Optimizing outcomes for patients with severe haemophilia A

Abstract

Haemophilia A is an inherited, sex-linked disorder inwhich coagulation factor VIII (FVIII) is deficient orabsent [1]. The hallmark of the severe form of thedisease, defined as plasma FVIII level of <1% ofnormal [2], is early, recurrent bleeding into softtissues and joints [3]. Intra-articular bleeding (haem-arthrosis) accounts for more than 90% of all seriousbleeding events in patients with severe haemophilia,and 80% of these bleeds involve the knees, elbowsand ankles [1]. An acute haemarthrosis is typified byrapid joint swelling that may be preceded by aprodrome of tingling, stiffness and pain (Fig. 1)[4,5]. Recurrent bleeding over time into the samejoint (a target joint) results in progressive jointdamage and the development of haemophilicarthropathy, characterized by synovial hypertrophy,cartilage damage, loss of joint space and bonychanges (Fig. 2) [6,7]. Decreased use of a target jointleads to ongoing muscle atrophy, ankylosis, osteo-porosis, bone cysts, and eventually, crippling arthri-tis by young adulthood [3,7].Thedevelopmentofarthropathyisdirectlylinkedtothe number of joint bleeding episodes [8,9]. In thelandmark Orthopaedic Outcome Study, which en-rolled 378 patients with severe haemophilia A,Aledortet al.reportedthePetterssonradiologicscoresincreased 1 point for every 40 joint bleeds [8]. Asubsequent evaluation by Fischer et al. of 117 severehaemophiliapatientsfoundthatfarfewerbleeds–just13 – were necessary to cause a 1 point increase in thePettersson score [9]. Yet even this lower number maybe an overestimate. A major limitation to the use ofplain film radiographs as a tool for assessing arthro-pathy is their ability to visualize only gross arthriticalterations [1]. When magnetic resonance imaging(MRI) was performed on children with haemophiliawho had no obvious clinical signs of arthropathy,early changes in the soft tissues (e.g., synovium andcartilage) were demonstrated [1]. These MRI findingsindicate that incipient joint damage may occur aftervery few bleeding episodes.On-demand therapy (episodic factor replacementin response to acute bleeding events), while effectivein controlling acute haemorrhage, cannot halt theongoing joint destruction many patients with severehaemophilia A experience [10]. An epidemiologicsurvey conducted by the French Study Group of 116haemophilia patients treated almost exclusively frombirth with on-demand therapy found that at a meanage of 23 years, only 3.7% had normal joints byradiographic examination and 54.3% had undergoneorthopaedic procedures [11]. Similarly dismal long-term outcomes were reported by Blanchette. Amongpatients with severe haemophilia managed in Canadawith on-demand therapy, approximately 50% hadevidence of joint disease by age 13 years; and by age18, 24% of the 54 patients had undergone surgicalsynovectomy of at least 1 joint [12].For children with severe haemophilia A and noevidence of inhibitors, the musculoskeletal compli-cations that follow repeated joint bleeding can beeffectively prevented with the early initiation ofprophylaxis, the routine scheduled replacement ofFVIII with the goal of maintaining FVIII trough