Gary Benson, Northern Ireland Haemophilia Comprehensive Care Centre, Belfast City Hospital, Belfast, UK. Tel: 02890263737; Fax: 02890263736; e-mail: firstname.lastname@example.org
For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications.
Patients with congenital hemophilia require lifelong replacement therapy with a clotting factor concentrate: factor (F) VIII in hemophilia A and FIX in hemophilia B (1). However, patients can develop inhibitors to these exogenous factors, resulting in the most serious treatment-related complication in hemophilia (2, 3). Once inhibitors have developed, it is more challenging to achieve hemostasis than in non-inhibitor patients. Furthermore, the presence of inhibitors has a major impact on patients’ physical functioning, quality of life, morbidity, and mortality (4–6).
In patients with high-titer inhibitors [≥5 Bethesda units (BU)], immune tolerance induction (ITI) aims to eradicate anamnestic inhibitors and restore normal responses to replacement therapy. The process of ITI involves regular infusion of FVIII or FIX concentrate with the goal of inducing antigen-specific tolerance. Certain ITI regimens may also include immunosuppressive or immunoregulative drugs or employ procedures such as plasmapheresis and immunoadsorption to help reduce and remove inhibitors (3, 7–9).
Thirty years’ experience has shown that ITI therapy has high success rates (7, 8, 10, 11). Between 60% and 80% of patients with hemophilia A given ITI respond to treatment, and the relapse rate is low [e.g., 15% after 15 yr in the International Immune Tolerance Registry (IITR)] (11). The success of ITI is lower in hemophilia B patients with inhibitors, at approximately 13–31%.
A number of recent reviews and consensus recommendations have distilled the available evidence base on ITI and describe the different regimens and their potential benefits and drawbacks (2, 3, 7). Nevertheless, there are several outstanding practical questions relating to the use of ITI in the clinic, such as when to start and stop ITI therapy, when ITI is not appropriate, which products and doses to use, whether ITI therapy should involve immune modulation or suppression agents, and how to manage those patients who experience a relapse or only achieve partial success from ITI.
These issues were discussed by a European hemophilia expert panel at the Sixth Zürich Haemophilia Forum in November 2010. Through a discussion of available literature and guidelines, and patient-case examples, the expert panel identified a number of practice points pertinent to clinical use of ITI. This article provides a summary of the panel’s consensus and recommendations.
Overview of ITI protocols
The panel noted that to date, there have been few randomized studies of ITI therapy. Most data come from national and international registries, with some additional information from the recently terminated, randomized International ITI study (12).
Registry data suggest that patients with hemophilia A given ITI achieve high success rates. For example, the IITR study group reported a 50.9% success rate, the North American Immune Tolerance Registry (NAITR) study group 70%, the Spanish registry study group 68%, and the German Immune Tolerance Registry (GITR) 79% (11, 13–15). Hemophilia B patients with inhibitors have a relatively low rate of ITI treatment success. Only 31% of patients with hemophilia B and inhibitors in the NAITR had successful ITI outcomes (13), and in the international FIX inhibitor registry, only 13% of ITI was successful (16).
The panel reported that there are several, different, effective ITI protocols for patients with hemophilia A (Table 1) (3, 7, 17–19). The panel recommendations on choosing the treatments to use within an ITI regimen for hemophilia A patients with inhibitors are described later in this article.
Table 1. Summary of the main immune tolerance induction protocols for patients with hemophilia A (3, 7, 17–19)
High-dose FVIII plus immunomodulation (adsorption and suppression)
Cyclophosphamide 12–15 mg/kg IV daily for 2 d, then 2–3 mg/kg PO daily for 8–10 d
FVIII to achieve a 40–100% FVIII level, followed by FVIII infusion every 8–12 h to achieve a 30–80% FVIII level
IVIG 2.5–5 g IV immediately after the first FVIII infusion, followed by 0.4 g/kg daily on days 4–8
Reported success rate, 59–82%
Median time to success, 1 months
The van Creveld (Dutch) protocol
Lower-dose/adaptive dosing of FVIII: neutralizing dose and tolerizing dose
FVIII 25–50 IU/kg BID for 1–2 wk, then 25 IU/kg every other day
Reported success rate, 61–88%
Median time to success, 1–12 months
Patients with hemophilia B have approximately a 10-fold lower risk of inhibitor development than patients with severe hemophilia A (3). The lower risk is thought to be linked to a lower rate of both ‘severe’ gene mutations (<20% vs. >60%) and non-sense mutations (6% vs. 30%) than is seen in patients with hemophilia A. Another explanation suggested by the panel is that FIX has homology to other vitamin K-dependent factors such as FII, FVII, or FX. Baseline genetic testing after a hemophilia B diagnosis may help identify mutations associated with a higher risk of inhibitor development (20, 21) and was recommended by the panel.
