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Haematologica 2000; 85(suppl. to n.10) p. 31-34 Epidemiological and Treatment Defects of FVIII and IX Inhibitors Antibodies to factor IX INDIRA WARRIER Professor of Pediatrics, Department of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, USA Antibodies to Factor IX Alloantibodies (inhibitors) against factor IX (FIX) develop in 1-3% of patients with hemophilia B and the incidence is higher in severe hemophilia B. 1-3 Alloimunization occurs only after exposure to FIX containing products. Factor IX antibodies usually occur in severe hemophilia B patients with total absence of FIX antigen, either due to total gene deletion or other major derangements of the FIX gene. The risk of inhibitor development is reported to be 50% for those hemophilia B patients with total gene deletions. 3 Frame shift mutations and stop codon abnormalities are associated with a 20% risk while missense mutations are not associated with any increased risk of inhibitor formation. 4 Similar to the FVIII inhibitors in hemophilia A, FIX antibodies in hemophilia B patients are detected either by routine surveillance or when the patients do not have an expected response to treatment. But most recently severe allergic reaction/anaphylactoid reaction occurring simultaneously with inhibitor development has identified a subset of patients with FIX inhibitors in hemophilia B. 5 This unique adverse reaction further complicates the treatment of acute bleeding episodes, since the readily available factor IX containing prothrombin complex concentrates can also induce allergic reactions in these patients. 6 Recently licensed recombinant factor VIIa appears to be the only logical treatment for acute bleeding episodes in factor IX inhibitor patients with anaphylaxis. Results with immune tolerance induction (ITI) are poor and this treatment is associated with a unique renal complication of nephrotic syndrome in FIX inhibitor patients with concurrent allergy. Clinical Experience Unlike in hemophilia A with FVIII inhibitors, a significant number of patients with FIX inhibitors in hemophilia B present with simul- Correspondence: Indira Warrier, MD, Children’s Hospital of Michigan , Department of Hematology/Oncology, 3901 Beaubien Boulevard, Detroit, Michigan 48201, USA. Phone: international +1-313-745- 5515 – Fax: international +1-313-745-5237. taneous allergic reactions at the time of inhibitor development. The small number of severely affected subjects and even smaller number with factor IX antibodies limit our clinical experience of this unique complication of hemophilia treatment. Currently, there are over 35 patients worldwide who have had both inhibitors and allergy to FIX products. In the majority of these patients there was a temporal relationship between inhibitor development and anaphylaxis. Other common features of this group include: 1. High titer inhibitors (> 10 BU); 2. Allergy to alternate FIX products when tested; 3. Genotyping demonstrating either deletions or frameshift mutations. Most of the reactions reported occurred in early life. The median age reported is 12 months with a range of 7 months–12 years. The median number of exposure days prior to inhibitor development is 11 days with a range of 2-50 days. All ethnic groups are affected, and we have seen this problem more commonly with the use of purer factor IX products. FIX antibodies Antibodies to FIX are not as well characterized as FVIII antibodies. From what we know they are predominantly IgG4 subclass. They do not fix complement and have equal affinity to both heavy and light chains of FIX. A recent study from Japan has shown the presence of an IgG 1 subclass of antibody in addition to IgG4 at the time of anaphylactic reaction in some of these FIX inhibitor patients. Management 1. Treatment of acute bleeding. Treatment of hemophilia B patients with FIX inhibitors is complicated. The readily available product, factor IX, containing prothrombin complex concentrate (PCC), can only be used in patients without concurrent allergy to FIX. rFVI- Ia appears to be the most appropriate treatment for bleeding episodes in hemophilia B patients with inhibitors and allergy to FIX. The recommended dose is 90-120 µg/kg every 2 Haematologica vol. 85(supplement to n. 10):October 2000
