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Inhibitor development

dose. The results of the recently reported International ITI study have influenced recent recommendations.13

In severe haemophilia A, the outcome of ITI is good if the inhibitor titre is <10 Bu/ml when it is commenced. As many patients will have a level above this at the time the inhibitor is identified, it is necessary to withhold any therapy containing factor VIII/IX to allow the inhibitor level to decrease to <10 Bu/ml. During this time, which lasts several months, bleeds should be treated with rVIIa (as FEIBA contains traces of factor VIII sufficient to stimulate the production of the inhibitor).

The choice of ITI regimen depends upon the level of inhibitor at the start of tolerance (good prognosis if less than 10 Bu/ml) and its previous historic maximum (good prognosis < 200Bu/ml). Current recommendations are summarised in Table 2. During ITI, it is essential to monitor the inhibitor level and, if it is not observed to decline steadily, to alter the factor VIII regimen. Regular infusions should continue until the inhibitor is no longer detectable in a Bethesda assay and the half-life of infused factor VIII is greater than seven hours. At this point, the patient is likely to experience successful prophylaxis with standard alternate day regimen with factor VIII. Overall, the success rate for ITI in severe haemophilia with the above regimens is about 80%; those failing to respond may benefit from alternative therapies. ITI therapy is expensive, as not only are large doses of factor VIII given frequently but the regimen may continue for up to three years.

Inhibitors in mild/moderate haemophilia A do not respond as readily as those with severe haemophilia to ITI.14 Their clinical phenotype may resemble bleeding in acquired haemophilia, particularly if there basal factor VIII declines to <1%. Use of an immunosuppressive may encourage decline of the inhibitor titre.

Haemophilia B

Inhibitors in haemophilia B are only observed in 1–2% patients and are almost exclusively confined to those with major factor IX gene deletions.15

Furthermore, 24

when they arise, they may lead to anaphylactic reactions and, for this reason, the first 20 infusions of factor IX concentrate should be given in hospital. Further factor IX therapy in the presence of a factor IX inhibitor may lead to

Table 2: Initial recommendations for immune tolerance induction Inhibitor titre at start of ITI < 5 Bu/ml < 10 Bu/ml >10 Bu/ml

Highest historic inhibitor titre < 5 Bu/ml

or Adapted from Reference 2.

“Acquired haemophilia is an uncommon auto- immune condition arising predominantly in older individuals”

irreversible nephrotic syndrome. Additionally, ITI is not as effective as in haemophilia A at eradicating the inhibitor. Successful outcomes have been reported in about 25% cases and the use of immune suppressants may contribute to success.

Acquired haemophilia Acquired haemophilia is an uncommon auto-immune condition arising predominantly in older individuals who spontaneously develop an anti-factor VIII antibody which substantially reduces their endogenous factor VIII level, often to <1%.16 Patients present with spontaneous bruising, soft tissue bleeding, haematuria and gastro-intestinal bleeds. Clinically it is quite distinct from haemorrhage observed in congenital haemophilia A, in which bleeding is predominantly into large joints and muscles. Significant bleeds will probably require treatment with a bypassing agent, although patients with measurable factor VIII levels may respond to desmopressin and some, with a low titre inhibitor, may do so to large doses of factor VIII. ITI as described above is not usually effective. Inhibitor eradication is promoted by immunosupression with a corticosteroid. l

References 1. Makris M, Hay CR, Gringeri A, D’Oiron R. How I treat inhibitors in haemophilia. Haemophilia 2012; 18(Suppl 4):48–53.

2. Collins PW et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization. Br J Haematol 2013;160(2):153–70.

3. Teitel JM, Sholzberg M. Current status and future prospects for the prophylactic management of hemophilia patients with inhibitor antibodies. Blood Rev 2013;27(2):103–9.

4. Bjorkman S et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012;119(2):612–8.

5. Santagostino E et al. A prospective randomized

trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost 2006;4(2):367–71.

6. Iorio A, Matino D, D’Amico R, Makris M. Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database Syst Rev 2010;(8):CD004449.

7. Negrier C et al. SURgical interventions with FEIBA (SURF): international registry of surgery in haemophilia patients with inhibitory antibodies. Haemophilia 2013 Jan 3.

8. Giangrande PL et al. Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors. Haemophilia 2009;15(2):501–8.

9. Teitel JM et al. Orthopaedic surgery in haemophilia patients with inhibitors: a practical guide to haemostatic, surgical and rehabilitative care. Haemophilia 2009;15(1):227–39.

10. Konkle BA et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007;5(9):1904–13.

11. Dimichele D, Negrier C. A retrospective postlicensure survey of FEIBA efficacy and safety. Haemophilia 2006;12(4):352–62.

12. Leissinger C et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011;365(18):1684–92.

13. Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119(6):1335–44.

14. Kempton CL et al. Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A. Am J Hematol 2012;87(9):933–6.

15. Thorland EC et al. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 1999;5(2):101–5.

16. Collins PW. Therapeutic challenges in acquired factor VIII deficiency. Hematology Am Soc Hematol Educ Program 2012;2012:369–74.

< 200 Bu/ml > 200 Bu/ml

ITI regimen

50 iu/kg alternate days 100 iu/kg/day 200 iu/kg/day

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