Optimizing outcomes for patients with severe haemophilia A.

Haemophilia A is an inherited, sex-linked disorder in which coagulation factor VIII (FVIII) is deficient or absent [1]. The hallmark of the severe form of the disease, defined as plasma FVIII level of <1% of normal [2], is early, recurrent bleeding into soft tissues and joints [3]. Intra-articular bleeding (haemarthrosis) accounts for more than 90% of all serious bleeding events in patients with severe haemophilia, and 80% of these bleeds involve the knees, elbows and ankles [1]. An acute haemarthrosis is typified by rapid joint swelling that may be preceded by a prodrome of tingling, stiffness and pain (Fig. 1) [4,5]. Recurrent bleeding over time into the same joint (a target joint) results in progressive joint damage and the development of haemophilic arthropathy, characterized by synovial hypertrophy, cartilage damage, loss of joint space and bony changes (Fig. 2) [6,7]. Decreased use of a target joint leads to ongoing muscle atrophy, ankylosis, osteoporosis, bone cysts, and eventually, crippling arthritis by young adulthood [3,7]. The development of arthropathy is directly linked to the number of joint bleeding episodes [8,9]. In the landmark Orthopaedic Outcome Study, which enrolled 378 patients with severe haemophilia A, Aledort et al. reported the Pettersson radiologic scores increased 1 point for every 40 joint bleeds [8]. A subsequent evaluation by Fischer et al. of 117 severe haemophilia patients found that far fewer bleeds – just 13 – were necessary to cause a 1 point increase in the Pettersson score [9]. Yet even this lower number may be an overestimate. A major limitation to the use of plain film radiographs as a tool for assessing arthropathy is their ability to visualize only gross arthritic alterations [1]. When magnetic resonance imaging (MRI) was performed on children with haemophilia who had no obvious clinical signs of arthropathy, early changes in the soft tissues (e.g., synovium and cartilage) were demonstrated [1]. These MRI findings indicate that incipient joint damage may occur after very few bleeding episodes. On-demand therapy (episodic factor replacement in response to acute bleeding events), while effective in controlling acute haemorrhage, cannot halt the ongoing joint destruction many patients with severe haemophilia A experience [10]. An epidemiologic survey conducted by the French Study Group of 116 haemophilia patients treated almost exclusively from birth with on-demand therapy found that at a mean age of 23 years, only 3.7% had normal joints by radiographic examination and 54.3% had undergone orthopaedic procedures [11]. Similarly dismal longterm outcomes were reported by Blanchette. Among patients with severe haemophilia managed in Canada with on-demand therapy, approximately 50% had evidence of joint disease by age 13 years; and by age 18, 24% of the 54 patients had undergone surgical synovectomy of at least 1 joint [12]. For children with severe haemophilia A and no evidence of inhibitors, the musculoskeletal complications that follow repeated joint bleeding can be effectively prevented with the early initiation of prophylaxis, the routine scheduled replacement of FVIII with the goal of maintaining FVIII trough Abbreviations: ADL, activities of daily living; AVF, arteriovenous fistulae; BIW, two times weekly; CVAD, central venous access device; DDAVP, desmopressin acetate; FFC, fixed flexion contracture; FVIII, factor VIII; FVIII:C, factor VIII coagulant activity; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTC, haemophilia treatment center; ICH, intracranial haemorrhage; MRI, magnetic resonance imaging; NHF, National Hemophilia Foundation; QOD, every other day; QOL, quality of life; QW, once weekly; RCT, randomized controlled trial; TIW, 3 times weekly; WFH, World Federation of Hemophilia; WHO, World Health Organization Correspondence: Leonard A. Valentino, MD, Associate Professor of Pediatrics, Director, Hemophilia and Thrombophilia Center, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612-3833, USA. Tel.: 312 942 8114; fax: 312 942 8975; e-mail: [email protected] This CME supplement is sponsored by Scienta Healthcare Education and supported by an unrestricted grant from Baxter BioScience.