Loss of Tolerance to Exogenous and Endogenous Factor VIII in a Mild Hemophilia A Patient With an Arg593 to Cys Mutation

Thompson, Arthur R.; Murphy, M.E.P.; Liu, Miao‐Liang; Saenko, Evgueni L.; Healey, John F.; Lollar, Pete; Scandella, Dorothea

doi:10.1182/blood.v90.5.1902

Cited by 75 publications

(79 citation statements)

References 38 publications

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“…We found a significant increased risk of inhibitor development with the Arg593Cys mutation causing a change of the arginine residue for cysteine, which is in accordance with several other published cases and case series [15,[22][23][24][25]. Risk of inhibitor development is associated with the type and location of mutation [3,26].…”

Section: Discussionsupporting

confidence: 91%

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Risk of inhibitor development in mild haemophilia A increases with age

et al. 2011

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Mild haemophilia A is a rare disease with a relatively mild phenotype. Treatment with factor VIII (FVIII) is indicated after trauma or for surgery only. FVIII infusion may result in the development of inhibiting antibodies against FVIII. This study describes the relation between age and other risk factors for inhibitor development in mild haemophilia. A retrospective cohort study was conducted among all patients with mild haemophilia (FVIII 0.05-0.40 IU mL(-1)) registered at the van Creveldkliniek, University Medical Centre Utrecht, The Netherlands. Data on peak treatment with FVIII, gene mutation and history of inhibitor development were obtained from patient files from the period between 1st January 1970 and 31st December 2009. A total of 231 out of 297 (78%) patients had at least one exposure to FVIII, of whom 14 (6.1%) developed an inhibitor to FVIII at a median age of 66 years after a median of 50 exposure days (ED). Age at first exposure, age at peak treatment, number of peak treatments and Arg593Cys mutation were significantly associated with the development of an inhibitor, while continuous infusion with FVIII was not. Although the incidence of inhibitors in mild haemophilia is low, it increases with age and peak treatments. With increasing age patients with mild haemophilia will suffer from co-morbidity more frequently, requiring surgical interventions and exposing them to an increased risk of inhibitor development. Especially patients with a change of arginine in cysteine at 593 are at risk for inhibitor development.

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Section: Discussionsupporting

confidence: 91%

“…The exact incidence of inhibitor development in mild haemophilia is unknown, but is reported to be between 3 and 13% [11][12][13]. Inhibitors may cross-react with endogenous FVIII resulting in a decrease of endogenous FVIII to <0.01 IU mL )1 , converting mild into moderate or severe haemophilia [14,15].…”

Section: Introductionmentioning

confidence: 99%

Risk of inhibitor development in mild haemophilia A increases with age

et al. 2011

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“…Analysis of FVIII produced by patients with mild/moderate haemophilia A demonstrated that mutations at residues Arg593, Arg2150, Arg2159 or Ala2201 eliminate FVIII epitopes (antigenic determinants) recognized by monoclonal inhibitor antibodies [22][23][24][25], which confirmed observations made using patientsÕ polyclonal antibodies [9,22,26]. By contrast, other antibodies do not make the distinction between the patient's mutant FVIII and the normal wild-type FVIII [27,28].…”

Section: Genetic Predisposition To Inhibitor Development In Patients mentioning

confidence: 84%

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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“…Following peri-operative factor VIII replacement therapy, a transient rise in a second class of antibodies was observed that cross-reacted with endogenous factor VIII. Cross-reactive antibodies directed towards residues Arg 484 -Ile 508 , a major binding site for factor VIII inhibitors in the A2 domain, have been described in two other unrelated inhibitor patients with the same genetic defect (Thompson et al, 1997;van den Brink et al, 1999). In these patients, antibodies reactive with Arg 593 were not observed.…”