32 Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor Table 1. Prevalence of factor IX inhibitors. U.S. survey. Yrs 97-98 (Warrier) Yr 95 (Katz) 97 centers responded 82 centers responded Total no. of patients 1990 1967 Severe 573 (30%) 735 (37%) Moderate 680 (36%) 644 (33%) Mild 647 (34%) 588 (30%) Inhibitors 44 ( 2.3%) 29 ( 1.5%) INH + allergy 20/44 (45%) NA hours until bleeding stops. The interval between doses is increased once the bleeding is controlled. Several of the patients in our initial report received rFVIIa with good results. 5 2. Immune tolerance induction (ITI) Available data indicate minimal success with ITI in hemophilia B patients with inhibitors. In those with concurrent allergy, the success rate is even lower. 5 In addition, nephrotic syndrome as a complication of ITI has been reported in 9 patients with FIX inhibitors and allergy to FIX (Table 2). Discussion Until recently, common serious complications following replacement therapy in hemophilia B patients were thrombosis and inhibitor development. However, with the advent of purer FIX products, thrombosis as an adverse event of treatment with FIX seems to have been overcome. But a new, potentially life-threatening complication, i.e., a severe allergic reaction has occurred in 45% of FIX inhibitor patients who have received FIX-containing products (Table 1). The simultaneous occurrence of allergy with FIX inhibitor development has limited the treatment options further for FIX inhibitor patients. The only logical treatment for those with allergy to FIX appears to be the most recently licensed rFVIIa. Although immune tolerance induction (ITI) with permanent eradication of inhibitor has been successful in 70-80% of cases of hemophilia A with inhibitors, 7 this is not the case with hemophilia B inhibitor patients. Moreover, the experience with ITI is limited in hemophilia B with FIX inhibitors. Most commonly cited reasons for the limited experience include low prevalence, thrombogenicity of FIX containing PCC, unavailability of high purity FIX products Table 2. Nephrotic sydrome as a complication of ITI in hemophilia B. MD/CTR Patient’s Gene INH titer Regimen Allergic Clinical Treatment Time to Refs. age defect (MAX) reaction symptoms resolution Evenstein/ Boston 2 Deletion 67 BU Mononine, 100 U/kg qd, Yes (Prior) Edema, oliguria, Reduction, Prednisone8 mo. 1,2 9 mo. proteinuria Warrier/ Detroit 2 29, R→stop 30 BU Mononine, 100 U/kg qd, Yes (Conco) Edema, Cessation 7 mo. 1 8 mo. + INH proteinuria Ettinger/ UMDNJ 5 NA 40 BU IVIG, Cf, Yes (After) Edema, proteinuria, Reduction, Mild proteinuria 1,3 Bebulin 100 U/kg qd, 8 mo. hypocomplementemia (2X)Hydroxyzine still Berntorp/ Sweden 11 6460, C→T; 29, 100 BU Mononine 100 U/kg, 18 mo. Yes Proteinuria Cessation 2 mo. PC R→stop Pollman/ Germany 8 Deletion 160 BU FIX, 100 U/kg bid, 12 mo. Yes (After) Edema, Proteinuria Steroids 4 Lenk/ Leipzig, Germany 6 6460, C→T 32 BU , 7 mo. Yes (Prior) Edema Cessation, Mild proteinuria 5 prednisone + CTX cyclosporine Tengborn/ Sweden 8 Deletion 45 BU Mononine CTX + IVIG, Yes (Conco) Edema Steroids + 3 attempts (15 mo.) + INH DC FIX PC: personal communication; 1. Ewenstein MB, Takemoto C, Warrier I, et al. 1997. Blood; 89:1115., 2. Dharnidbarka VR, Takemoto C, Ewenstein BM, et al. 1998. Pediatr Nephrol 1998; 12:654-7. 3. Constantinescu AR, Weiss LS, Saidi P, et al. 1997. J Ped Hematolo Oncolo; 19:345. 4. Lenk H, Bierbac U, Schille R. 1996. Haemophilia; 2(Suppl 1): 104. 5. Pollman H. 1996. Haemophilia; 2(Suppl 1): 72. Other cases: Brackmann / Bonn, Germany; Petrini/Sweden. Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: Acknowledgments We wish to thank th
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II Immune Tolerance and the Treatme
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