Current options for the management of inhibitors in hemophilia B are limited, particularly in patients with the anaphylactoid phenotype (2, 3). When inhibitors do develop, the panel considered FIX to be an ITI treatment option for low-titer patients (<5 BU). In patients with a high inhibitor titer (≥5 BU), there was no consensus recommendation for ITI, but it was suggested that it could be attempted with caution after considering the chances of success vs. the risk of adverse events. On-demand bypassing therapy with recombinant activated FVII (rFVIIa; NovoSeven®; Novo Nordisk, Bagsvaerd, Denmark) or plasma-derived activated prothrombin complex concentrate (pd-aPCC; FEIBA®; Baxter, Deerfield, IL, USA) can also be employed, although the panel commented that pd-aPCC can be associated with an anamnestic response and anaphylaxis.
Patient cases and practice points
The panel discussed five patient cases exemplifying the complexities of and differing approaches to ITI therapy in patients with inhibitors (Table 2). The optimal ITI therapy – in terms of when to initiate therapy, how long to treat, choice and dosing of ITI agents, and strategies to deal with bleeds, complications, and poor responses to ITI – needs to be individualized according to patient characteristics, clinical needs, and risks.
Table 2. Five patient cases exemplifying differing approaches to ITI and different ITI regimens that may be given to patients with inhibitors
Adult managed 40 yr with hemophilia A, intron 22 inversion
First joint bleed at 5 yr of age and developed inhibitors at the age of 7. Historical peak inhibitor, 50 BU
No attempts were made to tolerize the patient
Started ITI, at the age of 40, with FVIII 50 IU/kg given every 48 h for 5 months, after which the inhibitor titer fell to 1.14 BU/mL
Currently has an inhibitor titer <0.5 BU
Teenager, aged 15 yr, with hemophilia A and inhibitors (peak titer, 6.0 BU)
Treated for 9 yr and 7 months with FVIII 40 IU/kg alone, given 3× per week (Monday, Wednesday, Friday), with no immune modulation, in order to reduce inhibitor titers
On ITI. Breakthrough bleeds requiring bypassing agent: 2/yr
Six-yr-old child with hemophilia A, intron 22 inversion, and inhibitors (peak titer, 6.0 BU)
Received FVIII 100 IU/kg daily for 5 yr and 4 months to reduce inhibitor titer. Standard success outcome achieved, for example, half-life >6 h, >66% recovery, and inhibitor <0.5 BU
Patient D (brother of Patient C)
Four-yr-old child with hemophilia A, intron 22 inversion, and inhibitors (peak titer, 17.6 BU)
Given ITI of FVIII 100 IU/kg daily for 3 yr and 5 months
Inhibitor persistently 5 BU
Patient with hemophilia B and inhibitors
ITI regimen involved premedication with antihistamines, and ITI of high-dose FIX (2 × 125 IU/kg daily) for 75 d with dexamethasone and IVIG pulses every 3–4 wk
Regimen was effective in reducing inhibitors within 8 wk, and the dose of FIX was down-titrated slowly
Patient continued to receive IVIG every 3–4 wk for 1 yr
When to start and when to stop ITI
The case examples A–D in Table 2 illustrate that ITI is an effective option for both children and adults with inhibitors and highlight that successful responses to ITI may be achieved across very different timescales, depending on individual case characteristics and ITI strategies, with treatment success taking anything from a few months to as much as 10 yr.
