Prophylaxis in haemophilia and other inherited bleeding disorders

The main goal of the treatment of haemophilia patients is to prevent recurrent joint bleeds and later chronic arthropathy, through lifelong treatment with clotting factor concentrates. Treatment can either be given on-demand, after a bleed has occurred or prophylactically to prevent bleeding. Prophylaxis is defined as the regular infusion of factor replacement therapy (FVIII/FIX) given to prevent/reduce bleeding, in particular joints bleeds, in order to prevent haemophiliac arthropaty, and is accepted the gold standard treatment in children with severe haemophilia [1]. Prophylaxis is generally classified into primary and secondary. Primary prophylaxis is started before the development of joint damage, whereas secondary prophylaxis can either be continuous long-term treatment started after two or more bleeds or after the age of two or intermittent regular treatment. According to the World Health Organization (WHO) and the World Federation of Hemophilia (WFH), the main goal in the treatment of haemophilia should be prophylaxis, with the aim of preventing bleeding episodes and their consequences [1, 2]. Efforts have been made to consolidate definitions for haemophilia prophylaxis. In Europe, the European Paediatric Network for Haemophilia Management (PedNet) group defined primary prophylaxis in their 1998 meeting report and refined these definitions further in their 2003–2004 meeting report as either: regular continuous treatment started after the first joint bleed and before the age of 2 years or regular continuous treatment started before the age of 2 years without previous joint bleed [3, 4]. Berntorp et al. developed definitions during an international conference where prophylaxis was defined as treatment by intravenous injection of factor concentrate in anticipation of and in order to prevent bleeding. Primary prophylaxis was defined as long-term continuous (≥46 weeks per year) treatment, determined by age (started before the age of 2 years and prior to any clinically evident joint bleeding) or determined by first bleed (started prior to the onset of joint damage, presumptively defined and having had no more than one joint bleed, irrespective of age [5]. Several studies have established the superiority of prophylaxis over on-demand treatment in reducing the joint bleeds, and that is important to start treatment before arthropaty, the major cause of morbidity in severe haemophilia, has developed [6-8]. More recently, Manco-Johnson et al. in the frame of a randomized controlled trial, demonstrates the efficacy of prophylaxis in reducing the incidence of joint bleeds, life-threatening and other haemorrhages, lowering the risk of joint damage in boys with severe haemophilia A [9]. Despite the benefits of prophylactic treatment are well established, the optimum treatment regimen concerning dose and age at introduction remains under discussion. Two groups, from Sweden and the Netherlands, began programmes of prophylaxis in boys with severe haemophilia in the late 1950s/1960s [6, 7]. In both haemophilia treatment centres, prophylaxis was started in boys with a history of some joint bleeding (i.e., secondary prophylaxis), but evolved to programmes where factor infusions were given before, or after a very few, clinically reported joint bleeds. These programmes differed significantly with respect to age at introduction of prophylaxis and intensity of regimen. In Sweden, prophylaxis was given as high-doses of factor VIII (FVIII) (25–40 IU/kg on alternate days, minimum three times per week for haemophilia A patients and 25–40 IU/kg of factor IX (FIX) twice weekly for haemophilia B cases. Prophylaxis was initiated at a very young age (generally ≤2 years) or at the time of the first joint bleed if this occurred before age 2 years [10]. In the Netherlands, prophylaxis was started at an early age according to the individuals bleeding pattern, generally after the occurrence of at least one or two joint bleeds. The Dutch regimen involved the administration of 15–25 IU/kg of FVIII two or three times a week for haemophilia A cases, and 30–50 IU/kg of FIX once or twice a week for haemophilia B cases [11]. In Canada a dose-escalation regimen was implemented and a dose-escalation primary prophylaxis study was started in 1997. Boys’ ages 1 year to 30 months with severe haemophilia A, were started on once weekly infusions of FVIII (50 IU/kg). If clinically significant bleeding into muscles and/or joints occurred, the frequency of FVIII infusions was