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1.
Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis
Peyvandi F, Cannavo A, Garagiola I, Palla R, Mannucci PM, Rosendaal FR
Journal of Thrombosis and Haemostasis : Jth. 2017;16((1):):39-43
Abstract
BACKGROUND The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe haemophilia A. Recently a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a two-fold higher risk of inhibitors development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). OBJECTIVE/METHODS In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. RESULTS The highest rate of inhibitor development occurred in the first 10 EDs with a large contrast between rFVIII and pdFVIII during the first 5 ED: hazard ratio 3.14 (CI95% 1.01-9.74) for all inhibitors and 4.19 (CI95% 1.18-14.8) for high-titre inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6-10 EDs) and lasted shorter. CONCLUSION These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates with the strongest response to recombinant FVIII products. This article is protected by copyright. All rights reserved.
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2.
A randomized trial of factor VIII and neutralizing antibodies in hemophilia A
Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
The New England Journal of Medicine. 2016;374((21)):2054-64.
Abstract
BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).
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3.
Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial
Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann I, Ragni MV, Gill JC, Yee TT, Klamroth R, et al
Blood. 2013;122((5):):648-57.
Abstract
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.
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4.
Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression
Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A
Journal of Thrombosis & Haemostasis. 2013;11((9):):1655-62.
Abstract
BACKGROUND The development of neutralizing alloantibodies (inhibitors) is the most serious complication of factor VIII (FVIII) replacement therapy in patients with hemophilia A. Unlike previously untreated patients, no definite risk factors for inhibitor development are known for previously treated patients (PTPs). The investigation of the development of inhibitors in PTPs is hindered by several methodological limitations in the available literature. We conducted a systematic review to account for these limitations. METHODS We considered the studies reporting on PTPs that were included in the Wight and Paisley meta-analysis and a systematic search of MEDLINE, EMBASE, and The Cochrane Library was conducted to identify studies published after 2003. Studies that investigated the development of inhibitors in hemophilia A PTPs who were treated with any type of FVIII concentrate and that included at least 25 patients with follow-up were included in the analysis. RESULTS Thirty-three independent cohorts of PTPs with 4323 subjects and 43 incident de novo inhibitors were found and analyzed. The pooled incidence rate of inhibitor development for the 25 studies providing data on follow-up was 3 (95% confidence interval 1-4) per 1000 person-years. A significant association was not found between putative risk factors and inhibitor development in PTPs at meta-regression analysis and subgroup analysis, but the model was sensitive enough to the inclusion of the reports on the Belgian-Dutch experience with a highly immunogenic factor VIII. CONCLUSION We confirmed a low overall rate of de novo inhibitors in PTPs, without any significant effect of putative predictors, including the type of factor VIII concentrate. 2013 International Society on Thrombosis and Haemostasis.
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5.
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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6.
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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7.
A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors
Santagostino E, Mancuso ME, Rocino A, Mancuso G, Scaraggi F, Mannucci PM
Journal of Thrombosis and Haemostasis. 2006;4((2):):367-71.
Abstract
AIM: A multicenter randomized open-label crossover prospective trial was designed to compare the efficacy, safety, and cost of standard and high dosages of recombinant factor VIIa (rFVIIa) for home treatment of hemarthroses in hemophiliacs with inhibitors. METHODS Patients were instructed to treat, within 6 h from the onset of bleeding, four consecutive hemarthroses of ankles, knees, or elbows, either with the rFVIIa standard dose of 90 microg kg(-1) (repeated as necessary every 3 h) or with a single high dose of 270 microg kg(-1). Patients who did not achieve a clinical success within 9 h continued rFVIIa treatment with repeated standard doses. Response to treatment was assessed for up to 48 h by patients/caregivers, who reported on a Visual Analogue Scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the responses as effective, partially effective or ineffective. Success was defined a treatment course rated as effective and with a VAS score > or =70 and failure a treatment course rated as ineffective and VAS score < or =30, whereas treatment courses that did not fulfill these criteria were considered partial responses. RESULTS Twenty hemophiliacs with inhibitors were originally enrolled (median age: 27 years), 18 of them treated 32 hemarthroses assigned to the standard-dosage and 36 to the high-dosage regimen, during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dosage regimens were similar: 31% and 25% at 9 h, 53% and 50% at 24 h, 66% and 64% at 48 h, the end point for outcome assessment. The median number of rFVIIa infusions needed to achieve a successful course was significantly greater for the standard-dosage (n = 3) than for the high-dosage regimen (n = 1), and the median amount of rFVIIa ultimately used per successful course was identical (270 microg kg(-1)). CONCLUSION Our results indicate that a high-dosage regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of rFVIIa doses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.
