Inhibitor development is presently the most serious threat to the effective and safe replacement treatment of haemophilia. The need to increase the number of international clinical studies remains essential for addressing the numerous unsolved issues
Mirko Di Capua
Anna Maria Cerbone
Centre for Coagulation Disorders
Dept of Clinical and Experimental Medicine
Federico II University
Replacement of the congenitally deficient coagulation factor VIII (FVIII) or factor IX (FIX) through plasma-derived or recombinant factor concentrates is the mainstay of treatment for haemophilia A and B. Concentrate infusions when haemorrhages occur, typically in the joints and muscles (on-demand treatment), can resolve bleeding but do not prevent the progressive joint deterioration leading to the crippling haemophilic arthropathy. Therefore regular prophylactic concentrate administration, started after the first joint bleed and/or before the age of 2 years (primary prophylaxis), is now recognised as the first-choice treatment in children with severe haemophilia (FVIII/IX<1%).
In high-income countries, thanks to the wide availability of safe factor concentrates and the diffusion of primary prophylaxis to prevent arthropathy, haemophilia patients currently receive excellent treatment and achieve a satisfactory quality of life. Therefore the development of antibodies against therapeutically administered factors (inhibitors) remains the most serious complication of haemophilia treatment.
In the presence of inhibitors, the safe and effective standard of care, particularly prophylaxis, is precluded. As a result, patients are at a higher risk of life-threatening haemorrhages and management of bleeding is often challenging. On the whole, haemophilia patients with inhibitors experience higher morbidity]1] and a worse quality of life related to their orthopaedic status[2,3] than non-inhibitor patients. Moreover, the economic implications of such a complication are especially relevant, with more than 98% of the strikingly high amount of medical and economic resources absorbed for care of these patients related to the direct costs of clotting factor concentrates.
Management of inhibitor patients is aimed at controlling bleeding episodes and their possible long-term complications. However, restoring FVIII replacement efficacy and prophylaxis feasibility by inhibitor eradication is the leading objective of treatment, particularly in children with recent-onset inhibitors. This article reports on current clinical strategies in the management of haemophilia with inhibitors, addresses the latest significant improvements and looks at the ongoing challenges.
Inhibitor development and management in haemophilia patients
Approximately 30% of severe haemophilia A patients generate inhibitors, typically during the first 20-50 exposure days, as a result of a complex process in which multiple genetic and environmental factors interplay. Inhibitor incidence is lower in severe haemophilia B patients (3-6%), and in patients with moderate (FVIII/IX 1-5%) or mild (FVIII/IX 5-40%) haemophilia. According to the highest documented inhibitor level and the presence of anamnestic response at factor concentrate re-exposure, high-responding (HR,>5 BU ml-1) or low-responding (LR, always <5 BU ml-1) inhibitors are distinguished. In some patients, inhibitors are detected temporarily and are no longer found on replacement treatment (transient inhibitors).
The development of a specific inhibitor to FVIII or FIX results in partial or complete lack of efficacy of factor concentrates. Inhibitors are transient or low-responding in about half of previously unexposed patients. In these patients, bleeding episodes may be managed by increased FVIII/FIX dosages, which are able to overcome the interference of inhibitors (Figure 1). The same approach may be used for severe bleeds in patients with high-responding inhibitors but low actual titre, before the elicitation of the anamnestic response. However, in the majority of cases bypassing agents-that is, activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa)-are needed in patients with HR inhibitors (Figure 1).
Increasing data are being collected on prophylactic regimens with both bypassing agents. However, the long-term effects of these treatments are still uncertain and 10-15% of patients with severe haemophilia remain with troublesome HR inhibitors. Immune tolerance induction (ITI) by means of frequent and long-term administration of factor concentrate is currently the only strategy proven to eradicate inhibitors. ITI is attempted in most haemophilia A inhibitor patients (Figure 1), particularly in children. Management of inhibitors in haemophilia B is more challenging, as re-exposure to FIX may be complicated by severe anaphylactoid reactions and nephrotic syndrome, thus limiting recommendation for ITI in this setting.
Prevention and treatment of bleeding: bypassing agents
Bleeding frequency is not higher in inhibitor patients  but bleeds may be severe and, especially in HR patients, achieving haemostasis for bleeds or during invasive procedures is often more difficult than in non-inhibitor haemophilia patients. The products used in this setting are referred to as bypassing agents because of their ability to promote haemostasis through alternative mechanisms to the physiological tenase complex, in which a phospholipid-dependent reaction occurs with factor X as the substrate, activated FIX as the enzyme and activated FVIII as a cofactor (Figure 2). Currently, two preparations are primarily used in clinical practice: aPCC (factor eight inhibitor bypassing activity, FEIBA, Baxter AG, Austria) and rFVIIa (NovoSeven, Novo Nordisk, Denmark). Historically, prothrombin complex concentrates (PCC) have been used for treatment of inhibitor patients before the development of aPCC, which became clinically available in 1975 and in the current vapour-heated formulation in 1985. The first use of rFVIIa was reported in 1988 and NovoSeven was registered in Europe in 1996 and in the United States in 1999.
Characteristics of aPCC and rFVIIa products are summarised in Table 1. A relevant body of literature documents efficacy and safety profiles for these two products over more than three and two decades of clinical use, respectively. Despite this, mechanism(s) of action are still not completely understood, and a series of open issues remains of concern for clinicians treating inhibitor patients (Table 2).
