2003; baxter - Supplements - Haematologica

More documents

Recommendations

Info

[Molecular Genetics]review paperGenetic determinants of inhibitorformation in patients with hemophiliaAhaematologica 2003; 88(suppl. n. 12):2-3http://www.haematologica.org/free/immunotolerance2001.pdfANNE GOODEVEDivision of Genomic Medicine, Royal Hallamshire Hospital,Glossop Road, Sheffield, UKThere are several genetic influences uponinhibitor formation in hemophilia A. Inaddition to HLA type and race these includefactor VIII (FVIII) mutation type and mutationlocation within the FVIII gene.This article will consider two sources of evidencefor the genetic influence on inhibitor formation;the Recombinate PUP mutation study 1and an analysis of the hemophilia A mutationdatabase; HAMSTeRS:(http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/main.dir/main.htm).The first evidence that mutation type determinesrisk of inhibitor formation in hemophiliaA was presented by Schwaab and colleagues in1995. 2 A study of locally recruited patients, plusthose then reported to the international hemophiliaA mutation database showed that largedeletions, FVIII inversions and stop mutationswere each associated with an inhibitor incidenceof around 35%, whilst the incidence in patientshaving missense mutations and short deletionswas only around 5%. The patients included inthe study had been treated with a variety of differentFVIII products on a variety of differenttreatment regimes. Therefore a study was undertakento examine the relationship betweeninhibitor incidence and mutation type in acohort of previously untreated hemophilia Apatients, each having the same severity of hemophiliaA; severe disease, treated with the sameproduct; Recombinate, and each examined forinhibitor development following the same protocol,with the testing being performed at a singlecenter. 1 DNA analysis was performed on 55of the 73 patients enrolled in the study. Eachwas examined for the presence of the FVIII geneinversion mutation using Southern blotting.Where the mutation was absent, patients wereCorrespondence: Dr. Anne Goodeve, Division of Genomic Medicine,Royal Hallamshire Hospital, Glossop Road, Sheffield, S102JF, UK. Phone: international +44.114.2712679. Fax: international+44.114. 2721104. E-mail: a.goodeve@sheffield.ac.ukscreened for mutations elsewhere in their FVIIIgene using conformation sensitive gel electrophoresisfollowed by direct DNA sequencingand mutations were characterized in 51 of the55 patients. As found previously by Schwaab etal., 33% of patients with a FVIII inversion developedan inhibitor and of the other four patientswith a stop codon or large deletion mutation,half developed an inhibitor. The HAMSTeRSdatabase (2001) details 117 patients with stopmutations, and overall 35% of them have developedan inhibitor. The distribution of the stopmutations throughout the FVIII gene identifiedin inhibitor patients is very uneven; only 13% ofpatients with stop mutations in the A1, a1, A2and B domains developed an inhibitor, whilst69% of patients with stop mutations in A3, C1and C2 domains did so.Interestingly, in the Recombinate PUP study,none of the 11 patients with a small deletion orinsertion of one or a few nucleotides developedan inhibitory antibody. Five of these patients hadan insertion or deletion of an A nucleotide intoa run of As. A possible mechanism whereby suchpatients may produce very small quantities ofFVIII mRNA and protein, thus avoiding inhibitorformation, has been presented. 3 These findingswere compared with patient data available onthe HAMSTeRS database. Of patients with aninsertion or deletion of an A nucleotide into arun of As, 3 of 29 (10.3%) had developed aninhibitor, compared with 14 of 64 (21.9%) withinsertions or deletions into other sequences.Development of inhibitors in patients withinsertions or deletions into runs of A nucleotidestherefore appears relatively rare.Virtually all cases of moderate and mild hemophiliaA result from missense mutations and veryfew cases develop inhibitory antibodies. TheHAMSTeRS database details 29/606 patientswith moderate and mild hemophilia A and aninhibitor (4.8%). Again, the distribution of themutations resulting in inhibitors is uneventhroughout the FVIII gene with the majority(72%) of the mutations resulting in inhibitorshaematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia 3residing in the C1 and C2 domains.These observations show that both the mutationtype and its location within the FVIII geneinfluence the propensity of patients to developinhibitory antibodies. The observations ofSchwaab and colleagues 2 were replicated to anextent by the Recombinate PUP study, althoughinhibitor and mutation data from further suchstudies will help to enhance understanding of themutation-inhibitor relationship. The HAMSTeRSdatabase, although the inhibitor informationavailable is incomplete, also provides a usefulsource of information on previous patients’ experience.Newly diagnosed patients with hemophiliaA can now be analysed for their mutationtype and location within the FVIII gene and thisinformation can be used to predict inhibitor risk.In the future, this may enable treatment alterationin an attempt to reduce inhibitor formation.References1. Goodeve AC, Williams I, Bray GL, Peake IR, for theRecombinate® PUP Study Group Relationship betweenfactor VIII mutation type and inhibitor development ina cohort of previously untreated patients treated withrecombinant factor VIII (Recombinate®). ThrombHaemost 2000; 83:844-8.2. Schwaab R, Brackmann HH, Meyer C, Seehafer J,Kirchgesser M, Haack A, Olek K, Tuddenham EGD, OldenburgJ. Haemophilia A: Mutation type determines riskof inhibitor formation. Thromb Haemost 1995; 74:1402-6.3. Young M, Inaba H, Hoyer LW, Higuchi M, Kazazian HH,Antonarakis SE. Partial correction of a severe moleculardefect in hemophilia A, because of errors during expressionof the factor VIII gene. Am J Hum Genetics 1997;60:565-73.haematologica vol. 88(supplement n. 12):september 2003
Page 2 and 3: haematologicahinformation for autho
Page 4 and 5: haematologicahImmunobiology of Tole
Page 8 and 9: [Molecular Genetics]review paperGen
Page 10: 6R.C.R. LjungTable 2. Int database
Page 17 and 18: IV International Workshop on Immune
Page 33 and 34: [Round Table on Immune Tolerance Tr
Page 49 and 50: [Round Table on Immune Tolerance Tr
Page 57 and 58:
IV International Workshop on Immune
Page 59 and 60:
[Immunobiology of Tolerance Inducti
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
[New Aspects in Treatment of Hemoph
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
[Acquired Inhibitors in Non-Hemophi
Page 99 and 100:
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Page 109 and 110:
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
[Gene Therapy]review paperThe host
Page 117 and 118:
Page 119 and 120:
[Gene Therapy]review paperGene ther
Page 121 and 122:
Page 123 and 124:
Page 125 and 126:
Page 127 and 128:
Page 129 and 130:
Page 131 and 132:
Index of authorsAhmad, R.U., 56Albe
show all

2003; baxter - Supplements - Haematologica

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?