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8.
Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods
Goudemand J, Scharrer I, Berntorp E, Lee CA, Borel-Derlon A, Stieltjes N, Caron C, Scherrmann JM, Bridey F, Tellier Z, et al
Journal of Thrombosis and Haemostasis. 2005;3((10):):2219-27.
Abstract
OBJECTIVE In order to correct the primary von Willebrand factor (VWF) defect and avoid supra-physiologic plasma levels of factor VIII, a pure VWF concentrate almost devoid of FVIII was developed and used in France since 1989. METHODS The pharmacokinetic (PK) profile of the most recent version of this concentrate (Wilfactin; LFB, Les Ulis, France), treated with three virus-inactivation/removal methods (solvent/detergent, 35 nm filtration, dry heat treatment), was investigated in 25 patients. Seventeen patients with various types of clinically severe von Willebrand disease (VWD) were included in a crossover, randomized trial carried out in five European centers and comparing Wilfactin with concentrates containing both FVIII and VWF (FVIII/VWF). Eight type 3 VWD patients were included in another trial carried out in six French centers comparing Wilfactin with its previous version (Facteur Willebrand-LFB; LFB) that adopted one virus-inactivation method only. RESULTS For both the measurements evaluated in this study (VWF antigen, VWF:Ag; and VWF ristocetin co-factor activity, VWF:RCo), Wilfactin had a PK profile similar to that of the FVIII/VWF concentrates and of Facteur Willebrand-LFB. VWF:RCo and VWF:Ag recoveries were 2. 1 +/- 0. 3 and 1. 8 +/- 0. 3 per IU kg(-1), respectively, and the half-lives were 12. 4 +/- 1. 8 and 15. 9 +/- 1. 5 h. The FVIII synthesis rate was 5. 8 +/- 1. 0 IU dL(-1) h(-1), with a half-life of 15. 8 +/- 2. 4 h. CONCLUSION The PK of VWF and FVIII have not been altered by the three virus-inactivation/removal steps during the manufacturing of Wilfactin.
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9.
Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial
Mannucci PM, Tenconi PM, Castaman G, Rodeghiero F
Blood. 1992;79((12):):3130-7.
Abstract
Until recently, cryoprecipitate has been the treatment of choice in patients with severe von Willebrand disease (vWD) because it can transiently correct low plasma levels of factor VIII coagulant activity (FVIIIC) and shorten or normalize the prolonged bleeding time (BT), the two laboratory hallmarks of the disease. However, cryoprecipitate may still transmit blood-borne viruses, whereas the development of virucidal methods have rendered plasma concentrates containing FVIIIC and von Willebrand factor (vWF) safer. To establish their potential usefulness in the treatment of vWD, we compared the effect of four virus-inactivated concentrates on FVIIC and vWF plasma levels and the BT (template method) in 10 patients with severe vWD using a crossover randomized design. The concentrates were an intermediate-purity, pasteurized FVIII-vWF concentrate; an intermediate-purity, dry-heated FVIII-vWF concentrate; a solvent/detergent-treated vWF concentrate, containing little FVIII; and a high-purity solvent/detergent-treated FVIII-vWF concentrate. All concentrates were equally effective in attaining normal and sustained levels of FVIIIC postinfusion, although peak levels were more delayed after the vWF concentrate. The effect of concentrates on the BT, however, was less uniform and satisfactory. The pasteurized FVIII-vWF concentrate transiently corrected, completely or partially, the BT in 8 of 10 patients, the dry-heated and solvent/detergent FVIII/vWF concentrates in five, whereas in no patient did the vWF concentrate correct the BT according to the criteria used in this study. These effects on the BT were not related to the plasma levels of ristocetin cofactor activity-attained postinfusion (100 U/dL or more in the majority of patients) or to the multimeric structure of vWF in concentrates (defective in larger multimers in all cases). In conclusion, even though virus-inactivated concentrates can be used to increase FVIIIC levels in patients with severe vWD, none of the concentrates studied by us consistently normalizes the BT in a sustained fashion.
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10.
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.