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.

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.

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.

The effect of salicylates on the hemostatic properties of platelets in man.

Ingestion of 1.5 g of aspirin, but not of sodium salicylate, produced a significant prolongation of the bleeding time in six normal male subjects when compared with the effects of a placebo. Similar differences in the effect of the two drugs on platelets was also observed. Aspirin ingestion resulted in impaired platelet aggregation by connective tissue and was associated with a decreased release of platelet adenosine diphosphate (ADP); sodium salicylate had no effect on these values. In vitro, incubation of platelet-rich plasma with an optimum aspirin concentration of 0.50 mmole/liter (0.045 mg/ml) inhibited both the adhesion of platelets to connective tissue and the release of ADP as well as the secondary wave of platelet aggregation produced with ADP or epinephrine; sodium salicylate had no effect on these reactions, which were also normal in patients with von Willebrand's disease. The inhibitory effect produced by ingesting a single 1.8 g dose of aspirin was detectable for 4-7 days at which time salicylate was no longer detectable in the blood, which suggested an irreversible effect on the platelet. Aspirin also inhibited the release of platelet adenosine triphosphate (ATP), but had no effect on the platelet surface charge, available platelet ATP or ADP, or the destruction of ADP by plasma ADPase. These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.

Disseminated intravascular coagulation.

Known variously as disseminated intravascular coagulation, defibrination consumption coagulopathy or, more simply, as defibrination, disseminated intravascular coagulation is a serious epiphenomenon that occurs most often as a complicating factor of an underlying disease process. Although frequently triggered by underlying disease such as infection or tumor, if not recognized and treated appropriately, disseminated intravascular coagulation alone may lead to the patient's death as a result of hemorrhage or thrombosis, or both, of vital organs. Frequently, it may only manifest itself as an abnormality of coagulation tests, causing no immediate problem for the patient, and potentially normalizing when the inciting cause is appropriately managed. The central process that marks disseminated intravascular coagulation is the generation of thrombin in the circulating blood by means of the activation of the coagulation mechanism, leading to the conversion of fibrinogen to fibrin, which, in turn, may lead to thrombosis mainly of the microcirculation. Because platelets and coagulation factors are consumed and fibrinolysis is enhanced during the coagulation process, hemorrhage may also ensue. Although disseminated intravascular coagulation is frequently encountered in medical and obstetric patients, the difficulty in diagnosis and controversy regarding optimal therapy are frustrating for both patient and physician. By understanding the pathophysiology of disseminated intravascular coagulation and combining clinical observation and laboratory data, one can arrive at the appropriate diagnosis. Therapy must be individualized, and assessment of the benefit versus risk ratio of intervention must be made. Early recognition of acute and life-threatening disseminated intravascular coagulation can be lifesaving with appropriate supportive measures.

The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience.

The response to a highly purified concentrate of porcine factor VIII was evaluated in 45 bleeding episodes in 38 patients with high responding inhibitor antibodies to factor VIII. A total of 437 infusions were given. The patients came from 25 hemophilia centers in the United States. The majority had a life- or limb-threatening hemorrhage for which other modalities had not been successful. In 32 of 45 episodes, a good to excellent response was obtained. Adverse reactions were minimal, occurring in 17 treatment episodes, and were mostly treated with antihistamines and/or hydrocortisone. No clear predictor of clinical response to porcine factor VIII concentrate was identified, including pretreatment human and porcine inhibitor levels, percentage of cross-reactivity between the human and porcine antibodies, and the presence of measurable levels of factor VIII after the porcine factor concentrate was given. Anamnesis to porcine factor VIII did occur in some instances. Porcine factor VIII is a valuable modality in the treatment of serious hemorrhages in patients with inhibitors to factor VIII. Its use should be considered early in the course of severe hemorrhage in these patients.

Clinical efficacy of recombinant factor VIII. The rFactor VIII Clinical Trial Group.

This investigation has been an ongoing, multistage evaluation of the pharmacokinetics, safety and efficacy of a factor VIII concentrate prepared through recombinant DNA technology. In vivo activity of the rFVIII has been comparable to that of pdFVIII including half life and in vivo recovery. Recombinant factor VIII is safe and effective for prophylaxis and treatment of hemophilic bleeding episodes. Efficacy of rFVIII appears comparable with that of pdFVIII concentrates. Infusions were well tolerated with infrequent adverse reactions. As with any new product, the verdict regarding induction of inhibitors to factor VIII awaits evaluation of sufficient numbers of patients and passage of adequate observation time.

Cost-effectiveness and reimbursement in patient care.

