Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice

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.     

Prophylaxis in haemophilia patients with inhibitors

Summary.   The presence of high titre inhibitors makes the treatment of bleeding episodes in haemophilia patients difficult and increases the risk of uncontrollable bleeding and disability, despite optimum on-demand treatment with bypassing agents. The inability to effectively control joint bleeding leads to progressive joint disease in many patients with inhibitors. Significant mobility impairments are far more prevalent in patients with inhibitors than in those without inhibitors. Emerging data suggest that prophylaxis using bypassing agents may be effective and safe in reducing the incidence of joint bleeding during immune tolerance induction (ITI), and for patients who failed ITI or who were never candidates for ITI. Only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors. This article will review the published data on the use of bypassing agents in the prevention of bleeding, and will discuss ongoing clinical prophylaxis trials in inhibitor patients.     

Therapeutic choices for patients with hemophilia and high-titer inhibitors.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma‐derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one‐day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor. Am. J. Hematol. 67:240–246, 2001. © 2001 Wiley‐Liss, Inc.     

Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors

Haemophilia patients with inhibitors are treated for acute bleeding with prothrombin complex concentrates (PCCs) or activated prothrombin complex concentrates (aPCCs). Despite this therapy, patients with high-level inhibitors are at increased risk of developing devastating joint disease. This paper examines available information that supports the study of PCCs and/or aPCCs as prophylactic therapy for haemophilia patients with inhibitors. This strategy would require that PCCs or aPCCs be administered repetitively in a dose that is sufficient to prevent haemarthrosis without causing thrombogenic events, or causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U kg⁻¹ every other day for up to 8 months have resulted in subjective improvement both in bleeding associated with target joints and in the management of chronic joint inflammation. aPCC doses as low as 50–100 U kg⁻¹ every other day have been useful in postsurgical prophylaxis. The risk of developing a myocardial infarction or clinically relevant disseminated intravascular coagulation is linked to total dosages of either PCCs or aPCCs greater than 200 U kg⁻¹ day⁻¹. It is uncertain what anamnestic response would result from prophylaxis, but with typical therapy the aPCCs cause such a response in only a small percentage of patients. Based on these findings, a clinical trial of these products used in doses of 50–100 U kg⁻¹ every other day would appear to be warranted in patients who have permanent inhibitors and frequent joint bleeding.     

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.     

Current status and future prospects for the prophylactic management of hemophilia patients with inhibitor antibodies

Inhibitor antibodies to factor VIII arise in a substantial minority of patients with hemophilia A treated with replacement therapy; factor IX inhibitors in treated hemophilia B patients are considerably less common. As replacement therapy is not feasible in most such patients, hemostasis can generally only be achieved with “inhibitor bypassing agents”, namely (activated) prothrombin complex concentrates and recombinant factor VIIa. These agents are widely used to treat active bleeding in inhibitor patients but they have been used relatively infrequently as prophylactic agents to prevent bleeding and its consequences, mainly progressive joint damage. This is in contrast to hemophilia patients without inhibitors, in whom prophylactic replacement with concentrates of factor VIII or IX has become widely accepted as the optimal strategy to prevent these adverse outcomes. This review addresses the current experience and evidence and the future prospects regarding prophylaxis in inhibitor patients.     

The socioeconomic burden of patients affected by hemophilia with inhibitors

Hemophilia is associated with a high financial burden on individuals, healthcare systems, and society. The development of inhibitors significantly increases the socioeconomic burden of the diseases. This study aimed to review and describe the burden of hemophilia with inhibitors, providing a reference scenario to assess the impact of new products in the real word. Two systematic literature reviews were performed to collect data on (i) health economics and (ii) health‐related quality of life evidences in hemophilic patients with inhibitors. The costs associated with patients with hemophilia and inhibitors are more than 3 times greater than the costs incurred in those without inhibitors, with an annual cost per patient that can be higher than €1 000 000. The costs of bypassing agents account for the large majority of the total healthcare direct costs for hemophilia treatment. The quality of life is more compromised in patients with hemophilia and inhibitors compared to those without inhibitors, in particular the physical domains, whereas mental domains were comparable to that of the general population. The development of an inhibitor has a high impact on costs and quality of life. New treatments have the potential to change positively the management and socioeconomic burden of hemophilia with inhibitors.     

Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors

Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N = 5) and haemophilia inhibitor patients (N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg^?1 orally (O.R.) Patients were treated with aPCC 75 IU kg^?1 intravenous (I.V.) on day 1 followed by TXA 20 mg kg^?1 O.R. combined with aPCC 75 IU kg^?1 I.V. on day 2. A 14‐day washout occurred before crossover to rFVIIa 90 μg kg^?1 I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator‐based assay. Healthy controls showed a 20‐fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3–10 fold increase in MCF from baseline, with a decline in MCF starting after 60–120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.     

Immune tolerance induction in haemophilia A patients with high-responding inhibitors to factor VIII: experience at a single institution

Inhibitor antibodies to transfused factor VIII pose significant challenges in the management of haemophilia A patients. The main concern is the inefficacy of replacement therapy in patients with high-titre antibodies, who have a shorter life-span and a greater morbidity compared to subjects without inhibitors. The ultimate goal in treating these patients is to eliminate the inhibitor antibody entirely, allowing the recommencement of specific replacement therapy. The results of an immune tolerance regimen based on pharmacokinetic parameters are reported here. In 12 high-responder haemophilia A patients immune tolerance induction (ITI) was attempted with daily administration of factor VIII concentrates of very high purity, either plasma-derived or produced by recombinant-DNA technology. Patients were given 100 IU kg(-1) day(-1) until the inhibitor was shown to be absent by at least two negative assays 1 month apart, with normal recovery of infused factor VIII and normal half-life (> 6 h), as assessed after a 3-day washout period. After the patient was judged to be inhibitor-free, immune tolerance treatment was continued with unmodified factor VIII doses for 2 months. Doses were thereafter gradually reduced and finally, regular prophylaxis by administration of 25 IU kg(-1) three times weekly was instituted. Immune tolerance was achieved in 10 of the 12 patients (including six of seven with long-standing inhibitors) within a median time of 8 months. Outcome of immune tolerance was not influenced by age at start of ITI nor by the interval between inhibitor development and ITI. The success rate and the inhibitor disappearance time of our immune tolerance regimen, utilizing high-purity factor VIII, agrees with those reported by other investigators.     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience

Summary.  Non-activated and activated prothrombin complex concentrates have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 15 minor and six major surgical and invasive diagnostic or therapeutic procedures in eight inhibitor patients with congenital haemophilia A and in two patients with acquired haemophilia. Administration of a loading dose of 100 U kg⁻¹ of FEIBA^® followed by 200 U kg ⁻¹ day ⁻¹ in three doses every 8 h for 3 days and then tapering the daily dose to 150–100 U kg⁻¹, resulted in no severe or unexpected bleeding complications. One adverse event was observed. A 69-year-old man suffered a myocardial infarction the third postoperative day following sigmoidectomy. He was managed safely with opiate analgesia, nitrates and diuretics and the continued use of FEIBA^®.     

Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors

The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.     

Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry

We present a retrospective study of immune tolerance treatment (ITT) carried out in 42 Spanish haemophiliac patients. Most of the patients were high responders (39/42), with a median maximum titre of 67 Bethesda units (BU) (range 6-2984). The median inhibitor titre at the start the ITT was 11 BU (range 1-256 BU) and the median age of the patients was 7 years (range 0-57). The mean factor dosage was 140 IU kg bodyweight(-1) day(-1) (range 25-500). In most of the ITTs, plasma-derived factor concentrate of intermediate and high purity was used. The inhibitor was eradicated in 26/38 (68%) of the patients who completed the treatment and two patients changed their status from high to low responders. Multivariate logistic regression analysis showed that three significant variables were associated with the highest probability of success: (i) the use of low factor doses for ITT (< or = 100 IU kg(-1) day(-1); P = 0.0106; 95% CI 0.000289-0.342); (ii) a titre of < 10 BU at start of ITT (P = 0.0286; 95% CI 0.00253-0.7189) and (iii) a lower maximum titre (P = 0.0214; 95% CI 0.98-0.9994).     

