Приобретенная идиопатическая гемофилия с новой миссенс-мутацией гена фактора VIII (His2026Arg): обзор литературы и клиническое наблюдение
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Ключевые слова: ингибиторные коагулопатии, приобретенная гемофилия А, ген фактора VIII, мутации, антигенные детерминанты.
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The article provides review of possible mechanisms of inhibitor coagulopathies, in particular of acquired hemophilia A. This pathology is an extremely rare disease occurring in 1-2 cases in 1 million per year. In the present study we provide data for two clinical cases of hemophilia A in women. These cases had different development mechanisms, although both women have a newly discovered missense mutation His2026Arg in the VIII factor gene. The matter of main interest is the description of the disease development in the patient with an acquired idiopathic hemophilia A with a possible disease occurrence due to an asymmetric X-chromosome inactivation (lyonization). In this particular case lyonization led to the late manifestation of the hemophilia A carrier’s state and development of severe form of the inhibitor-associated acquired hemophilia A. We also discuss therapeutic approaches to these forms of the disease, considering there are no concise protocols for case management due to an extreme rarity of the pathology. Acquainting the clinical personnel working it the different areas of medicine with suchlike inhibitor coagulopathies has a major practical importance.
Keywords: inhibitor coagulopathies, acquired hemophilia A, factor VIII gene, mutations, antigenic determinant.
2. Cnoebl P, Marco P, Baudo F, Collins P Huth-Kühne A, Nemes L, Pellegrini F, Tengborn L, Lévesque H; EACH2 Registry Contributors. Demographic and clinical data in acquired hemophilia A: results from the European Asquired Hemophilia Registry (EACH2). Journal of Thrombosis and Hemostasis. 2012; 10:622-631. https://doi.org/10.1111/ j.1538-7836.2012.04654.x
3. Гатияров Ю.Ф., Цыбиков Н.Н. Аутоантитела к факторам свертывания крови. Сибирский медицинский журнал. 2011; 103(4). [Gatiyarov YuF, Tsybikov NN. Autoantibodies to coagulation factors. Sibirskii meditsinskii zhurnal. 2011;103(4). (In Russ.)].
4. Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagulation and Fibrinolysis. 2009; 20(7):517-523. https://doi.org/10. 1097/MBC.0b013e32832ca388
5. Kessler CM, Ma AD, Al-Mondhiry HA, Gut RZ, Cooper DL. Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry. Blood Coagulation and Fibrinolysis. 2016; 27(7):761-769. https://doi.org/10. 1097/MBC.0000000000000582
6. Di Michele DM. Immune tolerance induction in haemophilia: evidence and the way forward. Journal of Thrombosis and Haemostasis. 2011; 9(s1):216-225. https://doi.org/10.1111/j.1538-7836.2011.04349.x
7. Shepherd AJ, Skelton S, Sansom CE, Gomez K, Moss DS, Hart DP. A large-scale computational study of inhibitor risk in non-severe haemophilia A. British journal of haematology. 2015;168(3):413-420. https://doi.org/10.1111/bjh.13131
8. Gilles JG, Saint-Remy J-M. Coagulation factor autoantibodies. In: Shoenfeld Y, Meroni PL, Gershwin ME, eds. Autoantibodies. 2nd ed. Amsterdam: Elsevier; 2007:495-510.
9. Hofbauer CJ, Whelan SF, Hirschler M, Allacher P, Horling FM, Lawo JP, Oldenburg J, Tiede A, Male C, Windyga J, Greinacher A, Knöbl PN, Schrenk G, Koehn J, Scheiflinger F, Reipert BM. Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans. Blood. 2015;125(7):1180-1188. https://doi.org/10.1182/blood-2014-09-598268
10. Bagnall RD, Giannelli F, Green PM. Int22h-related inversions causing hemophilia A: a novel insight into their origin and a new more discriminant PCR test for their detection. Journal of Thrombosis and Haemostasis. 2006; 4(3):591-598. https://doi.org/10.1111/j.1538-7836.2006.01840.x
11. Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002; 99(1):168-174.
12. Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, Thompson AR, van Heerde W, Boekhorst J, Miller CH, le Cessie S, van der Bom JG. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012; 119(12):2922-2934. https://doi.org/ 10.1182/blood-2011-09-379453
13. Tiede A, Eisert R, Czwalinna A, Miesbach W, Scharrer I, Ganser A. Acquired haemophilia caused by non-haemophilic factor VIII gene variants. Annals of Hematology. 2010; 89(6):607-612. https://doi.org/ 10.1007/s00277-009-0887-3
14. Hwang SH, Lim JA, Kim HC, Lee HW, Kim HS. Identification of a shared F8 mutation in the Korean patients with acquired hemophilia A. The Korean Journal of Hematology. 2011; 46(1):49-51. https://dx.doi. org/10.5045%2Fkjh.2011.46.1.49
15. Higuchi M, Kazazian HHJr, Kasch L, Warren TC, McGinniss MJ, Phillips JAIII, Kasper C, Janco R, Antonarakis SE. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proceedings of the National Academy of Sciences. 1991; 88(16):7405-7409. https://doi.org/10.1073/pnas.88.16.7405
16. Favier R, Lavergne JM, Costa JM, Caron C, Mazurier C, Viémont M, Delpech M, Valleix S. Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female. Blood. 2000; 96(13):4373-4375.
17. Renault NK, Dyack S, Dobson MJ, Costa T, Lam WL, Greer WL. Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. European Journal of Human Genetics. 2007; 15(6):628-637. https://doi.org/10.1038/sj.ejhg.5201799
18. Di Michele DM, Gibb C, Lefkowitz JM, Ni Q, Gerber LM, Ganguly A. Severe and moderate haemophilia A and B in US females. Haemophilia. 2014; 20(2):e136-143. https://doi.org/10.1111/hae.12364
19. Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. The Journal of Immunology. 2006;177(2):1355-1363. https://doi.org/10.4049/jimmunol. 177.2.1355
20. Wootla B, Dasgupta S, Dimitrov JD, Bayry J, Lévesque H, Borg JY, Borel-Derlon A, Rao DN, Friboulet A, Kaveri SV, Lacroix-Desmazes S. Factor VIII hydrolysis mediated by anti-factor VIII autoantibodies in acquired hemophilia. The Journal of Immunology. 2008;180(11):7714-7720. https://doi.org/10.4049/jimmunol.180.11.7714
21. Mahendra A, Padiolleau-Lefevre S, Kaveri SV, Lacroix-Desmazes S. Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A? British journal of haematology. 2012;156(1):3-12. https://doi.org/10.1111/j.1365-2141.2011.08890.x
22. Astermark J. FVIII inhibitors: pathogenesis and avoidance. Blood. 2015;125(13):2045-2051. https://doi.org/10.1182/blood-2014-08-5353 28
23. Sakurai Y, Takeda T. Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder. Journal of Immunology Research. 2014; 2014:1-10. http://dx.doi.org/10.1155/2014/320674
24. Takeda T, Sakurai Y, Tatsumi K, Kato J, Kasuda S, Yoshioka A, Shima M. Elevation of B cell-activating factor belonging to the tumour necrosis family family (BAFF) in haemophilia A patient with inhibitor. Thrombosis and haemostasis. 2009; 101(2):408-410. https://doi.org/ 10.1160/TH08-08-0543
25. Stoilova-McPhie S, Lynch GC, Ludtke S, Pettitt BM. Domain organization of membrane-bound factor VIII. Biopolymers. 2013; 99(7):448-459. https://doi.org/10.1002/bip.22199
26. Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilleland DG. Nonrandom X-inactivation patterns in normal females: lionization ratios vary with age. Blood. 1996; 88(1):59-65.
27. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. American Journal of Human Genetics. 1992; 51(6):1229-1239.
