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.     

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.     

Low-dose immune tolerance induction in hemophilia A patients with inhibitors

In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.     

The management of hemophilia in elderly patients

After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder.     

Immune tolerance induction for patients with severe hemophilia A: a critical literature review

The development of inhibitors that neutralize the function of clotting factor VIII (FVIII) is currently the most challenging complication associated with the treatment of hemophilia A as it increases the disease-related morbidity and mortality. Immune tolerance induction (ITI) is the only documented strategy to eradicate persistent inhibitors in severe hemophilia A patients. Several studies have been conducted so far to identify patient- and treatment-related factors associated with greater ITI success. The currently available literature on ITI in hemophilia A will be critically reviewed in this article. In particular, we will focus on the role of the type of FVIII product on ITI outcome by analyzing the clinical and experimental data.     

The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with hemophilia

Introduction and objectivesHepatitis C virus (HCV) infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. Although recent progress in direct-acting-antivirals has facilitated a high rate of sustained virological response (SVR), the clinical influence of HCV eradication in hemophilia patients remains unclear. This study aimed to compare the clinical outcomes of SVR against HCV in patients with and without hemophilia.Patients and methodsThe study enrolled 699 patients who achieved SVR after HCV antiviral treatment. Patients were divided into two groups: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). We evaluated patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR.ResultsCompared with the NH group, patients in the H-group were significantly younger and had a lower hepatic fibrosis score. No difference was found in the incidence of liver-related disease or overall death between the two groups over a mean follow-up period of 7 years.Four patients in the H group and 36 patients in the NH group were diagnosed with HCC after SVR. Multivariate analysis showed that male sex, age, and cirrhosis were significant risk factors for HCC incidence. There was no significant difference in the cumulative incidence of HCC after propensity-score matching adjusting for the risk factors of HCC between the two groups.ConclusionHemophilia is not a significant risk factor for hepatocarcinogenesis after SVR against HCV.     

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.     

Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction

In patients with hemophilia, the development of high-responding inhibitors to factor VIII prevents adequate replacement therapy and results in increased risk of serious bleeding episodes, poor control of joint bleeding, and progressive, debilitating joint disease. Immune tolerance therapy can eradicate inhibitors, but it is not uniformly successful. Emerging data suggest that prophylaxis using activated prothrombin complex concentrates may be effective and safe in reducing the incidence of joint bleeding during immune tolerance therapy and for patients in whom immune tolerance induction fails. However, only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors.     

Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates

Recent data published on the prevalence of inhibitors to factor VIII in hemophiliacs on treatment show great variations, with prevalence rates ranging from 3.6 to 14.2%. We have studied the cumulative risk of inhibitor development in a cohort of 62 patients with hemophilia A. All patients were born after 1960, were natives of the Vienna area, had a factor VIII activity of less than 5%, and were treated at least once. Using the method of Cutler and Ederer, the cumulative risk of inhibitor development was found to be 24% at the age of 25 years. Most inhibitors developed between the ages of 3 and 7 years. The current prevalence of F VIII inhibitors in the group of patients studied is 17.5%. It is concluded that prevalence data underestimate the true risk of inhibitor development.     

系统性红斑狼疮合并获得性血友病A一例并文献复习

目的总结系统性红斑狼疮(SLE)合并获得性血友病A的临床表现及治疗,以提高对SLE合并获得性血友病A的认识。方法对1例SLE合并获得性血友病A的临床、实验室资料及治疗进行分析,并进行文献复习。结果患者为25岁女性患者,SLE病史5年,此次以腹痛为主诉,实验室检查活化部分凝血活酶时间(APTT,135．3s)明显延长,因子Ⅷ促凝活性(FⅧ：C,0．9%)减低,因子Ⅷ抑制物滴度26．1U/ml(Bethesda法),B超及核磁共振均发现子宫后血肿,治疗上给予激素、因子Ⅷ制品、大剂量丙种球蛋白等,临床症状及实验室指标明显好转,出院后给予激素及环磷酰胺治疗,随访10个月患者一般情况可。结论SLE合并血友病A在临床上应引起高度的重视,在治疗上目前尚无标准方案。     

Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: A report from the multi-center hemophilia cohort study

To evaluate the effects of human immunodeficiency virus type 1 (HIV-1) infection on the loss of factor VIII alloantibodies, we identified 77 patients with a history of inhibitors from among a large cohort of HIV-1-infected participants enrolled in a natural history study of HIV-1 infection in hemophilia. Fifty-six patients were high responders with inhibitors titers greater than 5 Bethesda Units (BU) measured on at least one occasion. From May 1985 to December 1989, 13 of the high-responder patients were rechallenged with factor VIII concentrates after several years of treatment with other plasma products. All exhibited excellent hemostasis upon reinstitution of factor VIII. Seven of the 13 patients (11.3–46.3 years of age) were in the advanced stages of HIV-1 infection at the time of rechallenge. Inhibitor titers measured subsequent to the reinstitution of factor VIII were consistently less than 1 BU in five of these seven patients. The remaining six patients (6.1–57.5 years of age) had mild to moderate CD4+ lymphocyte depletion (absolute CD4+ cells: 262–935/ mm³) at the time of factor VIII rechallenge. Follow-up inhibitor titers were negative 7–42 months after consistent factor VIII use in these six patients. The lack of anamnestic response to factor VIII in all 13 patients who were rechallenged indicates that HIV-1-infected patients who have a history of high-responder inhibitors frequently benefit from the reintroduction of factor VIII use for the control of bleeding, regardless of their stage of HIV-1 disease. © 1993 Wiley-Liss, Inc.     

