathy; Pathogenesis; Potential targets for therapy