HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg<sup>593</sup> to Cys mutation

Bril, Wendy S.; Maclean, Philip; Kaijen, Paul; Brink, Edward N. van den; Lardy, Neubury M.; Fijnvandraat, Karin; Peters, Marjolein; Voorberg, Jan

doi:10.1111/j.1365-2516.2004.01011.x

Cited by 21 publications

(28 citation statements)

References 19 publications

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“…Inhibitor formation in mild haemophilia appears to be associated with relatively few high‐risk FVIII gene mutations in the A2 or C2 domains of FVIII, such as Arg593Cys, Arg2150His and Trp2229Cys (Hay, 1998; Bril et al , 2004).…”

Section: Haemophilia a And Neutralising Anti‐factor VIII Antibodiesmentioning

confidence: 99%

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

et al. 2006

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SummaryIn its most severe form, haemophilia A is a life-threatening haemorrhagic bleeding disorder that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy with intravenous FVIII products develop neutralising antibodies (FVIII inhibitors) that inhibit the function of substituted FVIII. Long-term application of high or low doses of FVIII has evolved as an effective strategy for eradicating antibodies and inducing long-lasting immune tolerance. Despite clinical experience with the therapy, little is known about the immunological mechanisms that cause the downmodulation of FVIII-specific immune responses or the induction of long-lasting immune tolerance against FVIII. This review summarises current knowledge of the immunological mechanisms that might be involved in the induction of immune tolerance against FVIII in patients with haemophilia A who have FVIII inhibitors. In addition to data from patients with haemophilia A, data from patients who have had organ transplants or have immune-related disorders, such as autoimmune diseases, are considered as well as data from animal models.

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Section: Haemophilia a And Neutralising Anti‐factor VIII Antibodiesmentioning

confidence: 99%

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

et al. 2006

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“…Moreover, the associationbetween HLA class II alleles and the FVIII inhibitorsin Thai hemophilia patients was further investigated inthis study, as recent studies have indicated that inhibitorformation depends upon an adequate T-cell responseby major histocompatibility complex class II moleculesto FVIII resulting from the presentation of FVIII proteinantigen to T-cell receptors [18-21]. It was reported that inmild hemophilia A patients with inhibitor the frequencyof DRB1*01 and DQB1*05 was slightly higher than thecontrols (but not significantly) [25]. A comparison of thefrequency data for DRB1*15/16 in hemophilia A patientswith FVIII inhibitor reported in other studies showed thatDRB1*15 and DRB1*16 were high-risk alleles for inhibitorformation in patients with congenital hemophilia Aand acquired hemophilia A, respectively [8-10].…”

Section: Discussionmentioning

confidence: 99%

Association of HLA class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

Nathalang¹,

Sriwanitchrak²,

Sasanakul³

et al. 2012

Turk J Hematol

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Objective: This study aimed to investigate the association between HLA class II alleles and the occurrence of FVIIIinhibitor in Thai hemophilia A patients.Material and Methods: The distribution of HLA-DRB1 alleles and DQB1 alleles in 57 Thai hemophilia A patientsand 36 blood donors as controls was determined using the PCR sequence-specific primer (PCR-SSP) method, and theassociation between the occurrence of factor VIII (FVIII) inhibitor and the presence of certain HLA class II alleles wasinvestigated.Results: The frequency of HLA-DRB1*15 was higher in the hemophilia A patients with and without FVIII inhibitor,whereas that of DRB1*14, DRB1*07, and DQB1*02 was lower in the hemophilia A patients with FVIII inhibitor, ascompared to controls. Interestingly, only the frequency of DRB1*15 was significantly higher in the patients with inhibitorthan in the controls (P = 0.021). Moreover, the frequency of DRB1*15 in the patients with inhibitor was higher than inthose without inhibitor (P = 0.198).Conclusion: The study’s findings show that the DRB1*15 allele might have contributed to the occurrence of inhibitorin the Thai hemophilia A patients; however, additional research using larger samples and high-resolution DRB1 typingis warranted.

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“…Moreover, some specific mutations seem associated with particular high risk for inhibitor development. An Arg593 to Cys mutation in the A2 domain of FVIII was associated with a cumulative inhibitor incidence of 14% after FVIII replacement over a period of 20 years (7/49 patients from 12 families) [16]. In the HAMSTeRS database, this mutation is associated with an inhibitor in 16.2% (6/37) of reported patients.…”

Section: Genetic Predisposition To Inhibitor Development In Patients mentioning

confidence: 99%

Characteristics of inhibitors in mild/moderate haemophilia A

Peerlinck¹,

Jacquemin²

2006

Haemophilia

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Patients with mild or moderate haemophilia A usually have a mild bleeding disorder requiring only occasional treatment with factor VIII (FVIII) concentrates. The frequency of inhibitor development in such patients has been the subject of several recent surveys, which significantly modified our appreciation of this complication. Studies of the anti-FVIII antibodies provided an explanation for the different bleeding phenotypes observed in mild/moderate haemophilia A patients with inhibitors. Antibodies distinguishing between the patient's mutant FVIII and the normal wild-type FVIII were characterized, in addition to antibodies inhibiting completely or only partially FVIII activity. T lymphocytes recognizing FVIII and likely involved in the development of the immune response to FVIII were successfully identified. The FVIII peptides recognized by those FVIII-specific cells bind to many major histocompatibility complex (MHC) class II molecules, which may provide an explanation for the lack of strong association between MHC haplotypes and inhibitor development. Although these studies have advanced our understanding of the conditions leading to inhibitor development, further work is required to determine whether the mode of FVIII administration significantly influences inhibitor development. Further studies of the genetic factors are also required to fully understand the mechanisms leading to inhibitor development in patients with mild/moderate haemophilia A.

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HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg⁵⁹³ to Cys mutation

Cited by 21 publications

References 19 publications

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

Association of HLA class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

Characteristics of inhibitors in mild/moderate haemophilia A

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HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation

Cited by 21 publications

References 19 publications

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

Association of HLA class II Alleles and the Occurrence of Factor VIII Inhibitor in Thai Patients with Hemophilia A

Characteristics of inhibitors in mild/moderate haemophilia A

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HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg⁵⁹³ to Cys mutation