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Personalised treatment


Tailored and personalised approach to prophylaxis in patients with haemophilia A


It is now clear that a multi-dimensional approach should be adopted in tailoring and monitoring prophylactic regimens in patients with haemophilia as described below


Cedric Hermans Professor, Head Division of Haematology Haemostasis and Thrombosis Unit Haemophilia Clinic, St-Luc University Hospital, Belgium


Haemophilia A is one of the most common inherited bleeding disorders, caused by either a deficiency or impairment in function of the factor VIII (FVIII) pro-coagulant protein. The bleeding phenotype is related to the level of residual functional FVIII. Patients with severe disease have a FVIII activity of less than 1% (1 IU/dl) and present with spontaneous and recurrent joint and muscle bleeds leading to severe and progressive musculoskeletal damage and compromised mobility.1 Treatment of bleeding in patients with haemophilia is through intravenous infusions of FVIII concentrate.


Rationale and benefits for prophylaxis In the 1960s, Swedish researchers reported that patients with moderate or mild haemophilia, that is, those with a FVIII level above 1%, had a low frequency of joint bleeds and rarely developed severe arthropathy.2


These clinical


observations provided the rationale for therapeutically inducing a moderate clinical phenotype in severe haemophiliacs through regular and prolonged factor administration, in order to minimise the number of joint bleeds and improve long-term joint outcomes.3,4


Although used for many years, based on retrospective data, only recently have prospective trials demonstrated the major benefits of prophylaxis in the reduction of bleeding and preservation of joint function.3,5–9


Primary prophylaxis, started


after the first joint bleed and/or before the age of two years, is now the evidence- based first-choice treatment in children with severe haemophilia.10


When initiated


later in life, prophylaxis also provides substantial advantages over on-demand treatment because it decreases the number of joint bleeds, further deterioration of the joint status (especially in adolescents), and concurrent restrictions in patients’ activities.11–13


Current strategies for primary prophylaxis


The original concept of prophylaxis was to increase the trough level of FVIII above 1%, with the aim of converting the bleeding phenotype from severe to moderate.3,4,14 In Sweden, this treatment strategy was initially delivered using a weight-based


high-dose fixed regimen of 25–40 IU/kg, three times a week. This treatment regimen was based on the assumption of an average in vivo recovery of two and a half-life of approximately 12h of FVIII concentrates and was aimed at achieving trough factor levels >1% for all patients (Table 1). In The Netherlands, lower dose regimens were later implemented (FVIII 20–40 IU/kg, 2–3 times a week), tailoring dosages and frequency of infusions according to the patients’ bleeding tendency, with the aim of avoiding spontaneous joint bleeds.15,16 Compared with the high-dose Swedish prophylactic regimen, this intermediate- dose prophylaxis showed a higher annual number of joints bleeds with slightly higher Pettersson X-ray scores after two decades of follow-up but a two-fold less clotting factor consumption.17


Thus, the Dutch group


proposed that it is more cost effective to use the bleeding pattern rather than a residual plasma factor activity of 1% as the criterion to increase prophylactic therapy. Age at start of prophylaxis was also


Table 1: Strategies to optimise haemophilia therapy by individualising the prophylactic regimen to the needs of each patient Strategy


Parameter(s) Clinical approach Pharmacokinetic approach


Laboratory markers such as global haemostasis assays


Clinical bleeding pattern Clinical response to treatment


Individual PK data Number of infusions per week to maintain residual plasma FVIII >1%


Thrombin generation measurement may be useful for determining individually tailored prophylactic regimens


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