Clinical studies, in most cases retrospectively, demonstrated the effectiveness of both agents in achieving haemostasis in more than 90% of surgical procedures and in more than 80% of bleeding episodes, even for home treatment. In parallel, excellent safety records were collected. However, thrombotic complications-including myocardial infarction, venous thromboembolism and disseminated intravascular coagulation-remain the most serious concern with regards to administering bypassing agents. This issue is emphasised by the lack of easily available and validated laboratory tools for monitoring treatment and identifying an exaggerated activation of coagulation, although increasing data on thromboelastography and related global assays are being collected. Fortunately, the incidence of these adverse events is very low, occurring in most cases in the presence of other recognised risk factors and/or during prolonged, high-dose treatment.
According to a pharmacovigilance assessment, including data from published case reports and the US Food and Drug Administration MedWatch programme in the period 1999-2002, thrombotic complications resulted significantly more often in rFVIIa than aPCC recipients (24.6 vs 8.24 per 105 infusions, incidence rate ratio 2.98, CI 1.71-5.52). These data have been disputed, taking into account the inclusion of rFVIIa off-label treatments in non-haemophiliac patients and the possibility of underreporting adverse events for an older product like aPCC. Nevertheless, this debate highlights the need for caution regarding indications and dosages of treatment with bypassing agents and further vigilance and data collection in this setting.
Many clinicians tend to prefer rFVIIa in paediatric patients because of its recombinant origin and the lack of traces of FVIII or FIX potentially inducing an anamnestic response in children candidates to ITI. However, no general recommendations are possible for clinical choices in the management of bleeding episodes in inhibitor patients. Some patients may respond more efficaciously to rFVIIa and others to aPCC. Moreover, the same patient may achieve a better response to one product or the other on different occasions. Few studies have evaluated the comparative efficacy of aPCC vs rFVIIa, and the only prospective trial currently available (the FEIBA NovoSeven Comparative Study, FENOC) confirms this variability of response to treatment. The two products showed substantially similar efficacy, although statistical requirements for equivalence were not met. However, more discordant responses than expected (response to one agent vs the other for bleeds within the same patients) were reported.
Recently, prospective randomised studies documented comparable efficacy and safety of single rFVIIa high-dose (270 ¼g Kg-1) vs repeated standard doses (90 Î¼g Kg-1). Therefore a high-dose regimen may be convenient, avoiding multiple, short-interval infusions due to the reduced half-life of rFVIIa.
Anecdotal reports describe improved efficacy with combination or sequential use of the two bypassing products. Although in vitro thrombin generation data may support this strategy, it should be considered experimental and reserved for hospital treatment when other interventions fail and after appropriate risk-benefit assessment.
Prophylaxis in inhibitor patients
The need to avoid recurrent bleeding and the consequent joint deterioration in children with inhibitors prior to or during ITI, and for reducing the severity or the frequency of bleeds even in some adolescent or adult patients, led to the use of prophylaxis regimens with bypassing agents. Retrospective case series documented the efficacy and safety of a variety of regimens with both aPCC (50-100 IU Kg-1 from once daily to four times weekly) and rFVIIa (from 200 Î¼g Kg-1 per week to 270 Î¼g Kg-1 daily), in terms of reduction of frequency of bleeding episodes and improvements of patients’ physical activity and quality of life.5 A prospective randomised study also showed that these effects were not statistically different using rFVIIa doses of 90 or 270 Î¼g Kg-1 daily and, interestingly, were maintained over a three-month post-prophylaxis follow-up.11 Little, and not entirely consistent, data are available concerning the long-term effects of prophylaxis with bypassing agents on joint outcome. However, the encouraging clinical results generate a hypothesis for early prophylaxis even in children with inhibitors, with the aim of preventing life-threatening haemorrhages and minimising joint deterioration while awaiting the start of ITI.
Eradication of inhibitors: immune tolerance induction
ITI is a reliable option for eradicating inhibitors in patients with haemophilia A. Despite 30 year’s clinical experience, the optimal ITI regimen is still debated, as high success rates (60-80%) have been reported with widely heterogeneous dose and schedule of FVIII administration (Table 3) and evidence from large-scale and methodologically rigorous trials is substantially lacking.[6,12] Retrospective studies and registries have enabled the identification of some clinical predictors of success, particularly low pre-ITI and historical inhibitor titres (Table 4). ITI is a highly demanding treatment for patients, the managing clinicians and, ultimately, for health resources, mainly due to the costs of FVIII products. However, from a lifetime perspective, this economic burden further multiplying the strikingly high costs of managing inhibitor patients is limited to one to three years, and the high success rate and the low number of inhibitor recurrence after ITI means a considerable reduction of costs in the majority of treated patients can be predicted.
In this respect, children with recently diagnosed inhibitors are the best candidates for ITI, as inhibitor eradication allows restoration of FVIII prophylaxis and consequently prevention of arthropathy development. Adults with longstanding inhibitors often show bad predictors of ITI outcome. However, ITI may be considered as a suitable and cost-effective approach in cases with frequent bleeds that are not satisfactorily controlled by bypassing treatment and/or when orthopaedic surgery is needed. Randomised studies are addressing the optimal dose and type of FVIII concentrate for ITI. The recently terminated International ITI Study provided data which showed that low-dose regimens should be avoided in good-risk patients because of the higher number of bleeds in all phases of ITI and longer duration of treatment for achieving success.
Inhibitor development is currently the most serious threat to the effective and safe replacement treatment of haemophilia. New, more cost-effective strategies for inhibitor eradication based on immune modulation are in early development. However, standard ITI is effective in about two-thirds of haemophilia A inhibitor patients and should be attempted, particularly in children, for restoring the optimal prophylactic treatment. Management of inhibitor patients remains challenging, poorly standardised and affected by numerous, often unpredictable factors. However, on-demand treatment with bypassing agents is being progressively optimised and prophylaxis regimens are being increasingly employed, with an aim to minimise the deleterious effects of inhibitors. International collaboration for prospective, possibly randomised studies remains essential for addressing the numerous unresolved issues.
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