The panel endorsed current consensus to consider starting ITI therapy for all inhibitor patients, particularly children, who may benefit and are willing to receive this treatment (3, 7). Registry data show that adults can be considered candidates for ITI therapy if they have newly diagnosed inhibitors or inhibitors that were diagnosed within the past 5 yr (11, 13), although this was not reported in all registries, and International and European guidelines recommend starting ITI therapy when the patient’s inhibitor titer is <10 BU (2, 3, 7). Adults with persisting low-responding inhibitors (<5 BU) can also be considered for ITI therapy when bleeding episodes cannot be successfully treated with replacement therapy (2).
The panel recommended that when assessing patients for ITI, clinicians consider aspects of the patient’s condition and history that may impact on treatment success and choice of ITI regimen. In children, for example, the most consistent predictors of successful ITI therapy from registry data are a pre-ITI inhibitor titer of <10 BU and a peak historical inhibitor titer of <200 BU (7, 8, 11), but there are no clear cutoffs.
The panel noted that in patients who do not appear to achieve a successful outcome, it is difficult to know when to stop ITI therapy or when to consider that ITI has become a form of intense prophylaxis.
In keeping with current clinical guidance, the panel concurred that ITI therapy should be stopped when patients achieve successful tolerance (Table 3).
Table 3. Accepted definitions of success, partial success, failure, and relapse during and after ITI in patients with hemophilia A with inhibitors, based on (2, 3, 38)
BU, Bethesda units; F, factor; ITI, immune tolerance induction.
Inhibitor titer <0.6 BU/mL on ≥2 consecutive monthly measurements FVIII recovery ≥66% of expected values FVIII half-life ≥6 h after 72-h FVIII washout, and no anamnestic response upon subsequent FVIII exposure
Reduction in inhibitor titer to ≤5 BU/mL FVIII recovery <66% of predicted FVIII half-life <6 h after 72-h FVIII washout associated with clinical response to FVIII therapy, and no increase in inhibitor titer >5 BU over 6 months of on-demand treatment or 12 months of prophylaxis
Failure to attain defined success or partial success within 33 months of uninterrupted ITI Failure to demonstrate ongoing inhibitor titer reduction ≥20% during each interim, non-overlapping 6-months period of uninterrupted ITI, beginning 3 months after initiation to allow for expected anamnesis (reasonable duration of unsuccessful ITI: minimum 9 months, maximum 33 months)
Inhibitor recurrence within 12 months of successful ITI
Situations when ITI may not be beneficial
The majority of cases of hemophilia with inhibitors develop in patients before the age of 20 yr when there is a strong case for trying ITI to restore responsiveness to factor concentrates. In adulthood, inhibitors typically occur in three circumstances: in newly diagnosed patients, in patients who did not receive ITI in childhood, and in patients who fail or relapse following ITI.
The panel noted that in cases in which more than 5 yr have lapsed since the diagnosis of inhibitors, there may be a risk of poor outcome following ITI (3). While ITI may have clinical and cost-benefits in patients with frequent bleeds that are not satisfactorily controlled by bypassing agents, the use of ITI in adults who have failed ITI or have had inhibitors for more than 5 yr may not be warranted.
Choosing the treatments to use within an ITI regimen
The recent recommendations on ITI identify that there are no definitive data to support the superiority of one ITI regimen over another (3). The panel debated this issue further and offered the following top-line perspective of the available evidence on different treatment options for use within ITI.
Factor concentrates: which one and what dose?
When selecting factor concentrates, clinicians can choose either plasma-derived (pd) or recombinant factor concentrate. In the management of hemophilia A, there is a need to elect to treat with either high- or low-dose FVIII according to patient needs and risks.
The panel concurred with treatment guidelines which recommend that ITI therapy should be conducted with the same concentrate as the one against which antibodies were developed (2, 3). This should ensure successful tolerance induction and reduce the risk of further inhibitor development to new molecules. Importantly, a recent study reported that recombinant factor concentrates, unlike pd products, are not associated with the risk of transmission of a bloodborne pathogen: non-enveloped viral DNA was detected in 26% of the pd products tested, but in none of recombinant products tested (22). In hemophilia A, the panel also suggested that testing for inhibitor epitope specificity and/or in vitro cross-reactivity toward different FVIII products may help predict the individual response to ITI, supporting the choice for a specific type of FVIII concentrate.
