The evolution of comprehensive haemophilia care in the United States: perspectives from the frontline.

The establishment of dedicated comprehensive treatment centres more than a half century ago transformed the management of haemophilia in the United States. Formerly, a disease associated with crippling disability and premature death, today, persons with haemophilia who are treated appropriately from infancy and do not develop inhibitors can expect a normal life expectancy and relatively few bleeding episodes. The evolution of the comprehensive haemophilia care, while chastened by the viral epidemics of the 1980s, has been marked by ongoing advances, including prophylaxis, immune tolerance induction, new drugs and gene therapy research. Current challenges include sustaining the comprehensive care model despite decreased funding and expanding the delivery and affordability of comprehensive haemophilia care.

The EPIC study: a lesson to learn.

INTRODUCTION: Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not. AIMS: The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg(-1) rAHF-PFM before 1 year of age and immunological danger signals are minimized. METHODS: These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3-4 days before or after FVIII. RESULTS: Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board. CONCLUSION: Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity ≥0.6 BU mL(-1) may not always reflect the presence of FVIII-neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response.

Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate.

Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors.

Another role for the VW molecule.

My comments on the implication of the vW molecule in down-regulating the immunogenicity of factor VIII.

Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies.

BACKGROUND: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess. OBJECTIVES: A meta-analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full-length recombinant FVIII (FL-rFVIII) and B-domain deleted recombinant FVIII (BDD-rFVIII). METHODS: Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression. RESULTS: Twenty-nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63-1.88%. The corresponding rate for high-titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12-24.9; P = 0.0016) and of high-titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17-53.7; P = 0.0037), compared with FL-rFVIII. CONCLUSIONS: This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.

Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment.

At the present time, the most significant complication of hemophilia therapy is the development of neutralizing antibodies (inhibitors) to factor (F) VIII, which adds greatly to the difficulty and expense of preventing and treating bleeding episodes. Both patient-related and therapy-related variables contribute to the development of inhibitors. The multifactorial nature of inhibitor development and the relatively small numbers of patients that participate in clinical trials make it difficult to accurately assess the risk of inhibitor development. Adding to that challenge is the lack of a uniform standard of design for conducting clinical trials to evaluate the safety of FVIII products. This hinders the comparison of products and is an obstacle to the meta-analysis necessary to make statistically valid assessments of inhibitor risk. This article reviews similarities and differences in clinical trial guidelines of European and US regulatory agencies and discusses the need for their harmonization to facilitate the assessment of FVIII products.

Disseminated intravascular coagulation complicating Epstein-Barr virus infection in a cardiac transplant recipient: a case report.

Viral infections are particularly common after cardiac transplantation. Herein we have presented a case of Epstein-Barr infection that presented as a viral syndrome with respiratory symptoms, but was complicated by multiorgan failure and disseminated intravascular coagulation. Transplant physicians should be aware of this unique complication of an otherwise self-limited infection.

Optimizing the treatment of haemophilia B: laboratory and clinical perspectives.

Hemophilia A and B are traditionally thought of as a single bleeding disorder, viewed as opposite sides of the same coin. Yet the differences between the 2 forms of congenital hemophilia extend far beyond the type of deficient clotting factor--factor VIII for hemophilia A and factor IX (FIX) for hemophilia B. This supplement focuses on the unique laboratory and clinical issues associated with FIX replacement therapy for children and adults with hemophilia B.

Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP).

