Hemophilic arthropathy: Current knowledge and future perspectives

Abstract

Hemophilia A and B are rare X-linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. Unless appropriately managed, even subclinical hemarthrosis can lead to the development of hemophilic arthropathy, a disabling condition characterized by joint remodelling, chronic pain, and a reduced quality of life, and eventually requires joint replacement. Given the lack of specific treatments to reduce blood-induced synovitis, the prevention of bleeding is pivotal to the maintenance of joint health. Prophylactic coagulation factor replacement therapy using extended half-life recombinant drugs has significantly improved patients' quality of life by reducing the burden of intravenous injections, and the more recent introduction of nonreplacement therapies such as subcutaneous emicizumab injections has improved treatment adherence and led to the greater protection of patients with hemophilia A. However, despite these advances, chronic arthropathy is still a significant problem. The introduction of point-of-care ultrasound imaging has improved the diagnosis of acute hemarthrosis and early hemophilic arthropathy, and allowed the better monitoring of progressive joint damage, but further research into the underlying mechanisms of the disease is required to allow the development of more targeted treatment. In the meantime, patient management should be based on the risk factors for the onset and progression of arthropathy of each individual patient, and all patients should be collaboratively cared for by multidisciplinary teams of hematologists, rheumatologists, orthopedic surgeons, and physiotherapists at comprehensive hemophilia treatment centers.

Keywords: hemarthrosis; hemophilia; hemophilic arthropathy; sub-clinical joint bleeding.

FIGURE 1

The structure of (A) a healthy joint and (B) a joint with hemophilic arthropathy. Recurrent hemarthrosis (represented by blood drops for the sake of simplicity) induces the proliferation (synovial hyperplasia) of fibroblast‐like synoviocytes and macrophage‐like synoviocytes that produce the vascular endothelial growth factor responsible for angiogenesis and vascular remodelling, and pro‐inflammatory cytokines such as tumor necrosis factor‐alpha, and interleukin‐6 and 1‐beta. These further amplify the fibroblast‐like synoviocyte proliferation and production of reactive oxygen species that induce chondrocyte apoptosis. Osteochondral damage is an inevitable consequence of the direct exposure of chondrocytes to iron, metalloproteinases, and a disintegrin and metalloproteinase with thrombospondin motifs that is produced by fibroblast‐like synoviocytes when stimulated by inflammation. ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; IL‐1, interleukin‐1; IL‐6, interleukin‐6; MMPs, metalloproteinases; ROS, reactive oxygen species; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TNF‐alpha, tumor necrosis factor‐alpha; uPA, urokinase plasminogen activator; VEGF, vascular endothelial growth factor