2003; baxter - Supplements - Haematologica

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[Molecular Genetics]review paperGenetics of inhibitordevelopment in hemophilia Bhaematologica 2003; 88(suppl. n. 12):4-7http://www.haematologica.org/free/immunotolerance2001.pdfROLF C.R. LJUNGDepartments of Pediatrics and Coagulation Disorders, LundUniversity, University Hospital, Malmö, SwedenThe prevalence of inhibitors to FIX in hemophilia Bpatients varies from 1.5% to 23% in the literature,although in most series around 4% of the severecases. The vast majority of inhibitors are of the highrespondingtype and of the IgG4 subclass type. Thenature of the mutation in the FIX gene is an importantfactor in determining whether or not a patientwith hemophilia B will develop an inhibitor. Differencesin the frequency of inhibitors between populationscan be due to differences in the spectrum ofmutations. Up to 30% of patients with with grossdeletions, nonsense and frameshift/stop codonmutations develop inhibitors in contrast to virtuallynone of those with missense mutations. Genetic factorsother than the type of mutation are of importancefor inhibitors as suggested by the concordancebetween brothers with hemophilia.©2003, Ferrata Storti FoundationKey words: hemophilia B, inhibitors, factor IX,epidemiology.Correspondence: Rolf Ljung, Pediatric Clinic, University Hospital,SE-205 02 Malmö, Sweden. Phone: international+46.40.331639 Fax: international +46.40.336226.E-mail: rolf.ljung@pediatrik.mas.lu.seThe prevalence of inhibitors to FIX in hemophiliaB patients varies from 1,5% to 23% inthe literature, 1-5 but most studies show a frequencyof approximately 4% for patients withsevere hemophilia B. This is considerably lowerthan the corresponding figures for hemophilia A.The reason for this is not known. One couldspeculate that factors of importance could be thesize of the gene/protein, the concentration ofthe protein in plasma, the distribution in thebody of the protein etc. Table 1 shows the differencesand similarities in inhibitor developmentbetween hemophilia A and B. Inhibitors inhemophilia B affect all ethnic and racial groups,the type of mutation is known to be of importance,modulators of immune response may be ofimportance and certainly genetic factors otherthan type of mutation and immune response areof importance.The factor IX geneThe FIX gene is located in the distal part of thelong arm of the X-chromosome (Xq27.1).Yoshitake and coworkers have elucidated theentire nucleotide sequence, which is 33.5 kblong, has 8 exons (a-h) and manifests stronghomology with other vitamin K-dependent coagulationfactors. 6 The factor IX protein is a serineprotease synthesized in the liver via a vitamin K-dependent process and occurs in plasma as a singleglycoprotein of 415 amino acids and a molecularweight of 57,000 Daltons. 7 The normalFIX plasma concentration is 5 mg/mL which isconsiderably higher than the normal FVIII plasmaconcentration of 0.1 mg/mL.Hemophilia B is caused by a wide variation ofmutations distributed over the entire FIX gene.Since 1990, an annually updated database hasbeen published of characterised point mutations,small deletions and insertions. 8,9 In the 2001update of the database, a total of 2,421 mutationsare listed, of which approximately a thirdare unique molecular events while the remainderare repeats. 9The factor IX inhibitorInhibitors to FIX in hemophilia B may be of thehigh responding type or low responding type. Ahigh responder manifests a marked increase ininhibitor titer 4-10 days after exposure to FIX,that normally takes 6-12 months to return to itsoriginal level. During this period it is not possi-haematologica vol. 88(supplement n. 12):september 2003
IV International Workshop on Immune Tolerance in Hemophilia 5Table 1. Differences between inhibitors in Hemophilia A andB.Hemophilia AHemophilia Bhigher prevalence (15-52%) lower prevalence (1.5-23%)high and low respondersmainly high responderstype of mutation predisposing factor type of mutation predisposing factorbut less than in hemophilia B more than in hemophilia Ano anaphylactoid reactionsgood response to ITIno nephrotic syndrome during ITIanaphylactoid reactionspoor response to ITInephrotic syndrome during ITIble to saturate the inhibitor by increasing dosesof FIX. A low responding patient manifests onlya slight increase in inhibitor titer after exposureto FIX and it is possible to neutralise the inhibitorby giving higher doses of FIX. By definition thepeak titer is 10 BU for a high responder(some authors use 10 BU). Some patients mayhave very strongly neutralising inhibitors with>1000 BU. Most inhibitors in hemophilia B areof the high responding type, 82% in the survey bySultan, 1 58% in the survey in North America byKatz 5 and all patients in a survey in Japan. 