28. Collins PW, Hirsch S, Baglin T, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CRM. UK Haemophilia Centre Doctors' Organisation. Acquired haemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organistaion. Blood. 2007; 109(5):1870-1877. https://doi.org/10.1182/blood-2006-06-029850
29. Franchini M. Rituximab in the treatment of adult acquired haemophilia A: a systematic review. Clinical reviews in Oncology/Hematology. 2007; 63(1):47-52. https://doi.org/10.1016/j.critrevonc.2006.11.004
30. Lee YS, Ng HJ. Mycophenolate in the remission induction of a patient with acquired haemophilia A. Haemophilia. 2010;16(1):179-189. https://doi.org/10.1111/j.1365-2516.2009.02107.x
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1. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM. Acquired hemophilia A: Updated review of evidence and treatment guidance. American Journal of Hematology. 2017; 92(7):695-705. https://doi.org/10.1002/ajh.24777
2. Cnoebl P, Marco P, Baudo F, Collins P Huth-Kühne A, Nemes L, Pellegrini F, Tengborn L, Lévesque H; EACH2 Registry Contributors. Demographic and clinical data in acquired hemophilia A: results from the European Asquired Hemophilia Registry (EACH2). Journal of Thrombosis and Hemostasis. 2012; 10:622-631. https://doi.org/10.1111/ j.1538-7836.2012.04654.x
3. [Gatiyarov YuF, Tsybikov NN. Autoantibodies to coagulation factors. Sibirskii meditsinskii zhurnal. 2011;103(4). (In Russ.)].
4. Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagulation and Fibrinolysis. 2009; 20(7):517-523. https://doi.org/10. 1097/MBC.0b013e32832ca388
5. Kessler CM, Ma AD, Al-Mondhiry HA, Gut RZ, Cooper DL. Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry. Blood Coagulation and Fibrinolysis. 2016; 27(7):761-769. https://doi.org/10. 1097/MBC.0000000000000582
6. Di Michele DM. Immune tolerance induction in haemophilia: evidence and the way forward. Journal of Thrombosis and Haemostasis. 2011; 9(s1):216-225. https://doi.org/10.1111/j.1538-7836.2011.04349.x
7. Shepherd AJ, Skelton S, Sansom CE, Gomez K, Moss DS, Hart DP. A large-scale computational study of inhibitor risk in non-severe haemophilia A. British journal of haematology. 2015;168(3):413-420. https://doi.org/10.1111/bjh.13131
8. Gilles JG, Saint-Remy J-M. Coagulation factor autoantibodies. In: Shoenfeld Y, Meroni PL, Gershwin ME, eds. Autoantibodies. 2nd ed. Amsterdam: Elsevier; 2007:495-510.
9. Hofbauer CJ, Whelan SF, Hirschler M, Allacher P, Horling FM, Lawo JP, Oldenburg J, Tiede A, Male C, Windyga J, Greinacher A, Knöbl PN, Schrenk G, Koehn J, Scheiflinger F, Reipert BM. Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans. Blood. 2015;125(7):1180-1188. https://doi.org/10.1182/blood-2014-09-598268
10. Bagnall RD, Giannelli F, Green PM. Int22h-related inversions causing hemophilia A: a novel insight into their origin and a new more discriminant PCR test for their detection. Journal of Thrombosis and Haemostasis. 2006; 4(3):591-598. https://doi.org/10.1111/j.1538-7836.2006.01840.x
11. Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002; 99(1):168-174.
12. Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, Thompson AR, van Heerde W, Boekhorst J, Miller CH, le Cessie S, van der Bom JG. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012; 119(12):2922-2934. https://doi.org/ 10.1182/blood-2011-09-379453
13. Tiede A, Eisert R, Czwalinna A, Miesbach W, Scharrer I, Ganser A. Acquired haemophilia caused by non-haemophilic factor VIII gene variants. Annals of Hematology. 2010; 89(6):607-612. https://doi.org/ 10.1007/s00277-009-0887-3
14. Hwang SH, Lim JA, Kim HC, Lee HW, Kim HS. Identification of a shared F8 mutation in the Korean patients with acquired hemophilia A. The Korean Journal of Hematology. 2011; 46(1):49-51. https://dx.doi. org/10.5045%2Fkjh.2011.46.1.49
15. Higuchi M, Kazazian HHJr, Kasch L, Warren TC, McGinniss MJ, Phillips JAIII, Kasper C, Janco R, Antonarakis SE. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proceedings of the National Academy of Sciences. 1991; 88(16):7405-7409. https://doi.org/10.1073/pnas.88.16.7405
16. Favier R, Lavergne JM, Costa JM, Caron C, Mazurier C, Viémont M, Delpech M, Valleix S. Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female. Blood. 2000; 96(13):4373-4375.