It was noted by the expert panel that evidence from registries is helpful but may not fully inform factor choice in the clinic. For example, registry data suggest ITI success rates of between 25% and 50% with high-dose antihemophilic factor (Recombinant; Recombinate; Baxter) and 88% with high-dose human coagulation FVIII/von Willebrand factor (VWF) complex (Haemate® P; CSL Behring, King of Prussia, PA , USA), but there are no controlled trial data to delineate between these agents (10, 23, 24).
As demonstrated in the hemophilia A cases (A–D) in Table 2, the success of treatment does not always relate to the choice of FVIII dose. Treatment with high-dose FVIII was eventually successful in eradicating inhibitors in two pediatric cases, yet low-dose FVIII was effective in the adult patient (case A) within 5 months. However, in case B, a teenage patient, 9 yr of low-dose ITI would appear to have been a protracted course of ITI, and an alternative strategy might have allowed the patient to respond more quickly to therapy.
In addition, the panel reported that high-dose FVIII does not necessarily lead to more rapid or more effective outcomes. Registries have provided inconsistent findings with regard to the success rates for high-dose FVIII (>200 IU/kg) relative to low dose (<200 IU/kg). In the Italian ITI registry, relatively high daily doses (100–200 IU/kg) were used in children, based on the rationale that the cost of concentrates would be four times greater in adults. Some registry findings suggest that the early use of high-dose therapy leads to better rates of inhibitor eradication, while other registries, such as the NAITR, report an inverse relationship between factor dose and outcomes in hemophilia A (13). Adding to the uncertainties over whether to choose low or high doses of factors, patients (n = 133) in the International ITI study achieved tolerance earlier and experienced less bleeding in the high-dose FVIII arm (200 IU/kg daily) than in the low-dose arm (50 IU/kg, three times weekly), although there was no difference between arms in overall ITI success rates (12).
The opinion of the panel was thus that the choice of factor dose for ITI should be based on balancing individual patient needs against risks.
Does the patient need additional treatments?
Bleeding control during ITI. Bleeding episodes in inhibitor patients are often managed with bypassing agents, such as rFVIIa or pd-aPCC. The panel suggested that additional prophylaxis with pd-aPCC may also be beneficial as additional therapy during ITI for patients with a high bleeding frequency.
The panel noted potential limitations of bypassing treatment including the high costs of therapy and the need for frequent injections. In addition, they highlighted that pd-aPCC can be associated with an anamnestic response and anaphylaxis, and its long infusion time may be an issue when treating school-age children at home.
Immune modulation. From their discussions, the panel concluded that, despite the inclusion of cyclophosphamide within the Malmö protocol (Table 1), there is no clear evidence supporting inclusion of immune-modulating or immune-suppressing agents, such as rituximab or mycophenolate, within ITI regimens (25–28). However, they noted that data from a consecutive cohort of 15 hemophilia A patients with inhibitors treated with rituximab in the United Kingdom highlight some potential benefits when this agent is used together with FVIII (29). In clinical practice, the panel recommended that clinicians balance the risk of bleeding against the risk of infection, both of which can be life-threatening in inhibitor patients.
Hemophilia B: additional agents. The hemophilia B patient case described in Table 2 (Patient E) required premedication with antihistamines and use of corticosteroids to reduce the potential for allergic responses to FIX, in addition to intravenous immunoglobulin (IVIG) pulses every 3–4 wk for 1 yr after successful ITI. This case highlights the importance of tailoring regimens and titrating treatment to match the patient’s clinical need and likely reaction to therapies used within ITI regimens. Recent consensus recommendations note that many cases of ITI in hemophilia B with inhibitors fail because of allergic reactions (3).
The panel suggested that in hemophilia B inhibitor patients with life- or limb-threatening bleeding, in addition to FIX for ITI, clinicians should consider use of bypassing agents, plasmapheresis, or immunoadsorption. They also suggested that there may be a role for corticosteroids and IVIG therapy for the optimal management of these patients (2, 3, 30).
