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Chapter 136 Inhibitors in Hemophilias 2033

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20% to 25%. The latter cases may have a bleeding tendency that Hay CR, Brown S, Collins PW, et al: The diagnosis and management of
is more severe than hemophilia, characterized by central nervous factor VIII and IX inhibitors: A guideline from the United Kingdom Hae-
system or gastrointestinal bleeding soon after birth, or precocious mophilia Centre Doctors Organisation. Br J Haematol 133:591, 2006.
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joint bleeds. With the availability of specific concentrates, especially Hay CR, DiMichele DM: The principal results of the International Immune
rFVIIa, treatment has become widespread and the occurrence of Tolerance Study: a randomized dose comparison. Blood 119:1335, 2011.
complications fairly well known. As FVII shares considerable homol- Hay CRM, Palmer B, Chalmers E, et al on behalf of the United Kingdom
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ogy with FIX, both at the gene and protein levels, and displays a Hemophilia Centre Doctor’s Organisation (UKHCDO): Incidence of
comparable distribution of disease-causing mutations, with a large FVIII inhibitors throughout life in severe haemophilia A in the United
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predominance of missense changes, the occurrence of inhibitors to Kingdom. Blood 117:6367, 2011.
FVII was an expected finding. The lack of severe gene lesions, as large Ingerslev J: Hemophilia. Strategies for the treatment of inhibitor patients.
deletions, may account for the apparently lower prevalence of inhibi- Haematologica 85:15, 2000.
tors in comparison with hemophilia B. Only a recent prospective Kempton CL, Meeks SL: Towards optimal therapy for inhibitors in Hemo-
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study with a centralized inhibitor screening, provided clear cut data philia. Hematology Am Soc Hematol Educ Program 2014:364, 2014.
on the inhibitor prevalence and features; in fact, inhibitors to FVII Konkle B, Ebbesen LS, Erhardtsen E, et al: Randomized, prospective clinical
were detected in 3 of 115 (2.6%) patients (one de novo inhibitor and trial of recombinant factor VIIa for secondary prophylaxis in haemophilia
two preexisting inhibitors), all high titer, and their anamneses were patients with inhibitors. J Thromb Haemost 5:1904, 2008.
kinetically similar to those described in hemophilias. Importantly, Lacroix-Desmazes S, Bayry J, Misra N, et al: The prevalence of proteolytic
FVII inhibitors were in no case associated with allergic reactions. In antibodies against factor VIII in hemophilia A. N Engl J Med 346:662,
the presence of a high-titer inhibitor to FVII, treatment becomes a 2002.
problem as there are no bypassing agents capable of triggering blood Mariani G, Ghirardini A, Bellocco R: Immune tolerance in hemophilia-
coagulation. principal results from the International Registry. Report of the factor VIII
and IX Subcommittee. Thromb Haemost 72:155, 1994.
Mariani G, Siragusa S, Kroner B: Immune tolerance induction in hemophilia
SUGGESTED READINGS A: a review. Semin Thromb Hemost 29:69, 2003.
Miao CH: Immunemodulation for inhibitors in haemophilia A: the impor-
Alexander S, Hopewell S, Hunter S, et al: Rituximab and desensitization tant role of Treg cells. Expert Rev Hematol 3:469, 2010.
for a patient with severe factor IX deficiency, inhibitors and history of Oldenburg J, Schroeder J, Brackmann HH, et al: Environmental and
anaphylaxis. J Pediatr Hematol Oncol 30:93, 2008. genetic factors influencing inhibitor development. Semin Hematol 41:82,
Astermark J, Donfield SM, Gomperts ED, et al: The polygenic nature of 2004.
inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genet- Oldenburg J, Schwaab R, Brackmann HH: Induction of immune tolerance
ics Study (HIGHS) Combined Cohort. Blood 121:1445–1454, 2013. in haemophilia A inhibitor patients by the “Bonn Protocol”: Predictive
Darby SC, Kan SW, Spooner RJ, et al: Mortality rates, life expectancy and parameter for therapy duration and outcome. Vox Sang 77:49, 1999.
causes of death in people with haemophilia A or B in the United Kingdom Roberts HR, Monroe DM, White GC: The use of recombinant factor VIIa
who were not infected with HIV. Blood 110:815, 2007. in the treatment of bleeding disorders. Blood 104:3858, 2004.
Di Michele D: Hemophlia therapy – Navigating Speed Bumps on the Innova- Thompson AR, Murphy ME, Liu M, et al: Loss of tolerance to exogenous
tion Highway. N Engl J Med 374:2087–2089, 2016. and endogenous factor VIII in a mild hemophilia A patient with an
Faranoush M, Abolghasemi H, Mahboudi F, et al: A comparison of efficacy Arg593 to Cys mutation. Blood 90:1902, 1997.
between recombinant activated factor VII (Aryoseven) and Novoseven in Warrier I, Ewenstein BM, Koerper MA, et al: Factor IX inhibitors and
patients with hereditary FVIII deficiency with inhibitor. Clin App Thromb anaphylaxis in hemophilia B. J Pediatr Hematol Oncol 19:23, 1997.
Hemost 22:184, 2016.
Gouw SC, van den Berg HM, Fischer K, et al for the RODIN Study Group:
Intensity of factor VIII treatment and inhibitor development in children REFERENCES
with severe hemophilia A: the RODIN study. Blood 121:4046–4056,
2013. For the complete list of references, log on to www.expertconsult.com.