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]. Acute hemarthrosis. The right (R) knee is swollen, warm and painful to touch. Range of motion is limited. Palpation of the joint margin and patella is obscured. There is no muscle atrophy. Chronic synovitis and arthropathy. (a) Chronic synovitis of the right (R) knee is typified by a warm and swollen joint with reduced range of motion but no pain with palpation or motion. Palpation of the joint margins and patella are obscured by the spongy synovium, and muscle atrophy is present. (b) Radiograph of the knee showing narrowing of the joint space, erosions at the margins, sclerosis, osteoporosis, a widened intra-condylar notch and cyst formation. 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 long-term 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 levels above 1% [10,13–21]. Nonetheless, surveys of international practice patterns [22,23] and statistics from the Universal Data Collection Programme [24] indicate that the majority of patients with severe FVIII deficiency continue to receive on-demand therapy. In an effort to optimize outcomes in patients with severe haemophilia A through increasing the use of prophylaxis, a panel of clinicians from haemophilia treatment centres (HTCs) in North America convened in Miami, Florida, on January 27–28, 2007, to review the current state of knowledge about joint-protective therapeutic approaches and from this derive best treatment strategies. We hope that the information presented in this supplement, which summarizes our review of the literature and subsequent discussions and recommendations, will help physicians and their staffs develop protocols for the use of prophylaxis in children, adolescents and adults with severe haemophilia A. We appreciate the opportunity to be guest editors of this CME supplement to Haemophilia and to work with our colleagues from the United States and Canada. The names and affiliations of the coauthors in alphabetical order: Manuel CarcaoHospital for Sick ChildrenToronto, Ontario, Canada Amy DunnEmory University School of MedicineAtlanta, Georgia, USA Ralph GruppoCincinnati Children’s Hospital Medical CenterCincinnati, Ohio, USA W. Keith HootsUniversity of Texas Health Science CenterHouston, Texas, USA Marilyn Manco-JohnsonUniversity of Colorado Health Sciences CenterDenver, Colorado, USA Christopher WalshMount Sinai School of MedicineNew York, USA Guy YoungChildrens Hospital of Los AngelesLos Angeles, California, USA The rationale for prophylaxis is predicated on observations published by Swedish researchers more than 40 years ago. They reported that maintaining FVIII plasma levels between 1% and 3% of normal appeared to convert patients from a severe to a moderate haemophilia A phenotype, in which spontaneous bleeding events are less frequent and musculoskeletal complications are less likely to occur [25,26]. In the ensuing years, several observational studies demonstrated the efficacy of FVIII prophylaxis in preventing joint bleeding and the subsequent development of arthropathy, target joints and disability [8,13–20]. Moreover, the benefits of prophylaxis extended beyond joint protection and included preventing other serious or life-threatening haemorrhages, such as recurrent central nervous system bleeding following intracranial haemorrhage (ICH) [16,27], and indirectly improving academic performance [28] and quality of life (QOL) [19,20]. Because of these advantages, prophylaxis is recommended as optimal therapy for patients with severe haemophilia A by the National Hemophilia Foundation (NHF) [29], the World Federation of Hemophilia (WFH) [30] and the World Health Organization (WHO) [31]. While the empiric benefits of prophylaxis have been clear for decades, a key piece of information was missing: results from a randomized controlled trial (RCT). Because of this deficit, a systematic review conducted by the Cochrane Collaboration concluded that there was insufficient evidence to determine the effectiveness of prophylaxis in decreasing the frequency of joint bleeding [32]. Fortunately, the deficiency of RCT data has been rectified. In August 2007, Manco-Johnson published the findings from the prospective, controlled US Joint Outcome Study [10]. This trial enrolled 65 children between 12 and 30 months of age with severe haemophilia A randomized to a prophylactic regimen of every-other-day FVIII infusions of 25 IU kg−1 (n = 32) or enhanced episodic therapy consisting of three or more FVIII infusions totalling at least 80 IU kg−1 to treat joint haemorrhages (n = 33). At the end of the 5-year follow-up period, joint bleeding was significantly lower in the prophylaxis group compared with the enhanced episodic therapy group: 0.47 bleeds annually vs. 4.9 bleeds annually respectively (P < 0.001). The favourable results from the first RCT of primary prophylaxis coupled with more than four decades of observational studies have now firmly established the efficacy of this treatment strategy. Only a few joint bleeds may cause damage [33], and arthropathy, once established, does not reverse and may progress despite the use of prophylactic treatment [14]. Consequently, all children with severe haemophilia A ideally should be placed on primary prophylaxis. Primary prophylaxis is variably defined [34–36], but a commonly used definition