increased to twice weekly (dose 30 IU/kg); continuation of bleeding resulted in escalation of the prophylaxis regimen to 25 IU/kg on alternate days [12]. In the Canadian dose-escalation regimen the percentage of boys with severe haemophilia A on once weekly, twice weekly and alternate day treatment at 10 years from the start of the study is 37%, 34% and 29%, respectively [12]. Compared to on-demand therapy, intermediate-dose prophylaxis started at an early age in boys with severe haemophilia results in significantly fewer joint bleeds, a better joint status and a better quality of life [13]. Compared to the intermediate-dose Dutch prophylaxis regimen, the Swedish high-dose prophylaxis regimen is associated with a significantly lower rate of joint bleeding. With this regimen, however, the FVIII consumption, and therefore cost, is approximately twofold higher than the intermediate-dose regimen [14]. Despite various prophylactic regimens in use – Swedish high dose prophylaxis protocol, Dutch intermediate-dose prophylaxis protocol and Canadian dose-escalation primary prophylaxis protocol – there is good evidence that the early beginning of prophylactic treatment with concentrates, in children with severe haemophilia, results in fewer joint bleeds, reduced arthropaty, fewer life-threatening haemorrhages and better quality of life. The prophylaxis in adults is a matter of debate and there is no consensus on the management of patients on primary prophylaxis, as they pass through adolescence and young adulthood. The issue of when stop prophylaxis, is still largely debated, as adults with haemophilia remain at risk of having joint bleeds and other haemorrhages. In one study, in two Danish and one Dutch treatment centre, was evaluated the incidence and outcome of stopping prophylaxis in severe haemophilia patients who were offered prophylaxis during childhood [15]. One third of the patients had switched to on-demand treatment, while maintaining a low-joint bleed frequency. Long-term outcome in these patients was identical to outcome in patients on prophylaxis, in a 4 year follow-up [16]. Data of an European survey of haemophilia centres from 15 countries indicate that half of the cohort of patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached the age range of 16–22 years. Only 28% of the cohort of patients who stopped prophylaxis required reintroduction of a prophylactic regime and 20% of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. Although the lack of consensus on the management of prophylaxis in adolescent and adults with severe haemophilia, data suggest that a significant number of patients could stop prophylaxis or reduce the intensity of replacement therapy, but a substantial number of patients still requires regular prophylaxis [16]. Another issue is the prophylaxis in patients with high-titre inhibitors to FVIII or FIX. The development of antibodies to factor VIII/factor IX is today the most serious complication of haemophilia and replacement treatment. Overall, inhibitors appear in 20–30% of patients with severe haemophilia A and 1–3% of patients with haemophilia B [17, 18]. Patients with haemophilia and inhibitors are at an increased risk for developing joint damage and life-threatening haemorrhages, leading to a reduced quality of life when compared with patients without inhibitors [19, 20]. This is reflected in more absence from school or work, more frequent hospitalizations, reduced mobility and significantly worse orthopaedic status. Although antibody erradication is the ultimate goal of inhibitor management through the implementation of immune tolerance induction (ITI), patients who failed or who are not candidates to ITI are at an increased risk for developing joint damage and reduced quality of life [19, 21]. Agents that bypass the need for FVIII or FIX (activated prothrombin complex concentrates-aPCC and recombinant activated factor VII-rFVIIa) are the cornerstone in on-demand treatment for acute bleeds and can be an effective and a safe treatment for inhibitor patients in different clinical settings [22-24]. Data showed that prophylaxis with activated prothrombin complex concentrates (aPCC) reduced the frequency of bleeding episodes by a mean of 73–83% and also maintained or improved orthopaedic status in all patients [25, 26]. More recent data suggest that rFVIIa prophylaxis in patients with inhibitors is associated with a reduced bleeding tendency and improved patient quality of life [27]. In a prospective, randomized, double-blind trial of secondary prophylaxis, Konkle et