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HEMOPHILIA (FROM FATAL OUTCOME TO OUTPATIENT MANAGEMENT)

DOI: https://doi.org/10.29296/25877305-2020-08-05
Issue: 
8
Year: 
2020

Professor V. Delyagin, MD Dmitry Rogachev National Medical Research Center Of Pediatric
Hematology, Oncology and Immunology

Hemophilia is the most common form of severe hereditary bleeding. The prevalence of hemophilia among adolescents according to official statistics in Moscow is 12.2–16.0 per 100 thousand. Hemophilia B occurs 5 times less frequently than hemophilia A, hemophilia C - 10 times less often. Taking into account the localization of the FVIII and FIX genes on the X chromosome and their recessiveness, clinically significant manifestation of hemophilia A and B is characteristic almost only of men. Mild forms of hemophilia are much more common in female carriers than is commonly thought. New female carriers often arise from old fathers (that is, old paternal sperm). Clinically, depending on the degree of clotting factor deficiency (severity of hemophilia), bleeding of varying intensity is possible, up to disabling and life-threatening. Modern replacement therapy with recombinant clotting factors, the appointment of recombinant clotting factors prevents bleeding, allows surgical interventions and ensures a sufficiently high quality of life.

Keywords: 
hemophilia
clinical features
coagulation factors
replacement therapy
Octofactor
Innonafactor
Coagil VII