The recent collapse of the previously effective coalition of the federal government, universities and medical schools, the pharmaceutical industry, and third-party payers has resulted in the current crisis in funding of clinical trials. The reduced financial support for clinical research comes at a time when a number of new investigational therapies offer the promise of better medical care for patients with life-threatening diseases. Controversy exists regarding the role of physicians in encouraging federal support for clinical research and third-party reimbursement for patient care for patients on clinical trials. Some believe the physician should take an activist role on the issues in general, while others believe that the physician should focus on protecting the interests of individual patients by acting as the patient's agent. Many difficult choices lie ahead for society as a whole in determining what percentage of its health-care budget will be allocated for clinical research, who will pay for patient-care costs of patients in clinical trials, and how this relatively limited resource should be distributed among the population at large. Case-management programs are one attempt to monitor and control health-care costs, but in many instances case management has been used to determine if patients are enrolled in clinical research trials and to disallow coverage for other than standard patient care.

HIV-1 infection incidence among persons with hemophilia in the United States and western Europe, 1978-1990. Multicenter Hemophilia Cohort Study.

We studied human immunodeficiency virus type 1 (HIV-1) infection incidence over time in a 16-center cohort of hemophiliacs in the United States and Europe and estimated the most likely date of seroconversion for all seropositive subjects. Five U.S. centers enrolled subjects independent of HIV-1 status, whereas 11 centers preferentially included seropositive subjects. We obtained unbiased estimates of HIV-1 infection incidence rates from the five centers and estimated dates of seroconversion from the distribution seen among seropositives from all centers. In the five-center cohort, infection incidence began in 1978, peaked in October 1982 at 22 infections per 100 person-years at risk, and declined to 4 per 100 person-years by July 1984. Few infections occurred after 1987, and by that time, 50% of the cohort had become infected. Median seroconversion dates for subgroups of all seropositives ranged from July 1980 to December 1983, depending on the dose and type of factor concentrate. Median dates in Europe ranged from September 1981 to March 1983 and reflected the use of products manufactured from American plasma. Infection incidence apparently peaked about the same time that public health interventions were introduced to reduce transmission. These interventions, including heat treatment of factor concentrates and deferral of high-risk donors, have prevented HIV-1 infection from becoming endemic among younger birth cohorts of persons with hemophilia.

Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity.

Thrombosis is a rare but well-recognized potential complication of Factor VIII Inhibitor Bypass Activity (FEIBA) infusion. Recombinant factor VIIa (rFVIIa) is increasingly used as an alternative to FEIBA; however, the thrombotic safety profile of rFVIIa remains incompletely characterized. To determine the incidence rates of thrombotic adverse events (AEs) after infusion of rFVIIa and FEIBA. Data from the MedWatch pharmacovigilance program of the US Food and Drug Administration, as supplemented by published case reports, were used in conjunction with estimated numbers of infusions available from manufacturers to assess comparative incidence of thrombotic AEs in patients receiving rFVIIa or FEIBA in the period from April 1999 through June 2002. Reported thrombotic AEs were rare, with incidence rates of 24.6 per 10(5) infusions (CI, 19.1-31.2 per 10(5) infusions) for rFVIIa and 8.24 per 10(5) infusions (CI, 4.71-13.4 per 10(5) infusions) for FEIBA. Thrombotic AEs were significantly more frequent in rFVIIa than FEIBA recipients (incidence rate ratio, 2.98; CI, 1.71-5.52). The most commonly documented single type of thrombotic AE after rFVIIa infusion was cerebrovascular thrombosis, while myocardial infarction was the most frequent type in patients receiving FEIBA. Contrasting AE reporting patterns between rFVIIa and FEIBA may have contributed to the observed difference in thrombotic event incidence. Nevertheless, this comprehensive pharmacovigilance assessment does not support superior thrombotic safety of rFVIIa and suggests that thrombotic AE risk may be higher in rFVIIa than FEIBA recipients.

Leukemia after liver transplant.

INTRODUCTION: Acute leukemia is rare after solid organ transplantation. METHODS: Review of data on 3 patients with acute leukemia identified among 1365 who underwent liver transplantation at our center, and a review of the literature. RESULTS: In patient 1, AML-M4 developed 19 months after transplant for cryptogenic cirrhosis. In patient 2, B cell acute lymphoid leukemia was diagnosed 10 months after liver transplant for fulminant hepatitis. Both patients had normal cytogenetics, and achieved complete remission with chemotherapy. In patient 3, acute monocytic leukemia-M3 with t(15;17) arose 18 months after transplant for hepatitis C cirrhosis. This patient received treatment with retinoic acid and chemotherapy, but developed a disseminated intravascular coagulation and died before completing therapy. No patient presented with chromosomal abnormalities commonly seen in secondary leukemia. The latency period to diagnosis after transplant was 10-19 months. CONCLUSIONS: Acute leukemia, although rare after liver transplantation, should be considered in the differential diagnosis of hematological complications.

Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders.

