0
selected
-
1.
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.
-
2.
Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies
Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM
Haemophilia. 2012;18((3):):e173-87.
Abstract
Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment. Copyright 2012 Blackwell Publishing Ltd.
-
3.
Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies
Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM
Haemophilia. 2012;18((3):):e164-72.
Abstract
In the last three decades there have been dramatic improvements in the availability and quality of treatment for people with inherited coagulation disorders. Indeed, the improvement of methods of purification and viral inactivation for plasma-derived coagulation factor concentrates first and then the development of products utilizing recombinant DNA technology have greatly improved the life expectancy of hemophiliacs, which has progressively become similar to that of males in the general population. Nowadays, the most frequent complication of factor replacement therapy for hemophilia is the development of inhibitors. However, no studies so far have systematically analysed the type and incidence of other adverse reactions following the administration of coagulation factor concentrates. The aim of this systematic review was to screen the published literature data to evaluate the types and frequencies of non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates in patients with hemophilia A, hemophilia B and von Willebrand's disease. On behalf the European Haemophilia Safety Surveillance System (EUHASS), a systematic review of the prospective studies published in the last 20 years was performed using electronic databases and article references. Both severe and mild adverse events following infusion of coagulation factor concentrates are relatively rare in patients with inherited coagulation disorders; the most common events are of an allergic type. There are no differences in the rate of adverse events caused by plasma-derived or recombinant products. On the whole, these data confirm the high degree of safety of the products currently used for replacement therapy. Copyright 2012 Blackwell Publishing Ltd.
-
4.
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.
-
5.
A systematic overview of the first pasteurised VWF/FVIII medicinal product, Haemate®P/Humate®-P: history and clinical performance
Berntorp E, Archey W, Auerswald G, Federici AB, Franchini M, Knaub S, Kreuz W, Lethagen S, Mannucci PM, Pollmann H, et al
European Journal of Haematology. Supplementum. 2008;80((Suppl 70):):3-35.
-
6.
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.
-
7.
The effect of desmopressin on reducing blood loss in cardiac surgery: a meta-analysis of double-blind, placebo-controlled trials
Cattaneo M, Harris AS, Stromberg U, Mannucci PM
Thrombosis and Haemostasis. 1995;74((4):):1064-1070.
Abstract
The effect of desmopressin (DDAVP) on reducing postoperative blood loss after cardiac surgery has been studied in several randomized clinical trials with conflicting outcomes. Since most trials had insufficient statistical power to detect true differences in blood loss, we performed a meta-analysis of data from relevant studies. Seventeen randomized, double-blind, placebo-controlled trials were analyzed, which included 1171 patients undergoing cardiac surgery for various indications; 579 of them were treated with desmopressin and 592 with placebo. Efficacy parameters were blood loss volumes and transfusion requirements. Desmopressin significantly reduced postoperative blood loss by 9%, but had no statistically significant effect on transfusion requirements. A subanalysis revealed that desmopressin had no protective effects in trials in which the mean blood loss in placebo-treated patients fell in the lower and middle thirds of distribution of blood losses (687-1108 ml/24 h). In contrast, in trials in which the mean blood loss in placebo-treated patients fell in the upper third of distribution (> 1109 ml/24 h), desmopressin significantly decreased postoperative blood loss by 34%. Insufficient data were available to perform a sub-analysis on transfusion requirements. Therefore, desmopressin significantly reduces blood loss only in cardiac operations which induce excessive blood loss. Further studies are called to validate the results of this meta-analysis and to identify predictors of excessive blood loss after cardiac surgery.