developed by an international consensus panel describes it as long term, continual treatment started before the age of 2 years and prior to any clinically evident joint bleeding or started after the first joint haemorrhage, irrespective of age (Table 1) [35]. Whether primary prophylaxis should be started before the first joint haemorrhage or shortly thereafter remains a matter of debate. One argument for initiating treatment between 1 and 2 years of age and before the first bleeding event is that some children have developed joint disease despite no history or awareness of haemarthrosis [37]. This finding suggests that even subclinical joint bleeding may lead to slowly progressive arthropathy and underscores the need for early intervention. On the other hand, starting prophylaxis at a very young age is costly, can result in over treatment of a group of children who are not prone to haemarthroses despite low levels of endogenous FVIII, and often requires insertion of a central venous access device (CVAD) to administer factor [35]. Furthermore, patients on prophylaxis experience joint bleeding that starting prophylaxis before the first bleeding can haemarthrosis but does not in the severe haemophilia clinical has been and is to For patients with a phenotype, it may be to the initiation of primary prophylaxis in life a to experience a few episodes of joint bleeding before on a prophylactic as this the an opportunity to the bleeding and the the of While the of to primary prophylaxis remains there is no about the of initiating treatment after no more than a few joint A by Fischer et al. that patients with severe haemophilia A for years that the Pettersson score was for every prophylaxis was after the first of haemarthrosis should be in all patients with severe haemophilia A before 2 years of age and prior to clinically evident joint bleeding or after no more than a few joint haemorrhages the bleeding the clear of primary prophylaxis, this treatment remains a of the haemophilia can from prophylactic treatment in the form of prophylaxis, defined as long term, prophylaxis after joint bleeds (Table 1) [35]. prophylaxis can joint and other bleeding the not joint and in and other to be in children and adolescents with joint damage The of the benefits of prophylaxis on the number of bleeding episodes and the of joint damage, which with age at the of prophylaxis The the prophylactic regimen is the the Nonetheless, the of prophylaxis are of the age at initiation In other it is to patients with severe haemophilia have the frequency of bleeding a of patients with moderate haemophilia, defined as a FVIII level of of normal [2], experience haemarthroses and develop target arthropathy and while on-demand therapy (Fig. These may from prophylaxis. Joint complications in patients years by haemophilia In patients with severe haemophilia A in primary prophylaxis has been prophylaxis should be as as even after the of joint damage is to prophylaxis should be in patients with moderate haemophilia A who experience frequent joint prophylactic have been that with to frequency and treatment is on the of age or after joint bleeding has (Table 2) for severe haemophilia A was first in in [14]. has over the years, and in the current FVIII is at a of IU kg−1 three starting at age years, irrespective of bleeding history The goal is to FVIII above 1% of normal at all are used to In et al. 25 years of experience with prophylaxis in Swedish years, with severe haemophilia A or [14]. in the age who primary prophylaxis at a very early had outcomes than the group of some of had joint damage prophylaxis was at lower years (n = almost no bleeding had orthopaedic scores (Table and radiologic scores (Table of and were to lead normal In patients years (n = had joint haemorrhages and only four had joint scores of Nonetheless, patients who any level of prophylaxis had joint outcomes than patients in the on-demand therapy In the group published follow-up data that that the treatment (n = had not any and their orthopaedic and radiologic joint scores treatment episodes of joint bleeding in the (n = This finding that prophylaxis can but not progressive arthropathy in patients with joint The Medical and of the a of the regimen for FVIII IU kg−1 three or every other before the of frequent In the prophylaxis is started after the of at least of joint bleeding in has been over the years, and the current prophylactic regimen for patients with haemophilia A is FVIII IU kg−1 or three is in the event of spontaneous but FVIII trough levels are not the determine the of on long-term Fischer et al. compared haemophilia patients treated with prophylaxis at a age of years with Swedish haemophilia patients treated with prophylaxis at a age of 2 years a of years of the number of joint bleeds for was lower in patients treated with the regimen vs. The Pettersson score (Table was lower in the group vs. the group the in arthropathy as by the Pettersson score was not (P = or = on of in as by the orthopaedic joint score by the (Table or the of the (a and to the prophylaxis patients in to lead normal in were in the of the prophylactic Because prophylaxis was started and in in the Swedish the of factor was than in the The clinical of severe haemophilia A are and there is in prophylactic to the of that is to a bleeding an opportunity to