The status of human immunodeficiency virus type 1 (HIV-1) infection at the time of transmission to sexual contacts remains poorly defined. Transmission to nonsexual household contacts has appeared to be rare. A total of 505 sexual and nonsexual contacts of HIV-1-infected hemophiliacs in 349 households was observed. At entry, 10% of 201 sexual partners were anti-HIV-1-positive. Follow-up of 151 uninfected partners during a total of 351 person-years of observation showed no sero-conversions, although there were 13 pregnancies during that period. Eighty-seven percent of the seronegative respondents to a detailed questionnaire reported unprotected sexual contact at least occasionally. Among 304 other household members, including 108 parents who helped administer clotting factor concentrates to their children, none was seropositive at entry. Follow-up of 263 showed no seroconversions during a total of 605 person-years of observation. Thus, anti-HIV-1-positive hemophiliacs transmitted to their partners earlier in their course but were not found to do so when prospectively observed. No relationship to level of viremia as indicated by CD4 count, HIV-1 p24 antigenemia, or acquired immunodeficiency syndrome was found. Anti-HIV-1-positive hemophiliacs had not transmitted to their nonsexual household contacts before study entry and did not do so subsequently, indicating that the risk from even close nonsexual contact is extremely low.

von Willebrand disease: from the bedside to therapy.

Von Willebrand's disease was recognized by a careful observant clinician. Research advances in blood banking technology and molecular biology, in addition to astute clinical observation, have led to unraveling the factor VIII molecule, classification of a heterogenous disease, and rational therapy.

Prophylactic use of factor VIII: an economic evaluation.

BACKGROUND: Since the introduction of exogenous factor VIII therapy, several studies have explored the clinical benefits of prophylactic use of factor VIII. Little research, though, has focused on the economic aspects of this regimen. We conducted a cost analysis using data from the Orthopedic Outcomes Study, a prospective, cross-national study of the clinical outcomes associated with different patterns of factor VIII utilization to examine the health care costs incurred and expenditures averted in patients receiving on-demand versus prophylactic use of factor VIII in hemophilia. METHODS AND ANALYSIS: 831 patients with severe hemophilia aged 1 to 31 years, from 19 centers around the world were included in the cost analysis. Patients were categorized into three groups according to the number of weeks during the study years in which they received prophylactic regimens of factor VIII. For each subject, we estimated the costs of hospitalization, surgery, days lost from school or work, and factor VIII utilization. Costs were then stratified by age and by joint score to assess confounding, and a multivariate model developed to determine the relationship between use of factor VIII prophylaxis and total costs, while controlling for potential confounders. RESULTS: Patients who received factor VIII episodically incurred substantially greater disability-related costs (days lost from school or work, days hospitalized due to hemophilia, surgery) than patients who received factor VIII prophylactically for some or all of the study period. For all treatment regimens, most disability-related costs were accounted for by hospitalization for hemophilia-related conditions. The cost of factor VIII itself was substantial in all treatment categories but was highest among patients who received year-round prophylaxis, exceeding the savings resulting from reduced disability and other health care expenditures. CONCLUSIONS: Reductions in non-factor health care costs and disability associated with prophylactic use of factor VIII in hemophilia were substantial and helped somewhat to offset the much higher costs of this regimen. For certain subgroups, frequent episodic treatment may be more expensive than full-time prophylaxis. However, because of the very high cost of year-round prophylactic use of factor VIII, total health care expenditures were highest among patients receiving this therapeutic regimen. However, because prophylaxis clearly offers important clinical benefits, this approach may be warranted on medical rather than economic grounds.

Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.

OBJECTIVE: To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven) in the home setting for mild to moderately severe joint, muscle; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. DESIGN: Multicentre, open-label, single arm, phase III study of one year duration. METHODS; Patients or their caregivers administered up to three doses of rFVIIa (90 microg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been "effective" with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. RESULTS: Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as "effective" in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h (mean+/-SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and mucocutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. CONCLUSION: rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.

Congenital bleeding disorders. Rational treatment options.

There are rational, effective choices available for the treatment of common inherited bleeding disorders, according to assessment of safety, efficacy and cost. All currently available products for patients with haemophilia A (factor VIII deficiency) are comparable in terms of efficacy and viral safety. However, high purity products are recommended for those with coexisting human immunodeficiency virus (HIV) infection. Many patients with mild haemophilia A and most with von Willebrand's disease can be treated with desmopressin, which can be given as an intranasal spray in some countries. For the treatment of patients with factor XI deficiency, fresh frozen plasma remains the standard care, although solvent-detergent-treated fresh frozen plasma and factor XI concentrate are currently being investigated as alternatives. In the treatment of haemophilia B (factor IX deficiency), purified factor IX concentrates are particularly useful in clinical settings where large amounts of concentrate are to be used (e.g. surgical prophylaxis). Their usefulness in other contexts needs clarification. Treatment of inhibitors that may develop in response to administered coagulation factors is still limited to the use of prothrombin complex concentrates and porcine factor VIII. Active clinical trials are currently assessing the efficacy and safety of recombinant factor VIIa, Xa and tissue factor in this indication.