17. Renault NK, Dyack S, Dobson MJ, Costa T, Lam WL, Greer WL. Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. European Journal of Human Genetics. 2007; 15(6):628-637. https://doi.org/10.1038/sj.ejhg.5201799
18. Di Michele DM, Gibb C, Lefkowitz JM, Ni Q, Gerber LM, Ganguly A. Severe and moderate haemophilia A and B in US females. Haemophilia. 2014; 20(2):e136-143. https://doi.org/10.1111/hae.12364
19. Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. The Journal of Immunology. 2006;177(2):1355-1363. https://doi.org/10.4049/jimmunol. 177.2.1355
20. Wootla B, Dasgupta S, Dimitrov JD, Bayry J, Lévesque H, Borg JY, Borel-Derlon A, Rao DN, Friboulet A, Kaveri SV, Lacroix-Desmazes S. Factor VIII hydrolysis mediated by anti-factor VIII autoantibodies in acquired hemophilia. The Journal of Immunology. 2008;180(11):7714-7720. https://doi.org/10.4049/jimmunol.180.11.7714
21. Mahendra A, Padiolleau-Lefevre S, Kaveri SV, Lacroix-Desmazes S. Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A? British journal of haematology. 2012;156(1):3-12. https://doi.org/10.1111/j.1365-2141.2011.08890.x
22. Astermark J. FVIII inhibitors: pathogenesis and avoidance. Blood. 2015;125(13):2045-2051. https://doi.org/10.1182/blood-2014-08-5353 28
23. Sakurai Y, Takeda T. Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder. Journal of Immunology Research. 2014; 2014:1-10. http://dx.doi.org/10.1155/2014/320674
24. Takeda T, Sakurai Y, Tatsumi K, Kato J, Kasuda S, Yoshioka A, Shima M. Elevation of B cell-activating factor belonging to the tumour necrosis family family (BAFF) in haemophilia A patient with inhibitor. Thrombosis and haemostasis. 2009; 101(2):408-410. https://doi.org/ 10.1160/TH08-08-0543
25. Stoilova-McPhie S, Lynch GC, Ludtke S, Pettitt BM. Domain organization of membrane-bound factor VIII. Biopolymers. 2013; 99(7):448-459. https://doi.org/10.1002/bip.22199
26. Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilleland DG. Nonrandom X-inactivation patterns in normal females: lionization ratios vary with age. Blood. 1996; 88(1):59-65.
27. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. American Journal of Human Genetics. 1992; 51(6):1229-1239.
28. Collins PW, Hirsch S, Baglin T, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CRM. UK Haemophilia Centre Doctors' Organisation. Acquired haemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organistaion. Blood. 2007; 109(5):1870-1877. https://doi.org/10.1182/blood-2006-06-029850
29. Franchini M. Rituximab in the treatment of adult acquired haemophilia A: a systematic review. Clinical reviews in Oncology/Hematology. 2007; 63(1):47-52. https://doi.org/10.1016/j.critrevonc.2006.11.004
30. Lee YS, Ng HJ. Mycophenolate in the remission induction of a patient with acquired haemophilia A. Haemophilia. 2010;16(1):179-189. https://doi.org/10.1111/j.1365-2516.2009.02107.x
1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
2 ГБУЗ Свердловской области «Свердловская областная клиническая больница №1», Екатеринбург, Россия;
3 ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
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V.I. ERSHOV 1, I.Yu. GADAEV 1, D.A. BUDANOVA 1, F.G. PERINA 2, V.L. SURIN 3, V.V. SALOMASHKINA 3, O.S. PSHENICHNIKOVA 3, N.I. ZOZULYA 3
1 Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia;
2 State Budgetary Institution of Healthcare of Sverdlovsk region “Sverdlovsk Regional Clinical Hospital №1”, Ekaterinburg, Russia;
3 National medical research center for Hematology, Ministry of Healthcare of the Russian Federation, Moscow, Russia