prophylactic while FVIII A regimen developed by the Study Group FVIII prophylaxis at IU kg−1 once 1) The and frequency are increased to 30 IU kg−1 the target joint bleeding bleeds into a joint a bleeding by the as joint or soft haemorrhages a or has or more haemorrhages into a joint over any of time is increased to 25 IU kg−1 every other any of the while on 2 of IU kg−1 are bleeding This regimen was in 25 years with severe haemophilia A, of had a history of target joint bleeding years, patients to receive prophylaxis, patients had to 2 and prophylaxis, and patients prophylaxis from 1 to 2 to A of 116 joint haemorrhages the period, an of patients developed target joints years of starting prophylaxis, that the to this lower regimen may be that some patients frequent was this and no developed a target Furthermore, of the patients have not which has in on factor compared with more The of patients to some bleeding episodes before long-term prophylaxis requires the of FVIII IU kg−1 three or every other before the of frequent In that prophylactic can be in an effort to FVIII and the of prophylaxis. in of FVIII are used in the regimen to that trough levels 1% of normal between prophylactic infusions the between FVIII levels and the of joint bleeding is very A survey of from the over a found that some patients with trough levels 1% no bleeding while despite trough levels such as FVIII and have been used to the of not the of an FVIII trough should determine is and prophylaxis is bleeding may indicate that the prophylactic regimen is and requires bleeding in the and the number of haemorrhages that is of regimen and the need to treatment is The primary of the efficacy of prophylaxis is the of musculoskeletal by examination and plain film radiographs [12]. are The orthopaedic joint score (Table recommended by the Orthopaedic of the a to knee and and has a score of The Pettersson radiologic score (Table of these joints on a and has a score of [37]. The are performed in and a score is as of the orthopaedic joint system are to early haemophilic arthropathy and the use of that may be beyond the ability of young children to [12]. An joint evaluation of early or has been developed for young children with haemophilia and is in prospective, clinical plain film the tool for and assessing joint damage with haemophilic arthropathy are not to early joint damage [1]. MRI evaluation of soft changes that cartilage and bone destruction MRI is not for routine clinical [35]. have increased the life of patients with Consequently, in has of the major of haemophilia of for children with haemophilia are for use in clinical studies but are not used in clinical is by about the is with the this survey has not been for use in Because haemophilic arthritis often years after the of joint in young adults are to the outcomes of prophylactic used in early of musculoskeletal and should be a of any effort to outcomes in patients prophylaxis. to the initiation and of prophylaxis have been in surveys of practice patterns and venous access and with access are the for not prophylaxis or treatment may be for and patients and or are often to prophylaxis to young children is the major with used in haemophilia and it is the cause for their In a of studies that patients and et al. found that of patients and of were by an may occur with use While this may be and clinically patients may severe and life-threatening such as An prophylactic regimen is for the need for a regimen that with infusions very early in life to venous access and to prophylaxis by the time the 2 years When a is and is to and should be on a of the and by the haemophilia treatment is the access of for patients are now as an for venous access in with haemophilia 1 and in an effort to the complications of A of children with severe haemophilia found the were and used at by patients for a follow-up of months in after but and the was used for an et al. the use of in haemophilia of had a of before the of the to the of children with haemophilia requires surgical and long-term follow-up with and the should be haemophilia patients to lead normal and but at a FVIII for patients treated with the regimen may IU kg−1 annually Whether prophylaxis, as has been by the need for orthopaedic and other is An evaluation by et al. found that the to the of prophylaxis A subsequent of by and found that the in US for prophylaxis and on-demand therapy was were for patients on prophylaxis, but were for treated were for prophylaxis was to more than on-demand therapy, the findings of et al. that prophylaxis is the more intervention. and have the to by therapeutic benefits to of prophylaxis while lower of factor only these the of prophylaxis, but may optimal therapy to more patients with severe haemophilia to the prophylactic regimen is a to treatment A survey of practice patterns a of or and the of prophylaxis, which can with other and as to may to as by the that is in patients infusions are by their than adolescents who Yet the to was a of of the benefits of prophylaxis. knowledge of these benefits was as the primary of in a survey of prophylaxis patients and their and by the haemophilia treatment are key to patients and to the long-term to a treatment an regimen initiating prophylaxis to the need for in young are an for venous access in some children (e.g., who have repeated