Outcome measures for adult and pediatric hemophilia patients with inhibitors

Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long‐term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15^th Zürich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long‐term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX

Non-activated and activated prothrombin complex concentrates (PCC/aPCC) have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX (FVIII/IX) concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 14 minor and five major surgical and invasive diagnostic procedures in eight patients with congenital haemophilia A and inhibitors and in two patients with acquired haemophilia. When a loading dose of 100 U kg-1 of FEIBA was given followed by 200 U kg-1 day-1 in three divided doses every 8 h for 3 days, and then, when the daily dose was tapered to 100-150 U kg-1, no severe or unexpected bleeding complications were observed. However, one adverse event was observed. A 69-year-old man who suffered a myocardial infarction the third postoperative day following sigmoidectomy was managed safely with opiate analgesia, nitrates and diuretics, and the continued use of FEIBA(R).     

Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review

Summary. In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6–52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low‐dose protocols. There is no good evidence that immunosuppressive drug regimens are effective.     

Evaluation of Prophylactic Replacement Therapy in Haemophilia B

Prophylaxis replacement therapy has been assessed for a period of 12 months in 10 patients with severe haemophilia B showing a high incidence of spontaneous bleeding episodes. Two different schedules of administration of a freeze-dried factor IX concentrate were randomly evaluated: according to scheme A, 7.5 U/kg were administrated biweekly, whereas scheme B was based on the weekly infusion of 15 U/kg. On prophylaxis the frequency of bleeding episodes was significantly reduced (P < 0.005) when compared with that observed in the one-year period preceding the trial. Biweekly infusions were superior to weekly infusion (P < 0.01), and the benefit appeared to be related to the higher number of days in which measurable levels of factor IX were attained in plasma. Range of motion, which was reduced at the start of the trial in 26 joints, was found to have improved in 23. Favourable changes of the joint radiological picture were observed in 6 cases. Hepatitis and factor IX inhibitors did not develop during the trial period. Side effects were rare and mild.     

Assessing the benefits of FEIBA prophylaxis in haemophilia patients with inhibitors

Summary. Prophylaxis with concentrates of factor VIII has become the standard of care for patients with severe haemophilia A because of its ability to prevent joint and other bleeding events. Recent evidence suggests that the prophylactic use of bypassing therapy – activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) – provides similar benefits to haemophilia patients with inhibitors. To assess the efficacy and safety of prophylaxis with the aPCC FEIBA, a meta‐analysis was conducted of six studies and a total of 34 inhibitor patients. The mean prophylactic dose was 78.5 U kg^?1, typically infused three to four times weekly. A total of 31 of 33 patients (94%) for whom bleeding data were available prior to prophylaxis experienced a decrease in the rate of haemorrhage, albeit minor in some patients, and, regardless of the type of haemorrhage measured, had on average a 63.9% reduction in bleeding episodes during FEIBA prophylaxis. In the three studies that specifically assessed all joint bleeding, the 18 patients evaluated experienced an average reduction in annual joint bleeding of 74% while on prophylactic regimens. Among the four patients in this group who received concurrent immune tolerance induction and the 14 patients treated with prophylaxis only, annual joint bleeding decreased by an average of 79% and 78%, respectively. Anamnesis following FEIBA exposure was observed in some patients but had no impact on prophylactic efficacy. No thrombotic or other complications were reported. These results suggest that the prophylactic administration of FEIBA can be an effective and safe method for reducing bleeding events in patients with haemophilia A and inhibitors.     

Comparative efficacy of nonheated and heat-treated factor IX complex concentrate in treatment of hemophiliacs with inhibitors

To determine if heat-treated factor IX complex concentrate is as effective as nonheated factor IX complex concentrate for treatment of subjects with hemophilia A and antifactor VIII antibodies (inhibitor patients), we have retrospectively reviewed consecutive home treatment records of ten inhibitor patients who had been receiving nonheat-treated factor IX complex concentrate (NHT-Konyne) and subsequently converted to heat-treated factor complex concentrate (Konyne-HT) when it was licensed in late 1984. Overall, 162 of 284 (57%) separate bleeding episodes treated with NHT-Konyne and 53 of 80 (66.3%) separate bleeding episodes treated with Konyne-HT required only one treatment course of approximately 60-75 U/kg. The distribution of bleeding sites and the absolute factor IX unitage required per treatment episode were similar for both preparations. These data suggest that the percentage of hemophilic inhibitor patients responding to factor IX complex concentrate remains at least 50%, as was reported several years ago in a controlled study, and that inhibitor bypass activity has not altered by heat treatment.