Kinetics of factor VIII:C inhibitors and treatment response in severe hemophilia A patients

Severe hemophilia A (HA) patients develop inhibitory alloantibodies to factor VIII:C and therefore require bypass agents that are scarce, expensive and may provoke secondary effects. Twenty-three severe HA patients who were high-responders to FVIII inhibitors were studied. FVIII:C activity in plasma was measured by one-stage activated partial thromboplastin time method, and the quantification of FVIII:C inhibitors was carried out by the Nijmegen-Bethesda method. Inhibition kinetics was assessed through serial plasma dilutions. FVIII:C activity was <1% in all patients. Kinetics behavior of the inhibitors was classified as type I in 14 patients, type II in four and an intermediate pattern that we named type III in one case. We were unable to apply the regression model to the remaining four of 23 patients in the study because of their low inhibitory titer (<3 Nijmegen-Bethesda units per ml). Seventy-eight percent of the patients with inhibitor type I did not respond to high doses of FVIII therapy, whereas 50% of patients with type II kinetics did (P = 0.5323). Generally, patients belonging to the same family had similar kinetics behavior as well as concordant treatment response. Although nonsignificant, our results suggest an association between kinetics behavior and treatment response that may be a valuable prognostic parameter for the management of these patients.     

Clinical experience with human plasma-derived factor VIIa in patients with hemophilia A and high titer inhibitors

FVIIa purified from human plasma and spontaneously activated during the purification procedure was given to 4 patients with hemophilia A and inhibitors against FVIII:C in association with joint bleeds. A dose of 9-20 micrograms/kg b.w. (700-1,000 U/kg b.w.) seemed to be hemostatically active in moderate to severe joint bleeds. Plasma levels of FVII of 5-7 U/ml were achieved and recoveries varied between 17 and 66%. The lower recovery rates of 17-39% were all found in 1 of the patients. No immediate side effects were seen. Neither were any signs of a systemic activation of the coagulation system observed. It is concluded that highly purified FVIIa may be useful in the treatment of hemophilia A patients with inhibitors against FVIII:C.     

The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors

BACKGROUND AND OBJECTIVES. The modulation of disease severity in hemophilia A (HA) patients may be related to the co-inheritance of mutations in genes with a known thrombotic effect such as factor V Leiden (FVL) and prothrombin. In the Spanish population, the prothrombin 20210A (PT20210A) allele is the most prevalent genetic risk factor for venous thromboembolism. DESIGN AND METHODS. We investigated the presence of both mutations in a cohort of 265 hemophiliac patients divided into two groups: I) 140 unrelated patients with moderate and mild HA and II) 125 unrelated patients with severe HA (83 carrying an inversion of intron 22). RESULTS. In group I, 4 patients had the FVL (2.8% vs. 2.98% controls) and 5 had the PT20210A (3.6% vs. 6.46% controls). In group II, two patients with inversion had the FVL (1.6%) and PT20210A was found in 10 patients (8%), five of them with inversion of intron 22 without inhibitors. One of these patients had the FVL and PT20210A mutations concomitantly. In the subgroup of patients with inversion who were carriers of the PT20210A, three parameters i.e. spontaneous bleeding (p=0.008), factor VIII utilization (p=0.016) and number of hemophilic arthropathies (p<0.0005) were significantly lower than in a subgroup of 11 age-matched non-PT20210A severe HA patients with inversion and without inhibitors. INTERPRETATION AND CONCLUSIONS. These results indicate that the inheritance of PT20210A could be a protective factor that mitigates the clinical severity of HA.     

Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper

The development of inhibitory antibodies to factor VIII (FVIII) occurs in approximately 30% to 40% of patients with severe hemophilia A. Management options for patients with inhibitor include eradicating it via immune tolerance induction (ITI) or treating bleeding episodes with large quantities of hemostatic agents. ITI is costly, approaching $1 million for the average 5-year-old, but if successful results in improved clinical outcomes. We constructed a decision analysis using the Markov process to model expected clinical outcomes and costs over a lifetime for a typical 5-year-old hemophiliac with high inhibitor levels. Estimates of relevant variables were based on a thorough review of the medical literature. Outcomes modeled included total lifetime costs as well as life expectancy. The decision analytic model revealed that the ITI strategy was associated with an increase in projected life expectancy of 4.6 years. Total estimated lifetime costs for the ITI strategy were approximately $1.7 million less per patient. Sensitivity analyses over clinically and economically reasonable ranges did not change these findings. The insight that ITI can achieve an improved clinical outcome while being cost-saving is not reflected in many current treatment regimens. This example also illustrates that expensive therapy for patients with a chronic disease may be cost effective when analyzed from a societal perspective over the patient's lifetime. This finding has important policy implications for medical decision makers at many levels and reinforces the need to undertake pharmacoeconomic analyses and choose therapies from a long-term, societal perspective. (Blood. 2000;96:1698-1702)     

Immune tolerance induction with recombinant factor VIII in hemophilia A patients with high responding inhibitors

Immune tolerance induction (ITI) eradicates inhibitors in patients with hemophilia A. This study was designed to investigate the success rate of ITI in high-responding inhibitor patients with severe hemophilia A using recombinant factor VIII (rFVIII). Twenty-six patients received different ITI regimens until a normal recovery (>66%) and half-life (>6 h) of infused FVIII was achieved. In order to maximize the chance of success, the initiation of ITI was deferred in the majority of patients until the inhibitor declined to <10 BU. Twenty-two patients (85%) had baseline inhibitor levels <10 BU (median 2.3 BU) when ITI began. Within a median of 6 months, immune tolerance was achieved in 19 of 26 patients (73%) including 12/17 (70%) with intron 22 inversion, 5/7 (71%) with other null mutations and two with small deletion/insertions in the F8 gene. In conclusion, recombinant FVIII induces a high rate of immune tolerance even in carriers of null F8 mutations.