and may while therapeutic benefits to of prophylaxis. patients and with and to their long-term to prophylaxis. In the first of was in a US haemophilia who had no by infusions of factor on to the haemophilia (Fig. in the of FVIII the but by that more than 50% of haemophilia patients in the United States had been For many years and (Fig. joint the of patients and and the of Consequently, adults with haemophilia have been treated with primary or prophylaxis. as of of with haemophilia enrolled in as of of with haemophilia enrolled in are in the in the use of prophylaxis in while many treat children and some centres only have a may be to an with prophylaxis or of the of the prophylactic regimen into changes to lower of prophylaxis in The of and may time for with the of prophylaxis is factor that may lead to treatment for patients who started prophylaxis at a very young the some patients to prophylaxis. who were their may not have their as Furthermore, benefits from state to state and may not haemophilia prophylaxis after age the in maintaining prophylactic into is it to prophylaxis at some The [29], and that prophylaxis be as the of bleeding events in the of haemophilia is the same as in and the benefits of prophylaxis are by all age On the other hand, there may be some rationale for or a least the are less than children, the of is In there is in data to that joint cartilage is less to damage than is cartilage in joints clinical data on the of prophylaxis in et al. reported on 80 patients with severe haemophilia between and treated with prophylaxis in and the The age at the of prophylaxis was years and years and the follow-up was the age of years, of the patients from had to on-demand only three bleeds years after the patients prophylaxis, their joint by clinical and radiologic appeared and outcomes were to in patients who on prophylaxis. A by Fischer et which only the of the of patients who prophylaxis They included a of prophylaxis, a lower of FVIII, and reduced of joint bleeding on prophylaxis, all of which a bleeding to of prophylaxis the patients by the findings from studies indicate that it may be to for of prophylaxis. are to determine some patients can treatment and to determine the of such a Primary or prophylaxis is the treatment for severe haemophilia A, for For patients who are not on prophylactic other may serious prophylaxis, to as or episodic prophylaxis, is defined as a of factor replacement to bleeding in (Table is the of prophylaxis. prophylaxis may be prior to in or other the will not have rapid access to and before such as or a There is data on prophylaxis the surgical In a four adults with severe haemophilia A and arthropathy factor to FVIII levels to prior to of therapy a period, the patients an mean in the number of bleeding in joint as by increased and pain and an in FVIII The goal of prophylaxis is to to this to may be For patients with severe haemophilia A, the panel recommended a of IU kg−1 prior to the or with repeated for with haemophilia may from prophylaxis with the of and prophylaxis to recurrent bleeding following major haemorrhage, such as or other is form of prophylaxis (Table While the optimal and of therapy in this is several not treatment may be to into an clinical have demonstrated that the majority of acute bleeding events in severe haemophilia can be managed with on-demand infusions that a target plasma of approximately 50% of haemorrhages may target plasma levels over a of on-demand therapy to the of factor at and frequency and for a to FVIII levels bleeding episodes (Table on-demand therapy has been used for the of and may be for muscle and other bleeding events in patients with severe haemophilia A who are not on prophylaxis A of has been used for this of on-demand therapy, some of which are more than In the US Joint Outcome Study, on-demand therapy of at least three FVIII infusions totalling at least 80 IU kg−1 [10]. While this that on-demand therapy was to prophylaxis, it was not to the efficacy of vs. The panel recommended that on-demand therapy is an of the FVIII level should be than the (Table at a should be for range of and at least every 12 Primary or prophylaxis is for patients with severe haemophilia A. prophylaxis to bleeding in may to not of prophylaxis may be in to on-demand therapy may be for the of and for and other bleeding events in patients with severe haemophilia A who are not on prophylaxis. The recurrent episodes of haemarthrosis that severe haemophilia A result in progressive joint damage and lead to disability and of bleeding is the goal of therapy. is the effective for outcomes in patients with severe haemophilia A. Primary prophylaxis can the development of arthropathy, other serious bleeding and patients to on it is prophylaxis may many of the same benefits as primary prophylaxis, it cannot reverse joint damage that has The and prophylactic have been used for prophylaxis that into in bleeding patterns and FVIII can factor lower treatment and the need for a some of the to prophylaxis may be Because of the of joint and other bleeding events in patients with severe haemophilia A, prophylaxis should be ideally into adulthood to the benefits in in to cause some patients to For these prophylaxis and on-demand therapy are that may bleeding episodes or

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