Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation

Lusher, Jeanne M.; Abildgaard, Charles F.; Arkin, Steven; Mannucci, Pier Mannuccio; Zimmermann, Rainer; Schwartz, Lawrence A.; Hurst, Deborah

doi:10.1111/j.1538-7933.2004.00646.x

Cited by 71 publications

(70 citation statements)

References 30 publications

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“…These patients may received more amounts of and an earlier exogenous of FVIII, which is helpful for the generation of inhibitor to the FVIII (Sharathkumar et al, 2003;Lusher et al, 2004; Chalm- Gouw et al, 2007). At the same time, FVIII or vWF protein of these patients may exhibit abnormalities in their molecular structure or in the vision of these patients, which would increase the effect of immune recognition of T cells.…”

Section: Inhibitor Formation In Ha Patientsmentioning

confidence: 99%

Higher frequency of CD4+CD25high Treg cells in hemophilia patients with factor VIII inhibitor

Ding¹,

Ji²,

Wu³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The production of factor VIII inhibitor antibodies remains the most costly and serious complication in replacement therapy of hemophilia A. We investigated the clinical significance of CD4 + CD25high T regulatory (Treg) cells in hemophilia patients. Our trial included 6 severe hemophilia A patients with factor VIII inhibitors, 6 hemophilia patients without inhibition of factor VIII, and 6 healthy persons (controls). Plasma factor VIII: c was measured by clotting assay. Peripheral blood samples were examined using mutiparameter flow cytometry with fluorescent-labeled monoclonal antibodies. Plasma levels of IFN-γ, IL-2, IL-10, and TGF-β were measured by ELISA. The frequency of CD4high Treg cells in CD4 + cells was 1.07 ± 0.38% in inhibitor patients and 0.57 ± 0.14% in non-inhibitor patients. The proportion of Treg cells in healthy controls was similar to that of the non-inhibitor patients. However, there were significant differences between the inhibitor and non-inhibitor patients in levels of IFN-γ, IL-2, IL-10, and TGF-β. We conclude that the proportions of Treg cells and the concentrations of T cell cytokines in inhibitor patients are higher than those in non-inhibitor patients. The increased number of Treg cells and increased T-cell cytokines may be related to the development and efficiency of the factor VIII inhibitor.

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Section: Inhibitor Formation In Ha Patientsmentioning

confidence: 99%

Higher frequency of CD4+CD25high Treg cells in hemophilia patients with factor VIII inhibitor

Ding¹,

Ji²,

Wu³

et al. 2014

Genet. Mol. Res.

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“…[18][19][20][21][22][23] These incidences were considerably higher than the previously observed 0% to 12% in patients treated with single plasma-derived products. 1,24 However, methodologic differences between studies rendered comparisons inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Gouw

Bom

Auerswald

et al. 2007

Blood

215

209

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It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasmaderived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A. IntroductionAt present, the main concern in the treatment of children with severe hemophilia A is the development of inhibitory antibodies that neutralize infused factor VIII, occurring in 10% to 30% of patients. 1 Several patient-related factors have been associated with the risk of developing inhibitors, such as factor VIII gene mutation, 2-4 other genetic factors, 5-8 family history of inhibitors, 9-11 and ethnicity. 11,12 In addition to these determinants, a number of treatment-related factors have been suggested to affect the risk of inhibitor development, such as prophylaxis, 13,14 age at first exposure, 15,16 and intensity of treatment. 17 One of the most intensively discussed potential risk factors is the factor VIII product type.Indications for a potential role of the factor VIII product type in inhibitor development arose when prospective registration studies of recombinant factor VIII products among previously untreated hemophilia A patients reported inhibitor incidences between 29% and 32%. [18][19][20][21][22][23] These incidences were considerably higher than the previously observed 0% to 12% in patients treated with single plasma-derived products. 1,24 However, methodologic differences between studies rendered comparisons inconclusive. 25 More convincing were the findings of a recent comparative study in which the inhibitor risk in patients treated with full-length recombinant factor VIII was again higher than the risk in patients treated with a high-purity plasma-derived factor VIII product containing von Willebrand factor (VWF)...

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“…1 In patients with high-titer inhibitors, acute bleeding can be controlled by infusion of bypass clotting factors, including activated prothrombin complex concentrates and recombinant human factor VIIa. Bypass factors are considerably more expensive than standard FVIII concentrates and have a less reliable hemostatic profile, including a thrombogenic potential that limits their use in long-term prophylaxis regimens.…”

Section: Introductionmentioning

confidence: 99%

Suppression of FVIII Inhibitor Formation in Hemophilic Mice by Delivery of Transgene Modified Apoptotic Fibroblasts

Epp

Latchman

et al. 2010

Molecular Therapy

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Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation

Cited by 71 publications

References 30 publications

Higher frequency of CD4+CD25high Treg cells in hemophilia patients with factor VIII inhibitor

Higher frequency of CD4+CD25high Treg cells in hemophilia patients with factor VIII inhibitor

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Suppression of FVIII Inhibitor Formation in Hemophilic Mice by Delivery of Transgene Modified Apoptotic Fibroblasts

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