al. evaluated whether rFVIIa could reduce bleeding frequency when compared with on-demand therapy. Overall bleeding frequency was reduced by 45–59% during prophylaxis period and joint bleeds reduced by 43–61% [28]. This data suggest that prophylaxis can be an effective and safe treatment for inhibitor patients in much the same way that prophylaxis works in non-inhibitor patients. In von Willebrand (vWD) disease although the primary symptom is mucosal bleeding and the majority of vWD patients have a mild bleeding tendency controlled with antifibrinolytic agents and desmopressine (DDAVP), the severe form of the disease can occur with joint bleeds, resulting in chronic morbidity [29]. Long-term prophylaxis, with factor VIII/vW concentrates, is not the standard in vWD, but replacement therapy has to be given in case of severe bleeding, surgery and some invasive procedures. Type 3 vWD may cause significant joint bleeds or severe and frequent mucosal bleeds, that if not effectively prevented can lead to arthropathy with significant impairment of health and quality of life. Data from a cohort of 35 patients (with vWD types 3, 2A, 2B, and 1) who have received long-term prophylaxis at Malmö University Hospital and Karolinska University Hospital in Stockholm, have demonstrated a substantial reduction of bleeding episodes since the beginning of treatment. Patients who began prophylaxis at a young age (<5 years) to prevent nose and mouth bleeds have had no joint bleeds and have no clinical signs of arthropathy. These data suggest that long-term prophylaxis is warranted in the majority of patients with type 3 vWD and in other subtypes with severe bleeding tendencies, and that such an approach may help in the avoidance of joint disease if started early [30]. Based on the evidence currently available and the outcome expected in patients with clinically severe forms of vWD, it seems reasonable to recommend prophylaxis in selected cases, especially in type 3 patients with a history of life-threatening or serious recurrent bleeds and in type 2 patients with severe gastrointestinal bleeds [30, 31]. Other rare bleeding disorders (RBDs) that include the inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FV + FVIII, FVII, FX, FXI, FXIII, and multiple deficiency of vitamin K-dependent factors, with a prevalence in the general population varying between 1 in 500 000 and 1 in 2 million, have clinical manifestations ranging from mild to severe. The personal and familial history is important before choosing the therapeutic approach, as well as the type of bleeding episode. In most RBDs treatment must be administered as soon as possible after onset of bleeding (on demand) and prophylaxis can be given either from an early age to prevent bleeding (primary prophylaxis) or after bleeding to prevent recurrences (secondary prophylaxis) [32]. In specific cases, like congenital afibrinogenemia and severe factor XIII deficiency, prophylaxis may be recommended because the high risk of recurrent intracranial haemorrhage, joint bleeds and also during pregnancy because it usually results in spontaneous abortions [33, 34]. Despite the progress made in past years, as a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the lack of specific concentrates and the potential adverse events, the actual management of bleeding episodes and particularly the prophylactic treatment in patients affected with RBDs are not well established. It has been proven that early prophylactic therapy can prevent bleeds and arthropathy in severe haemophilia patients. Nevertheless, because it is a very demanding lifelong treatment, several barriers have been identified: the very high cost, the challenge of venous access and the compliance to treatment. To overcome barriers we must consider an escalating-dose regimen when initiating prophylaxis, tailored-dose regimens that may reduce costs and provide patients and family with education to facilitate commitment to prophylaxis. Bleeding prophylaxis can be achieved in patients with vWD by administering replacement therapy with VWF/FVIII concentrates, but there is an urgent need for studies of prophylaxis in vWD to allow development of evidence-based guidelines for long-term prophylaxis. Primary and secondary prophylaxis should be discussed for severe RBDs, even in absence of evidence-based data. When deciding for prophylaxis regular surveillance for both the disease and treatment related-complications in a comprehensive care setting is highly recommended. None.

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