BACKGROUND: Romiplostim is a peptibody protein that raises platelet counts during long-term treatment of patients with chronic immune thrombocytopenia (ITP). Clinical outcomes related to increased platelet counts include a reduced risk of bleeding and a potential risk of thrombosis. OBJECTIVE: To evaluate bleeding and thrombotic events occurring in chronic ITP patients during two phase 3, randomized, placebo-controlled, 24-week studies of romiplostim and during subsequent treatment in an open-label extension study. PATIENTS/METHODS: In the phase 3 trials, 125 patients were randomized to romiplostim or placebo; romiplostim dose was adjusted to maintain platelet counts of 50-200 x 10(9) L(-1). Patients who completed the phase 3 trials could enroll in the extension study in which all patients received romiplostim. RESULTS: In the phase 3 trials, a significantly greater percentage of patients treated with placebo (34%) had bleeding adverse events of moderate or greater severity than did patients treated with romiplostim (15%, P = 0.018). In the extension study, the incidence of bleeding adverse events of moderate or greater severity decreased from 23% of patients in the first 24 weeks to 12% after 24-48 weeks, remaining < or = 6% thereafter. The exposure-adjusted incidence of thrombotic events was 0.1 per 100 patient-weeks in the phase 3 studies, and 0.08 per 100 patient-weeks in the extension study where patients received romiplostim for up to 144 additional weeks. CONCLUSIONS: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.

Factor VIII inhibitor bypassing activity (FEIBA) - addressing safety issues.

Bypassing therapy is usually necessary to control or prevent bleeding episodes in patients with haemophilia A or B and high-titre inhibitors. Factor VIII inhibitor bypassing activity (FEIBA) has a long history of successful use in the acute, surgical and prophylactic treatment settings, but safety concerns have made some reluctant to administer this bypassing agent. A review of the literature and clinical trial data show that FEIBA has a low prevalence of thrombosis, a low prevalence of anamnesis that does not impact haemostatic efficacy and an excellent record of pathogen safety and clinical tolerability.

Surgical interventions in a cohort of patients with haemophilia A and inhibitors: an experiential retrospective chart review.

Strategies for the management of perioperative bleeding in patients with haemophilia and inhibitors have evolved rapidly as a result of the development of the bypassing agents Factor Eight Inhibitor Bypassing Activity, Anti-inhibitor Coagulant Complex (FEIBA) and activated recombinant factor VII (rFVIIa). However, there are currently no established guidelines for perioperative use of bypassing agents, and few controlled clinical studies have been carried out. Thus, case reports, such as those presented here, provide useful anecdotal evidence to guide the treatment of inhibitor patients. The purpose of this report was to describe experiences in the use of bypassing agents in a small cohort of patients with haemophilia A and inhibitors undergoing surgical procedures. Cases from five treatment centres were reviewed. Twenty-two procedures using FEIBA, rFVIIa or a combination of both agents were compiled from seven inhibitor patients (six with an alloantibody inhibitor and one with an acquired autoantibody inhibitor). Eleven procedures used FEIBA monotherapy, two employed rFVIIa monotherapy and nine were performed using combination therapy. Supplemental therapies were required to manage bleeding in some cases. Haemostatic control was achieved in all cases, and treatment regimens were generally well tolerated. One thrombotic adverse event was reported: evidence of disseminated intravascular coagulation (DIC) was found after rFVIIa use in one case, although the direct cause of DIC was unknown. The experiences in this case review demonstrate that both major and minor surgical procedures can be safely performed in patients with haemophilia and high-titre inhibitors under the cover of bypassing agents, with a high expectation of success.

Efficacy and safety of intravenous anti-D immunoglobulin (Rhophylac) in chronic immune thrombocytopenic purpura.

OBJECTIVES: This Phase III study examined the efficacy and safety of Rhophylac (CSL Behring AG, Bern, Switzerland), a highly pure, liquid-stable anti-D preparation, in chronic immune thrombocytopenic purpura (ITP). MATERIALS AND METHODS: Ninety-eight patients (96 adults, two adolescents) with chronic ITP and platelet counts < 30 x 10(9)/l received a single intravenous injection of 50 microg/kg bodyweight Rhophylac. RESULTS: A response (defined as an increase in platelet count by >or= 20 x 10(9)/l to >or= 30 x 10(9)/l in the first 15 days after treatment) was seen in 66% of patients. Mean time to response was 3.1 +/- 3.0 days, and mean duration of response was 19.2 +/- 1.1 days for responders. The most frequent drug-related adverse events were chills, pyrexia, an increase in bilirubin, and headache; events were mainly mild or moderate. there was no severe hemolysis or renal failure. CONCLUSION: rhophylac is well tolerated and efficacious in chronic itp.