Donna DiMichele

International workshop on immune tolerance induction: Consensus recommendations

Summary.  Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decision‐making. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence .

Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.

Summary.  A North American registry for rare bleeding disorders [factor (F)II, factor (F)VII, factor (F)X, factor (F)V, factor (F)XIII, fibrinogen deficiencies and dysfibrinogenemias] was established to gather information about disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment and prophylaxis strategies, as well as disease‐ and treatment‐related complications. Questionnaires were sent to 225 hemophilia treatment centers in the USA and Canada. Among 26% of responding centers, 294 individuals [4.4% of the registered children (200/4583) and 2.4% of adults (94/3809)] were diagnosed with one or more of the rare bleeding disorders (RBDs) included in this survey. The ethnic distribution for each disorder paralleled that of the general US population with the exception of the disproportionately large number of Latinos with FII deficiency. Only 5.4% of affected individuals were genotyped. An abnormal preoperative bleeding screen most often led to diagnosis. The most common coagulopathy was FVII deficiency; however, 40% of homozygous patients were asymptomatic. FX and FXIII deficiencies caused the most severe bleeding manifestations. Among all RBDs, the most common sites of bleeding were skin and mucus membranes. Multiple products were used to treat hemorrhage; however, half of the bleeding episodes required no therapy. The majority of patients suffered no long‐term complications from hemorrhage. Treatment‐related complications included viral seroconversion, anemia, allergic reactions and venous access device‐related events. This registry provides the most comprehensive information to date about North American individuals with RBDs and could serve as an important resource for both basic scientist and clinician.

Inhibitor development in haemophilia B: an orphan disease in need of attention

Factor IX (FIX) inhibitors develop in 1·5–3% of haemophilia B patients. Due to its low incidence compared with that in haemophilia A, few comparable data exist on host and treatment‐related risk factors, and immunological processes associated with FIX inhibitor development. Moreover, the safety and efficacy of bypass therapy as well as the outcome predictors of successful inhibitor eradication have been poorly characterised. The lack of a useful evidence‐based approach to the diagnosis and management of FIX inhibitors complicates their significant morbidity due to the frequency of allergic reactions that often herald antibody development. This review discusses what is currently known about the epidemiology, natural history and immunology of anti‐FIX antibody development. It addresses several special considerations in the approach to the treatment of bleeding and inhibitor eradication. A case is made for moving forward with an integrated international collaboration for the further study of the nature and treatment of this problem.

Factor IX inhibitors and anaphylaxis in hemophilia B

PURPOSE We present clinical and laboratory data on 18 children from 12 hemophilia treatment centers in the United States, Canada, and Europe with the purpose of disseminating information regarding a recently recognized, potentially life-threatening complication of treatment in very young children with hemophilia B. PATIENTS AND METHODS Twelve hemophilia centers from the United States, Canada, and Europe provided clinical information and laboratory data concerning 18 children who had severe allergic reactions to infused factor (F) IX in close association with the development of an inhibitor to FIX. Laboratory testing for establishment of the diagnosis of hemophilia B and inhibitor to FIX was done locally at the centers treating these patients. FIX gene analysis was performed at one of six molecular genetics institutes. RESULTS All 18 children had severe hemophilia B, and in each an inhibitor antibody to FIX developed. The median age at the time of anaphylaxis (or anaphylactoid reaction) was 16 months, and the median number of exposure days to FIX was 11. The FIX inhibitor was detected almost simultaneously with the first occurrence of anaphylaxis in 12 of 18 patients. Maximum inhibitor titers were 4.5-600 Bethesda units (BU), with a median titer of 48 BU. FIX gene analysis, performed in 17 of 18 patients, demonstrated complete deletion of the FIX gene in 10 and major derangements in seven. Immune tolerance induction (ITI) regimens have been attempted in 12 patients, with generally poor responses. Two of the 12 experienced nephrotic syndrome while on ITI. Recombinant FVIIa has been successfully used to treat bleeding episodes in 11 of these children. CONCLUSION Physicians treating young children with hemophilia B should be aware of the potentially life-threatening complication of anaphylaxis. Children with complete gene deletions or major derangements of the FIX gene appear to be at greater risk. Those identified by genotype as being at greater risk may need to receive their first 10-20 treatments in a medical facility equipped for handling such emergencies. Recombinant FVIIa, although not licensed for use in the United States, appears to be the most suitable treatment option for bleeding episodes in such patients.