Section: Longitudinal Analysis Of Factor VIII Inhibitors In Patient Amentioning

confidence: 99%

Analysis of factor VIII inhibitors in a haemophilia A patient with an Arg⁵⁹³→Cys mutation using phage display

et al. 2002

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Summary. We characterized anti-factor VIII antibodies in a mild haemophilia A patient with an Arg 593 fiCys mutation in the A2 domain, using V gene phage-display technology. All isolated single-chain variable-domain antibody fragments were directed against residues Arg 484 -Ile 508 , a binding site for factor VIII inhibitors in the A2 domain. After a further period of replacement therapy, a transient rise in inhibitor titre was observed. These antibodies were directed against the A2 domain. Activation of a pre-existing pool of B cells, which express antibodies against residues Arg 484 -Ile 508 , could explain the rapid anamnestic response.Keywords: factor VIII inhibitors, haemophilia A, phage display, B lymphocyte, immunoglobulin repertoire.A serious complication in haemophilia A treatment is the development of antibodies that neutralize factor VIII activity (inhibitors). The prevalence of factor VIII inhibitors in patients with severe haemophilia A is approximately 25% (Mannucci & Tuddenham, 2001). Factor VIII inhibitors are infrequently observed in patients with mild or moderate haemophilia A (Sultan, 1992). The lower risk of inhibitor formation in this group of patients can be explained by the presence of tolerizing amounts of circulating endogenous factor VIII. Inhibitor development in these patients commonly arises after intensive factor VIII replacement therapy and is usually a transient event (Hay et al, 1998). Interestingly, some genetic defects are frequently observed in patients with mild haemophilia A who developed inhibitors. Amino acid substitutions located at the junction between the C1 and C2 domain or located in the A2 domain of factor VIII may predispose towards the development of factor VIII inhibitors (Hay et al, 1998). We have previously reported on the presence of human alloantibodies in a patient with an Arg 593 fiCys mutation (Fijnvandraat et al, 1997). In this patient, the anti-factor VIII antibodies were directed to wild-type A2 domain and not to the A2 domain containing the Arg 593 fiCys mutation when analysed at a late stage of inhibitor formation. These findings indicate that the missense mutation Arg 593 fiCys was related to antibody development.In the present study, phage display technology was used for the characterization of anti-factor VIII antibodies in the patient. Our findings showed that peripheral IgG + B cells can express human antibodies reactive with residues Arg 484 -Ile 508 . These antibodies are distinct from the alloantibodies found in plasma. Following a period of intensive treatment with FVIII concentrate after a surgical intervention, the patient developed a transient low-titre inhibitor that cross-reacted with endogenous factor VIII. We propose that activation of pre-existing factor VIII-specific B cells underlies the rapid appearance of cross-reactive antibodies. MATERIALS AND METHODSExpression, metabolic labelling and immunoprecipitation of A2 domain variants. The wild-type factor VIII A2 domain, the A2 domain containing the Arg 593 fiCys mutation (A2-R593C) and...

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Loss of Tolerance to Exogenous and Endogenous Factor VIII in a Mild Hemophilia A Patient With an Arg593 to Cys Mutation

Cited by 75 publications

References 38 publications

Risk of inhibitor development in mild haemophilia A increases with age

Risk of inhibitor development in mild haemophilia A increases with age

Characteristics of inhibitors in mild/moderate haemophilia A

Analysis of factor VIII inhibitors in a haemophilia A patient with an Arg⁵⁹³→Cys mutation using phage display

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Loss of Tolerance to Exogenous and Endogenous Factor VIII in a Mild Hemophilia A Patient With an Arg593 to Cys Mutation

Cited by 75 publications

References 38 publications

Risk of inhibitor development in mild haemophilia A increases with age

Risk of inhibitor development in mild haemophilia A increases with age

Characteristics of inhibitors in mild/moderate haemophilia A

Analysis of factor VIII inhibitors in a haemophilia A patient with an Arg593→Cys mutation using phage display

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Product

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Analysis of factor VIII inhibitors in a haemophilia A patient with an Arg⁵⁹³→Cys mutation using phage display