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A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study)
Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci PM
Journal of Thrombosis and Haemostasis. 2011;9((4):):700-10.
Abstract
Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. Objective:This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Methods: Forty-five children with severe hemophilia A, aged 1-7years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25IUkg-1 3x week) or episodic therapy with >=25IUkg-1 every 12-24h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results:Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P<0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P< 0.05). Prophylaxis was more effective when started early (<=36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion:This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. 2011 International Society on Thrombosis and Haemostasis.
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2.
Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review
Iorio A, Halimeh S, Holzhauer S, Goldenberg N, Marchesini E, Marcucci M, Young G, Bidlingmaier C, Brandao LR, Ettingshausen CE, et al
Journal of Thrombosis and Haemostasis. 2010;8((6):):1256-65.
Abstract
Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way anova study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII. 2010 International Society on Thrombosis and Haemostasis.
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A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study
Astermark J, Donfield SM, DiMichele DM, Gringeri A, Gilbert SA, Waters J, Berntorp E, FENOC Study Group
Blood. 2007;109((2):):546-51.
Abstract
The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11. 4%-15. 7%), P=. 059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www. clinicaltrials. gov as #NCT00166309.
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Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors
Gringeri A, Mannucci PM, Italian Association of Haemophilia Centres
Haemophilia. 2005;11((6):):611-9.
Abstract
The Italian Association of Haemophilia Centres reviewed and finally approved in November 2004 the new Italian Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors. The recommendations have been based on the identification of levels of clinical evidence derived from the systematic review carried out in 2003 by the School of Health and Related Research, the University of Sheffield, UK, and further integrated by clinical studies published from 2003 to 2004. The Italian guidelines consist of six major domains concerning inhibitor definition, epidemiology, risk factors, diagnosis, inhibitor eradication, management of bleeding episodes, in patients with congenital and acquired coagulation disorders, with 121 statements, 59 synthesis and 54 recommendations. We report here recommendations and open issues concerning the diagnosis and monitoring of inhibitors, inhibitor eradication and the management of bleeding in patients with haemophilia A and B.
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Immune status of asymptomatic HIV-infected hemophiliacs: randomized, prospective, two-year comparison of treatment with a high-purity or an intermediate-purity factor VIII concentrate
Mannucci PM, Gringeri A, de Biasi R, Baudo F, Morfini M, Ciavarella N
Thrombosis & Haemostasis. 1992;67((3):):310-3.
Abstract
It has been postulated that high-purity factor VIII (FVIII) concentrates, since they contain less alloantigenic proteins than intermediate-purity concentrates, might cause lesser deterioration of the immune systems of hemophilic patients infected with the human immunodeficiency virus (HIV). To evaluate this hypothesis, we have prospectively compared T-lymphocytes subsets and delayed hypersensitivity reactions to skin tests in 17 asymptomatic HIV-positive hemophiliacs randomly assigned to continue treatment with an intermediate-purity concentrate with those of 16 hemophiliacs changed to a high-purity concentrate. For both groups, during the 24-month follow-up period CD4 cell counts showed similar rates of fall from baseline values. There was also no difference in the number of patients anergic to skin tests. Three patients treated with the intermediate purity concentrate and one treated with the high-purity concentrate developed symptoms of HIV infection. On the whole, no striking benefit is conferred to the immune status of asymptomatic HIV-positive hemophiliacs by using this high-purity concentrate for 2 years.
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6.
Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate
Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Bottasso B, Simoni L, Rosenberg RD
Blood. 1990;76((12):):2540-5.
Abstract
Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15-42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.