Effect of factor VIII concentrate on leucocyte cytokine receptor expression <i>in vitro</i>: relevance to inhibitor formation and tolerance induction

Hodge, Greg; Saxon, Ben; Révész, Tom

doi:10.1111/j.1365-2516.2006.01200.x

Cited by 14 publications

(7 citation statements)

References 18 publications

(29 reference statements)

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“…An accumulating pool of evidence from clinical observations suggests that VWF‐containing pdFVIII replacement products are associated with a lower incidence of inhibitor development especially when compared with currently commercialized rFVIII products manufactured from hamster cell lines [10,13,22–24]. In a systematic review of the literature, Wight and Paisley reported that the cumulative risk in PUPs treated with a single pdFVIII ranged from 0 to 12.4%, compared with 36–39% in PUPs treated with a single rFVIII; however, the authors noted that disparate testing schedules may account for some of the differences [25].…”

Section: Discussionmentioning

confidence: 99%

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study

et al. 2010

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For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate(®) is a plasma-derived, human, von Willebrand factor-stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate(®) in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate(®) dose change. All inhibitors developed under on-demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate(®). Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22-inversions or large deletions. Octanate(®) was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate(®) in prophylaxis and treatment of bleeding were generally rated as 'excellent', and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (± 0.6) % IU(-1) kg(-1) . These interim results indicate Octanate(®) to be an efficacious, well-tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.

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Section: Discussionmentioning

confidence: 99%

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study

et al. 2010

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“…However, comparing the results of those studies is problematic, as the study populations as well as study designs are heterogeneous. There are in vitro data concerning the immunomodulatory effects of pdFVIII [28–30], as well as the high concentration of FVIII:Ag and the reduced ability to bind exogenous VWF in recombinant FVIII products [25], differences that may influence inhibitor development. As the existing studies investigating inhibitor development cannot answer this question as to whether recombinant and pdFVIII products present differing risks for inhibitor development, there is a need for further investigations (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Hodge et al showed that production of the T‐cell cytokines IL‐2, IL‐4, IL‐5 and TNF‐ α was reduced. IFN‐ γ and the monocyte cytokines TNF‐ α , IL‐1 α , IL‐1 β , IL‐6, IL‐8 and IL‐12 were inhibited in the presence of pdFVIII but not rFVIII in vitro [28,29]. In addition, Hodge and Han recently demonstrated a dose‐ and batch‐dependent immunomodulatory effect of an intermediate purity pdFVIII concentrate in an in vitro study: in the presence of pdFVIII, but not rFVIII, the up‐regulation of many cytokine receptors was inhibited on T cells, B cells, and monocytes [30].…”

Section: Hypothetical Considerationsmentioning

confidence: 99%

Recombinant vs. plasma‐derived products, especially those with intact VWF, regarding inhibitor development

Ettingshausen

Kreuz

2006

Haemophilia

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The development of inhibitors in previously untreated patients (PUPs) with haemophilia A is correlated with a variety of endogenous and exogenous risk factors. It is still controversial whether recombinant factor VIII (rFVIII) products pose a higher risk for inhibitor development than plasma-derived (pd) FVIII concentrates, particularly with intact von Willebrand factor (VWF). A systematic review on the epidemiology of inhibitors in haemophilia A investigated the influence of different FVIII products on inhibitor formation. Patients treated with a single pd product had a lower cumulative incidence (0-12.4%) than those treated with a single recombinant concentrate (36.0-38.7%) independent of disease severity, study size, or inhibitor testing frequency. However, this analysis does not take into account the heterogeneity of the study populations. A study investigating the effects of different variables on inhibitor development in PUPs was started 13 years ago by the Paediatric Committee of the German, Austrian and Swiss Society on Thrombosis and Haemostasis Research. This prospectively conducted study revealed a slight difference (P = 0.08) in terms of type of concentrate. In the group of severe haemophiliacs treated with pdFVIII concentrate (n = 57), 12 patients developed an inhibitor (21%), whereas 17 of 47 patients receiving rFVIII (36%) were affected by this complication. This observation was substantiated by retrospective Italian and French analyses. These results, as well as hypothetical considerations, indicate that there is a body of evidence that FVIII products with VWF may be less immunogenic in PUPs. However, in order to provide more evidence a well-designed randomized study is needed.

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“…Our results confirm and extend these observations at the peptide level, particularly regarding our observation of a change in the Ab specificity profile during the patient’s treatment (samples S2A and S2B). This production of inhibitors with different specificity could be caused by changes in treatment and usage of different factor concentrates (Orsini et al , 2005; Hodge et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

Reactivity profile of anti‐factor VIII antibodies with designed synthetic peptides mimicking epitopes of the C2 and a1 domains

Chaves¹,

Velloso-Rodrigues²,

Moreau³

et al. 2008

Br J Haematol

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Summary Antibodies (Abs) that block factor VIII (FVIII) activity occur in hemophilia A patients treated with FVIII replacement therapy and severely impair treatment. In this work, we designed and synthesized ten peptides whose sequences are found in putative epitopes at the surface of a1 and C2 domains of the FVIII molecule. These peptides were screened for their ability to inhibit the binding of anti‐FVIII Abs from plasmas of hemophilia A patients to FVIII. All peptides were efficient in inhibiting anti‐FVIII Abs in plasma from patients with inhibitors, with however different efficiencies. It was found that each tested patient’s plasma had a different profile of reactivity with peptides, consistent with an individual anti‐FVIII Ab specificity. The profile of recognized peptides was also changing during the treatment of the patients. Three peptides were used in an affinity chromatography assay to attempt to remove anti‐FVIII Abs from patients’ plasma. Anti‐FVIII IgGs were significantly captured by the peptide‐Sepharose affinity matrixes as assessed by enzyme‐linked immunosorbent assay. However, due to the low level of Abs in the plasma samples, other methods (Chromogenic and Bethesda assays) were not sensitive enough to properly detect the reduction of inhibitors.

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Effect of factor VIII concentrate on leucocyte cytokine receptor expression in vitro: relevance to inhibitor formation and tolerance induction

Cited by 14 publications

References 18 publications

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study

Recombinant vs. plasma‐derived products, especially those with intact VWF, regarding inhibitor development

Reactivity profile of anti‐factor VIII antibodies with designed synthetic peptides mimicking epitopes of the C2 and a1 domains

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