The burden of ITI therapy: complications and their management
The panel agreed that ITI therapy can exact a potentially high clinical burden and carries a considerably increased risk of infection in those patients using central venous access devices (3). The randomized International ITI study provides valuable data on the safety of ITI in severe hemophilia A. Preliminary findings from 45 patients in the ITI study reported 102 serious adverse events, 85% of which were judged by the Data Safety Monitoring Committee to be unrelated to the study/product. All required hospitalization, for reasons including 29 bleeding episodes (14 patients) and 44 catheter infections in 13 patients with central venous access catheters (31).
In patients undergoing ITI who develop infections through venous access sites, the panel concurred with recommendations for standard medical management of port infection, change and removal of infected ports, and use of alternative infusion routes via fistula (3). In addition, bleeds occurring during or as a result of ITI should be treated on demand (or potentially prophylactically) with a bypassing agent (32). It was noted that since the International ITI study, there has been wider use of bypassing agents as an alternative means of managing patients with hemophilia and inhibitors.
The panel cautioned that in the management of hemophilia B with inhibitors, the use of ITI regimens, including high-dose FIX as used in the Bonn ITI protocol, may be accompanied by life-threatening side effects, such as bleeding, anaphylaxis, and nephrotic syndrome (21). As cyclophosphamide use has been associated with a risk of reduced fertility (33), the use of this drug in patients with hemophilia B presents another potential ITI-related treatment disadvantage. It was observed by the panel that the study of agents such as rituximab within ITI regimens is in its infancy, yet such novel approaches to inhibitor reduction in hemophilia B may hold some promise of remission (26).
Psychological burden of ITI
The presence of inhibitors may adversely affect health-related quality of life (6, 34). However, despite observational data suggesting that ITI can increase the risk of complications and burden on patients, the panel advised that the available literature provides no empirical data on the impact of ITI on psychological health or well-being.
The diagnosis of inhibitors can induce feelings of sadness, helplessness, or anger in patients and parents (35, 36), and thus the need for ITI might increase distress. To counter such concerns, the panel recommended that clinicians help patients and their families to find strategies to cope with an inhibitor diagnosis and need for ITI therapy. This should include provision of a full explanation of what to expect from ITI therapy, so patients/families can take more responsibility for their role in the success of ITI.
Management of patients with relapse or partial success
As described earlier, successful responses to ITI may be achieved over very different time spans – ranging from a few months to several years – depending on patient characteristics and circumstances. When patients experience an increase in their inhibitor level, decisions regarding changing treatment dose or product can be challenging.
Figure 1 summarizes the panel’s view, based on published recommendations (2, 3), on when to stop and when to reconsider a failing or partially successful ITI strategy. Current consensus recommendations offer definitions of partial success, failure, and relapse (Table 3), which can be used in clinical practice to help guide treatment decision-making (37, 38).
In patients with incomplete or no response to first-line ITI regimens, the panel concurred with international consensus recommendations that suggest a number of strategies in an attempt to achieve a positive ITI outcome (3) (Fig. 1):
• Continue the current ITI regimen or maximize ITI doses (3, 39).
• Switch to a VWF-containing FVIII product (40–47).
• In patients with high-risk inhibitors, consider adding rituximab or another immune-modulating drug, such as mycophenolate, to the current regimen (28, 48–50).
The panel agreed that the management of patients who fail ITI despite all attempts continues to pose dilemmas. Currently, it is unclear whether FVIII/VWF is a suitable option in patients who fail initial ITI therapy (2, 3). In this respect, retrospective data on the use of a single VWF-containing pd-FVIII product concentrate in rescue ITI reported that 52% of patients attained partial or complete success (41). Two prospective ITI studies are now assessing FVIII/VWF as either rescue therapy in ITI-experienced patients (RESISTexp) or as first-line therapy in ITI-naive patients (RESISTnaive) (51).
Until there are more data to guide treatment decisions, the panel advised that it is important to appreciate that some patients may not be suitable candidates for salvage ITI, including those who have shown poor compliance, patients for whom availability and cost of factor concentrates is a barrier, adult patients with long-standing inhibitors, and perhaps also patients who have previously failed salvage ITI therapy. According to the panel, rather than salvage ITI, prophylaxis with a bypassing agent could be considered for these patients.