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry

Summary.  Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg−1 every 2–3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90–300 mcg kg−1. High‐dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrands disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100–150, 150–200 and >200 mcg kg−1. Investigator‐reported efficacy for the first 72 h of treatment was evaluated. Thirty‐eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1–55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg−1 (range: 40–4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100–150, 0% for 150–200, <1% for >200 mcg kg−1 dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg−1 appear to be well‐tolerated. Additionally, rFVIIa doses >200 mcg kg−1 appear to significantly increase efficacy (97% in the high‐dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high‐dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

Rare inherited disorders of fibrinogen

Summary.  Fibrinogen, a hexameric glycoprotein encoded by three genes –FGA, FGB, FGG– clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross‐linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life‐threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma‐derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

Summary.  Background: The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. Objectives: To assess the pharmacokinetics, efficacy and safety of a plasma‐free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin‐Free Method, rAHF‐PFM], in children < 6 years of age with severe hemophilia. Patients/methods: Fifty‐two boys, one girl, mean (± SD) age 3.1 ± 1.5 years and ≥ 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF‐PFM at 23 centers. Results: The mean terminal phase half‐life (t1/2) was 9.88 ± 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 ± 0.43 IU dL−1 (IU kg−1)−1. Over the 1–6‐year age range, t1/2 of rAHF‐PFM increased by 0.40 h year−1. IVR increased by 0.095IU dL−1(IU kg−1)−1 (kg m−2)−1 in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0–5.8), 0.0 (0.0–6.1) and 14.2 (0.0–34.5) for standard prophylaxis, modified prophylaxis and on‐demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF‐PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non‐serious adverse events were seen. Conclusions: Children < 6 years of age appear to have shorter FVIII t1/2 and lower IVR values than older subjects. However, these parameters increased with age (t1/2) and BMI (adjusted IVR), respectively. rAHF‐PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

A retrospective postlicensure survey of FEIBA efficacy and safety

Summary.   Patients with haemophilia who develop inhibitors have unique treatment needs; bypassing agents such as Factor Eight Inhibitor Bypassing Activity, Anti‐Inhibitor Coagulant Complex (FEIBA; Baxter AG, Vienna, Austria) are part of this therapeutic armamentarium. This study sought to increase comprehension of the full therapeutic profile of FEIBA by evaluating its safety and efficacy in the settings of acute bleeding, surgery, and prophylaxis. Information was collected through a postmarketing surveillance study; questionnaire booklets were distributed to 72 treatment centers in the United States and Europe. The booklets contained questions related to patient demographics, inhibitor titre determinations, and FEIBA treatment. Information comprising 200 FEIBA treatment periods and representing >4500 infusions was available for 63 patients with inhibitors (n = 60, haemophilia A; n = 3, haemophilia B). Twelve patients were in more than one treatment group. Efficacy was determined by a subjective global evaluation and was good or excellent in 82% of all acute, and 91% of all surgical, treatments. Additionally, prophylactic treatment resulted in improved or stabilised clinical orthopaedic status in 11 of 13 patients (85%). Based on available data, FEIBA was judged safe in all treatment situations by the small number of adverse events (<0.04%). No thrombotic complications occurred during any treatment episode. Results indicated that FEIBA was safe and effective in acute, surgical, and prophylactic treatment settings, supporting the utility of FEIBA as a treatment option for patients with inhibitors. However, prospective studies are advised.

Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference.

Summary.  Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment‐related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enrol cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.