Blood-Induced Arthropathy: A Major Disabling Complication of Haemophilia

Abstract

Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment over the past two decades and recent guidelines from ISTH and WFH recommending FVIII trough levels of at least 3 IU/dL during prophylaxis, patients with haemophilia still develop joint disease. The pathophysiology of HA is complex, involving both inflammatory and degenerative components. Early diagnosis is key for proper management. Imaging can detect joint subclinical changes and influence prophylaxis. Magnetic resonance imagining (MRI) and ultrasound are the most frequently used methods in comprehensive haemophilia care centres. Biomarkers of joint health have been proposed to determine osteochondral joint deterioration, but none of these biomarkers has been validated or used in clinical practice. Early prophylaxis is key in all severe haemophilia patients to prevent arthropathy. Treatment is essentially based on prophylaxis intensification and chronic joint pain management. However, there remain significant gaps in the knowledge of the mechanisms responsible for HA and prognosis-influencing factors. Better understanding in this area could produce more effective interventions likely to ultimately prevent or attenuate the development of HA.

Keywords: MRI; arthropathy; haemophilia; joint bleed; prophylaxis; ultrasound.

Figure 1

After blood vessel injury in the synovial membrane, blood and blood degradation products such as fibrin, activated protein C, plasmin, haemoglobin and iron are freed inside the articulation capsule. Fibrin deposits on the synovial membrane will be engulfed by proliferating synovial fibroblasts. APC will induce the activation of TNF-α, IL-1 and IL-6 as well as activate pro-MMP-2 and -9. The dysregulation of plasmin activity, downregulation of α2-antiplasmin and upregulation of u-PA will promote plasmin activation toward pro-MMP-2 and -9 activity. Together, pro-MMP-2 and -9 will degrade articular cartilage. On the other hand, haemoglobin will be degraded in haem and iron, increasing iron deposits inside the capsule. Iron accumulation in the synovial membrane will induce an overexpression of adhesion molecules (ICAM, VCAM) that will help recruit macrophages into the synovial fluid. In reaction, macrophages will produce IL1-β and TNF-α. TNF-α itself promotes a macrophage phenotype switch to M1 and M2 in parallel to synovial membrane phenotype switch. Synovial cells will produce TNF-α, IL-1 and IL-6, representing a positive feedback of inflammation inside the articulation. They will also produce MMP1, 3 and 13 leading to cartilage degradation. Inside the capsule, the RANK pathway will also be disturbed with a downregulation of OPG (osteoprotegerin) and upregulation of RANKL (RANK ligand). This will increase osteoclast activity and cartilage degradation. In this context, macrophages represent another pathway to promote osteoclast activity. This inflammation state can ultimately lead to gene dysregulation such as the c-myc gene, promoting hyperplasia and contributing to pannus formation. VEGF is also produced in this context, increasing the risk of blood vessel lesions, thus amplifying and sustaining the whole process towards cartilage degradation and articular destruction. ICAM: InterCellular Adhesion Molecule; VCAM: Vascular Cell Adhesion Protein; pro-MMP2-9: pro-matrix metalloproteinases; IL-1, IL-6: interleukin-1, interleukin-6; RANK: Receptor Activator of Nuclear Factor κ B; APC: Activated Protein C; Hb: haemoglobin; Fe²⁺: iron (II); u-PA: urokinase-type plasminogen activator; OPG: osteoprotegerin.

Figure 2

Severe arthropathy of the knee (A), elbow (B) and ankle (C): (A) shows subchondral cysts of various size, joint space compression, cartilage destruction, articular surface irregularities and changes in the joint axis. (B) shows a destroyed elbow joint and (C) shows spontaneous ankylosis of the ankle. Gauche: left, D: right.

Figure 3

Chronic synovitis with major thickening of the synovium.