There are a number of options for patients with hemophilia B who fail ITI. If a patient has a low inhibitor titer (<5 BU), ITI with FIX may be suitable. In patients with higher inhibitor titers, on-demand rFVIIa (90–160 μg/kg every 2–3 h) was the preferred choice of the panel because it lacks anamnestic risk. Other options for patients failing ITI include pd-aPCC 50–100 IU/kg maximal twice daily or secondary prophylaxis with rFVIIa up to 270 μg/kg (or pd-aPCC 50–100 IU/kg once daily). Currently, prophylactic use of rFVIIa is approved for use in hemophilia patients with inhibitors in Argentina, Australia, New Zealand, and Russia.
The management of hemophilia with inhibitors is challenging for physicians and patients. Various forms of ITI offer the means to reduce inhibitor titers and restore responses to factor concentrates; however, the optimal regimen and strategy for ITI needs to be decided on a case-by-case basis. When ITI is delayed to allow the inhibitor titer to decline, management of bleeds with rFVIIa is preferred (3).
To help physicians in decision-making, the panel agreed that further randomized, controlled clinical trials of ITI therapy are needed. In the meantime, ITI registry data and clinical experience have provided valuable insights on how to address some of the challenges facing physicians.
The expert panel reached the following conclusions regarding ITI therapy in patients with hemophilia A, based on their review of the literature and clinical experiences:
• ITI therapy should be started when the patient’s inhibitor titer is <10 BU.
• Long-standing inhibitors (>5 yr since detection) are difficult to treat; thus, therapy should begin as soon as possible after diagnosis.
• Based on ITI study results, and following consideration of patient characteristics, optimal ITI treatment for high-titer patients could include rFVIII at high doses, if available.
• In patients with a high bleeding frequency, prophylaxis with pd-aPCC or rFVIIa may be beneficial.
• ITI therapy should be stopped when successful tolerance is achieved, and patients should be switched to prophylaxis.
• ITI therapy complications tend to be serious and associated with infusion risks, particularly infection caused by the use of central venous access devices.
• In patients who do not achieve complete success with ITI therapy, an alteration of treatment regimen is advised, such as optimizing the ITI dose, switching to a VWF-containing FVIII, or, in high-titer patients, using an immune-modulating drug.
• Further work is needed to find an alternative to ITI therapy with a longer effect and perhaps an alternative route to intravenous administration.
The panel reached the following conclusions for ITI therapy in patients with hemophilia B:
• Patients should receive baseline genetic testing to identify large mutations that may be associated with a higher risk of inhibitor development.
• Patients with low-titer inhibitors (<5 BU) should receive ITI.
• There are no consensus recommendations for ITI in patients with high inhibitor titers (≥5 BU), but ITI could be attempted with caution. rFVIIa or pd-aPCC can be given on demand in addition to ITI for the management of bleeds.
• For patients who fail ITI, options include high-dose (270 μg/kg), on-demand rFVIIa in children (or pd-aPCC).
Gary Benson, Ivo Elezović, Thierry Lambert, and Silva ZupančićŠalek declare no conflicts of interest for this manuscript. Günter Auerswald has received honoraria and research support, has been a P.I. for Baxter, Bayer, CSL Behring, and Novo Nordisk, has been a consultant for Pfizer and Novo Nordisk, and has participated in Scientific Advisory Boards for Baxter and Novo Nordisk. Rolf Ljung has during the last 5 yr received consultatory or speaker’s fees from Bayer, Baxter, Novo Nordisk, and Octapharma. Massimo Morfini has received a fee for speaking and for consulting from Novo Nordisk, CSL Behring, Pfizer, Baxter, and Bayer. Eduardo Remor has received a fee for speaking from Novo Nordisk Region Europe A/S. He has no interests that might be perceived as posing a conflict or bias. Financial support for the Sixth Zurich Haemophilia Forum was provided by Novo Nordisk Region Europe A/S, who also financially supported medical writing assistance by Anne Stirland and Winnie McFadzean of PAREXEL in compliance with international guidelines for good publication practice.