2003; baxter - Supplements - Haematologica

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76D. LillicrapTable 1. Role of factor IX genotype in anaphylaxis (Thorland,Hemophilia 1999).mutations, whereas all patients with severe missensemutations were inhibitor-free. 14,15 Interestingly,and presently unexplained, is the fact thatthe prevalence of factor IX inhibitors in theSwedish population of patients with severehemophilia B is 23%, an approximately five-foldhigher prevalence than that reported in otherpopulations.Management of factor IX inhibitorsIn the light of the severe adverse reactions experiencedby hemophilia B patients who developallo-antibodies, a good case can be made for earlygenotyping of new cases of severe hemophiliaB. These studies should most effectively proceedwith polymerase chain reaction amplification ofthe eight factor IX exons followed by sequencingof the amplicons. Failure to amplify one or severalexons is highly likely to be indicative of afactor IX deletion mutation. With currentlyavailable information, the risk of factor IXinhibitor development with a factor IX deletionmutation is between 25-50%. With a missensemutation the inhibitor risk is negligible and witha nonsense mutation the risk is probably between5-25%.If a new factor IX deletion or nonsense mutationis detected, two revisions to routine treatmentmerit consideration. Firstly, that the initial15-25 infusions of factor IX be performed in amedically supervised environment with access todrugs for the treatment of an anaphylactic reaction.The second treatment revision that deservesevaluation is either the co-administration ofpulse immunosuppressive therapy during theearly phase of factor IX administration or the useof an alternative hemostatic agent, most probablyrecombinant factor VIIa, to treat bleedingduring the first two to three years of life. If a factorIX inhibitor develops and immune toleranceinduction is attempted, careful monitoring forthe development of proteinuria should be performed.Figure 1. The factor IX geneand adjacent mcf2 proto-oncogenelocus. The extent of thirteen,partial and total factor IXgene deletion mutations isshown with documentation ofaccompanying inhibitor generation(I) or no inhibitor (NI*).haematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia 77Unfortunately, the number of patients whodevelop anti-factor IX inhibitors is so small thatan objective evaluation of any of these therapeuticstrategies will require the collation of informationfrom a multi-center, international study.AcknowledgmentsThe author’s genetic studies of hemophilia B arefunded, in part, by Health Canada. DL is a CareerInvestigator of the Heart and Stroke Foundation ofOntario and a recipient of a Canada Research Chairin Molecular Hemostasis.References1. Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M,Gungor T, et al. Incidence of development of factor VIIIand factor IX inhibitors in haemophiliacs. Lancet1992;339:594-8.2. Colvin BT, Hay CR, Hill FG, Preston FE. The incidenceof factor VIII inhibitors in the United Kingdom, 1990-93. Inhibitor Working Party. United KingdomHaemophilia Centre Directors Organization. BritishJournal of Haematology. 1995;89:908-10.3. Briet E. Factor IX inhibitors in haemophilia B patients:their incidence and prospects for development with highpurity factor IX products. Blood Coagulation and Fibrinolysis.1991;2 Suppl 1:47-50.4. High KA. Factor IX: molecular structure, epitopes, andmutations associated with inhibitor formation. Adv ExpMed Biol 1995;386:79-86.5. Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY,Eaton DH, et al. Characterization of the human factorVIII gene. Nature 1984;312: 326-30.6. Yoshitake S, Schach BG, Foster DC, Davie EW, KurachiW. Nucleotide sequence of the gene for human factorIX (antihaemophilic factor B). Biochemistry 1985;24:3736-50.7. Warrier I, Lusher JM. Development of anaphylacticshock in haemophilia B patients with inhibitors. BloodCoagul Fibrinolysis 1998;9 Suppl 1:S125-S128.8. Warrier I. Antibodies to factor IX. Haematologica 2000;85(suppl. to n. 10):31-34.9. Hay CR, Colvin BT, Ludlam CA, Hill FG, Preston FE.Recommendations for the treatment of factor VIIIinhibitors: from the UK Haemophilia Centre Directors'Organisation Inhibitor Working Party. Blood CoagulFibrinolysis 1996;7:134-8.10. Dharnidharka VR, Takemoto C, Ewenstein BM, RosenS, Harris HW. Membranous glomerulonephritis andnephrosis post factor IX infusions in hemophilia B.Pediatr Nephrol 1998;12:654-7.11. Gill JC. The role of genetics in inhibitor formation.Thromb Haemost 1999;82:500-4.12. Schwaab R, Brackmann HH, Meyer C, Seehafer J,Kirchgesser M, Haack A, et al. Haemophilia A: mutationtype determines risk of inhibitor formation. ThrombHaemost 1995;74:1402-6.13. Thorland EC, Drost JB, Lusher JM, Warrier I, Shapiro A,Koerper MA, et al. Anaphylactic response to factor IXreplacement therapy in haemophilia B patients: completegene deletions confer the highest risk. Haemophilia1999;5:101-5.14. Ljung RC. Gene mutations and inhibitor formation inpatients with hemophilia B. Acta Haematologica 1995;94 Suppl 1:49-52.15. Ljung R, Petrini P, Tengborn L, Sjorin E. Haemophilia Bmutations in Sweden: a population-based study ofmutational heterogeneity. Br J Haematol 2001;113:81-6.haematologica vol. 88(supplement n. 12):september 2003
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