Impact of Choice of Treatment for Bleeding Episodes on Inhibitor Outcome in Patients With Mild/Moderate Hemophilia A and Inhibitors

d’Oiron, Roseline; Volot, Fabienne; Reynaud, J.; Peerlinck, Kathelijne; Goudemand, Jenny; Guérois, C.; Rothschild, Chantal; Chambost, Hérvè; Borel‐Derlon, Annie; Roussel-Robert, V.; Marquès-Verdier, Alain; Lienhart, Anne; Berthier, Anne-Marie; Moreau, Philippe; Lambert, Thierry

doi:10.1053/j.seminhematol.2005.11.002

Cited by 20 publications

(18 citation statements)

References 38 publications

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“…However, this pattern did not prevent the three patients with Arg2159Cys in having a complete response to desmopressin and a normal FVIII:C halflife (Table 1). Interestingly, Arg2150His also reduces FVIII intracellular trafficking and/or secretion [27], but, as previously reported [28], these patients had a normalization of FVIII:C after desmopressin, whereas its half-life was slightly shorter. Our patient with Arg2150His and one with Arg2159Cys have been treated on several occasions with desmopressin without mishap to prevent bleeding after tooth extraction and for posttraumatic bleeding (G. Castaman and E. Santagostino, unpublished data).…”

Section: Molecular Determinants Of the Fviii Response To Desmopressinmentioning

confidence: 69%

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Castaman

Mancuso

Giacomelli

et al. 2009

Journal of Thrombosis and Haemostasis

101

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Summary. Background: The relationship of the biologic response to desmopressin with the F8 mutation and physiological characteristics has been poorly investigated in patients with mild hemophilia A. Objectives: We prospectively assessed the molecular and phenotypic determinants of the biologic response to desmopressin in a cohort of 50 patients with mild hemophilia A. Methods: Up to 24 h after desmopressin, blood samples were serially obtained and factor (F)VIII and von Willebrand factor (VWF) measured. The promoter region, all exons and exonintron boundaries of the F8 gene were screened using denaturing high-performance liquid chromatography (DHPLC). Direct sequencing was done when DHPLC screening was normal. Genomic DNA was also sequenced for exons 18-21, 24 and 27 of VWF. Results: Mean basal FVIII:C was 19 ± 9 IU dL )1 (range 6-37) and the median postdesmopressin peak increase was 2.5-fold (range 1.1-7.1). Eleven patients with a cross-reacting material positive (CRM + ) phenotype had similar basal levels and relative increases of FVIII:C to the remaining patients with low FVIII:Ag. Using multivariate regression, FVIII:C half-life was positively related to basal and peak VWF:Ag levels (P = 0.008) and patient age (P = 0.004). Eleven patients had evidence of reduced FVIII survival. While 27 different gene mutations were identified in 41 patients, nine patients had no detectable mutation. These patients had significantly smaller peaks and smaller relative increase of postdesmopressin FVIII:C (median FVIII:C 26 IU dL )1 vs. IU dL )1; P < 0.001; fold 1.8 ± 0.6 vs. 2.9 ± 0.8; P = 0.002). Conclusions: In this cohort of patients with mild hemophilia A, a poor biologic response to desmopressin was frequently associated with the absence of detectable F8 mutations.

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Section: Molecular Determinants Of the Fviii Response To Desmopressinmentioning

confidence: 69%

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Castaman

Mancuso

Giacomelli

et al. 2009

Journal of Thrombosis and Haemostasis

101

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“…No recommendations can be made for ITI, but if treatment is initiated, the data should be reported to national and international registries. A retrospective collection of data is currently being performed in France and Belgium, in an effort to increase knowledge and improve the understanding of mild haemophilia A complicated by an inhibitor [135]. Preliminary results from this group of patients, who have a significantly lower median age than that reported by Hay [133], suggest a higher response rate to ITI [135].…”

Section: Immune Tolerance Induction In Patients With Mild Haemophilia Amentioning

confidence: 99%

International workshop on immune tolerance induction: consensus recommendations¹

et al. 2007

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Summary. Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decisionmaking. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence .

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“…A French/Belgian retrospective review of the epidemiology and management (including ITI) of inhibitors in moderate/mild hemophilia A is in progress. The results of this study should add significantly to the existing literature [73].…”

Section: Immune Tolerance: Special Considerationsmentioning

confidence: 51%

Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach

DiMichele

2007

Journal of Thrombosis and Haemostasis

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To cite this article: DiMichele D. Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach. Summary. Currently, the only proven strategy for achieving antigen-specific tolerance to factor VIII (FVIII) is immune tolerance induction (ITI) therapy. This paper discusses our current knowledge of the host and treatment factors, as well as supportive care initiatives, known or suspected to influence the outcome of ITI in the treatment of inhibitors arising in patients with severe hemophilia A. Among these, questions surrounding the choice of therapeutic product and/or dosing regimen generate the most controversy, given the lack of a definitive evidence-based approach to either. Furthermore, the potential for central venous access device (CVAD) and intercurrent bleeding complications to impact the ultimate success of ITI remains unclear. The ongoing clinical trials designed to further clarify several of these polarizing issues are reviewed. This paper also explores the current and future role of immune modulation in possible salvage, ancillary or primary alternative tolerance induction strategies. The special cases of low titer/ responding inhibitors and inhibitors developing in mild hemophilia A patients are considered. Finally, this paper summarizes the currently recommended approach to ITI and makes the case for a move from empiric therapeutics to a risk-stratified evidencebased approach to FVIII inhibitor eradication.

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Impact of Choice of Treatment for Bleeding Episodes on Inhibitor Outcome in Patients With Mild/Moderate Hemophilia A and Inhibitors

Cited by 20 publications

References 38 publications

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

International workshop on immune tolerance induction: consensus recommendations¹

Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach

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Impact of Choice of Treatment for Bleeding Episodes on Inhibitor Outcome in Patients With Mild/Moderate Hemophilia A and Inhibitors

Cited by 20 publications

References 38 publications

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A

International workshop on immune tolerance induction: consensus recommendations1

Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach

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International workshop on immune tolerance induction: consensus recommendations¹