10The inhibitors (allo-antibodies) to Factor IX areof the IgG type and mainly of the subclass IgG4.In the series of Sawamoto (n=10) all sampleswere positive for IgG4, however, three were alsopositive for IgG2 antibodies. 11 In an early work,Örstavik and Miller also found all inhibitors tobe of the IgG4 subclass, although some patientshad a heterogenous nature of the inhibitorsincluding also IgG1 and IgG2 subclasses. 12 TheIgG4 subclass is specific since it does not bindcomplement.The epitopes of the inhibitor have been mappedin a few cases in a few studies and were found tobe amino acid 168 to amino acid 182. 13 It hasalso been shown that synthetic peptides includingthis epitope and sorrounding regions arecapable of neutralising some FIX inhibitors. 13Non-neutralising inhibitors to FIX has also beendiscussed. 14FIX inhibitors and geneticsBefore the genes for FVIII and IX were characterised,it was suggested by several studies thatthere may exist a genetic predisposition forinhibitor development. 15 It was the fact thatinhibitors developed mainly in severe hemophiliaA and B and the observed concordancebetween brother pairs that led to this conclusion.In 1983 Giannelli and coworkers found thatthree out of four hemophilia B patients withinhibitors had gross deletions of the FIX gene. 16In subsequent larger studies it has been clearlyshown that the nature of the mutation in the FIXgene is an important factor in determiningwhether a patient with hemophilia B will developan inhibitor. 17-18 In a recent overview of theInternational database of hemophilia B mutationsby Peter Green, UK at the ISTH congress2001, 39 patients with inhibitors were reportedworldwide in whom the type of mutation wascharacterised. All but 2 had mutations abolishingprotein synthesis. There were only two reportedmissense mutations, Q191K and S365G, inHemophilia B patients with inhibitors. It is reasonableto assume that exogenous FIX are moreimmunogenic if the patient is totally devoid ofthe protein: i.e. carrying a deletion, nonsense,frameshift/stop codon mutation. Most patientswith missense mutations have a circulating, butin many cases, functionally less active protein.There were 76 reported patients with large deletions(Aug. 2001) of whom 20 (26%) had developedinhibitors. However, one has to take intoconsideration that the material in the Internationaldatabase may be biassed since some centersreport all cases and many centers do notreport at all.Table 2 shows details of the patients reportedwho had point mutations and developedinhibitors. As can be seen there is a cluster ofinhibitors for the mutation C 6460 T,Arg29→stop although this a frequent mutationper se. Furthermore, 4 of the other point mutationsare in the same part of the gene, i.e. nc.6383-6402.The International database is not representativefor a certain population and may be biassed dueto the mode of inclusion of patients (random ona volontary basis from different centers/countries).The most representative population basedfigures on record are from UK and Sweden.In UK the mutation has been characterised in421 families which represent 75% of the totalnumber of families (P Green, personal communicationat the ISTH Congress 2001). Only 8patients developed inhibitor of whom 3 had totaldeletions, 1 partial deletion, 2 frame-shift stopcodon and 2 Arg 29→stop. Thus the frequency ofinhibitors in hemophilia B in UK is very low.In Sweden the mutations have been characterisedin all 77 families with hemophilia B. 19 Tenof the mutations recurred in 1-6 other families.Haplotype analysis by study of polymorphismsrevealed that at least 65 families had uniquemutation, i.e. almost all families had their ownunique mutation. In this population based study,11/48 (23%) patients with severe hemophilia Bdeveloped inhibitors, and all of them had deletionsor nonsense mutations. If one looked at thepatients with severe hemophilia B due to deletion/nonsensemutation, 11/37 (30%) developedinhibitors, as compared to 0/11 of thepatients 19 with missense mutations. One mayhaematologica vol. 88(supplement n. 12):september 2003
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Index of authorsAhmad, R.U., 56Albe
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