References: 
  1. Deljagin V.M., Mal'tsev V.I., Rumjantsev A.G. Lektsii po klinicheskoj diagnostike vnutrennih boleznej. Kiev: MORION, 2007; 664 s. [Delyagin V.M., Mal’tsev V.I., Rumyantsev A.G. Lektsii po klinicheskoi diagnostike vnutrennikh boleznei. Kiev: MORION, 2007; 664 s. (in Russ.)].
  2. Rumjantsev A.G., Rumjantsev S.A., Chernov V.M. Gemofilija v praktike vrachej razlichnyh spetsial'nostej. M.: GEOTAR-Media, 2012; 132 s. [Rumyantsev A.G., Rumyantsev S.A., Chernov V.M. Gemofiliya v praktike vrachei razlichnykh spetsial’nostei. M.: GEOTAR-Media, 2012; 132 s. (in Russ.)].
  3. Bolton-Maggs P. Hemophilia C. Updated: Mar 01, 2019. URL: https://emedicine.medscape.com/article/955690-overview
  4. Hemophilia C. Clinical Overview. Elsevier Point of Care. Updated February 5, 2020.
  5. Al'tfeder A.V., Arutjunova N.E., Belkina A.I. i dr. Osnovnye pokazateli zdorov'ja naselenija goroda Moskvy, dejatel'nost' meditsinskih organizatsij gosudarstvennoj sistemy zdravoohranenija goroda Moskvy. M.: Departament zdravoohranenija g. Moskvy, 2018; 162 s. [Al’tfeder A.V., Arutyunova N.E., Belkina A.I. i dr. Osnovnye pokazateli zdorov’ya naseleniya goroda Moskvy, deyatel’nost’ meditsinskikh organizatsii gosudarstvennoi sistemy zdravookhraneniya goroda Moskvy. M.: Departament zdravookhraneniya g. Moskvy, 2018; 162 s. (in Russ.)].
  6. Rathore B. Hemophilia. In: Ferri F. (Ed.) Ferri’s Clinical Advisor. Elsevier, 2020; 644–6.e1
  7. Asselta R., Paraboschi E., Rimoldi V. et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood. 2017; 130 (4): e1–e6. DOI: 10.1182/blood-2017-04-780148
  8. Bowen D. Haemophilia A and haemophilia B: molecular insights. Mol Pathol. 2002; 55 (2): 127–44. DOI: 10.1136/mp.55.2.127
  9. Rallapalli P., Kemball-Cook G., Tuddenham E. et. al. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost. 2013; 11 (7): 1329–40. DOI: 10.1111/jth.12276
  10. Peyvandi F., Kunicki T., Lillicrap D. Genetic sequence analysis of inherited bleeding diseases. Blood. 2013; 122 (20): 3423–31. DOI: 10.1182/blood-2013-05-505511
  11. Lakich D., Kazazian H., Antonarakis S. et. al. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia. Ann Nat Genet. 1993; 5 (3): 236–41. DOI: 10.1038/ng1193-236
  12. Rossiter J., Young M., Kimberland M. et. al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum Mol Genet. 1994; 3 (7): 1035–9. DOI: 10.1093/hmg/3.7.1035
  13. Croteau St. Evolving Complexity in Hemophilia Management. Pediatric Clin North Am. 2018; 65 (3): 407–25. DOI: 10.1016/j.pcl.2018.01.004
  14. Venkateswaran L., Wilimas J., Jones D. et al. Mild hemophilia in children: prevalence, complications, and treatment. J Pediatr Hematol Oncol. 1998; 20 (1): 32–5.
  15. Staber J., Croteau S., Davis J. et al. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia. 2018; 24 (2): 180–5. DOI: 10.1111/hae.13376
  16. Konkle B., Huston H., Fletcher Sh. Hemophilia A (Factor VIII Deficiency). In: Adam M., Ardinger H., Pagon R., Walles St. et al. (Eds.) GeneReviews® [Internet] (WA): Last Revision: June 22, 2017. University of Washington, Seattle; 1993–2020. URL: https://pubmed.ncbi.nlm.nih.gov/20301295/
  17. Coagulation factor XI; F11. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Updated November 20, 2008. Edited September 19, 2016. Accessed August 15, 2019. URL: https://omim.org/entry/264900
  18. Wheeler A., Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol. 2016; 9 (7): 629–37. DOI: 10.1080/17474086.2016.1191944
  19. Gomez K., Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008; 14 (6): 1183–9. DOI: 10.1111/j.1365-2516.2008.01667.x
  20. Li Z., Weng X. Hemophilic Pseudotumor. N Engl J Med. 2020; 382 (21): 2033. DOI: 10.1056/NEJMicm1914118
  21. Osooli M., Lovdahl S., Carlsson St. et al. Comparative burden of arthropathy in mild haemophilia: a register-based study in Sweden. Haemophilia. 2017; 23 (2): e79–e86. DOI: 10.1111/hae.13166
  22. Zucker M., Seligsohn U., Salomon O. et al. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost. 2014; 12 (7): 1121–30. DOI: 10.1111/jth.12600
  23. De Alarcon P., Manco-Johnson M. Evaluation of a child with bleeding or abnormal coagulation screening tests. In: Sills R., Hochberg Z. (Eds): Practical Algorithms in Pediatric Hematology and Oncology. Basel, Karger, 2003; p. 52–3. DOI: 10.1159/isbn.978-3-318-00857-9
  24. Kumar R., Bouskill V., Schneiderman J. et al. Impact of aerobic exercise on haemostatic indices in pediatric patients with haemophilia. Thromb Haemost. 2016; 115 (6): 1120–8. DOI: 10.1160/TH15-09-0757
  25. Zourikian N., Merlen C.T., St-Louis J. et al. Effects of moderate-intansity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study. Haemophilia. 2016; 22 (3): e177–83. DOI: 10.1111/hae.12869
  26. Kuznik B.I., Sturov V.G., Levshin N.Ju. i dr. Gemorragicheskie i tromboticheskie zabolevanija i sindromy u detej i podrostkov: Patogenez, klinika, diagnostika, terapija i profilaktika. Novosibirsk: Nauka, 2018; 524 s. [Kuznik B.I., Sturov V.G., Levshin N.Yu. et al. Gemorragicheskie i tromboticheskie zabolevaniya i sindromy u detei i podrostkov: Patogenez, klinika, diagnostika, terapiya i profilaktika. Novosibirsk: Nauka, 2018; 524 (in Russ.)].
  27. Kudlaj D.A. Razrabotka i primenenie otechestvennyh rekombinantnyh preparatov faktorov svertyvanija krovi VII, VIII, IX u detej s gemofiliej A i B. Pediatrija. 2019; 98 (1): 9–17 [Kudlay D.A.. Development and use of Russian recombinant blood coagulation factor VII, VIII, IX drugs in children with hemophilia A and B. Pediatria. 2019; 98 (1): 9–17 (in Russ.)]. DOI: 10.24110/0031-403X-2019-98-1-9-17
  28. Davydkin I.L., Andreeva T.A., Zorenko V.Ju. i dr. Effektivnost' i bezopasnost' preparata Oktofaktor pri profilakticheskom lechenii bol'nyh s tjazheloj i srednetjazheloj formoj gemofilii A (rezul'taty 1-j chasti klinicheskogo issledovanija II–III fazy). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2013; 12 (3): 29–37 [Davydkin I.L., Andreeva TA., Zorenko V.Yu. et al. Efficiency and safety of Octofactor in prevention of bleeding episodes in patients with severe and moderate hemophilia A: results of part 1 of phase II–III clinical trial. Pediatric Hematology/Oncology and Immunopathology. 2013; 12 (3): 29–37 (in Russ.)].
  29. Andreeva T.A., Zorenko V.Ju., Davydkin I.L. i dr. Effektivnost' i bezopasnost' preparata Oktofaktor v lechenii bol'nyh s tjazheloj i srednetjazheloj formoj gemofilii A (rezul'taty 2-j chasti klinicheskogo issledovanija II i III fazy). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2013; 12 (4): 31–7 [Andreeva T.A., Zorenko V.Yu., Davydkin I.L. et al. Efficiency and safety of octofactor in the treatment of patients with severe and moderate hemophilia A: results of part 2 of phase II–III clinical trial. Pediatric Hematology/Oncology and Immunopathology. 2013; 12 (4): 31–7 (in Russ.)].
  30. Zorenko V.Ju., Mishin G.V., Severova T.V. i dr. Farmakokineticheskie svojstva, bezopasnost' i perenosimost' preparata Oktofaktor (rezul'taty I fazy klinicheskogo issledovanija u bol'nyh gemofiliej A). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2013; 12 (2): 30–7 [Zorenko V.Yu., Mishin G.V., Severova T.V. et al. Pharmacokinetics, safety, and tolerability of Octofactor in patients with hemophilia A: Results of phase I clinical study. Pediatric Hematology/Oncology and Immunopathology. 2013; 12 (2): 30–7 (in Russ.)].
  31. Vdovin V.V., Andreeva T.A., Davydkin I.L. i dr. Effektivnost' i bezopasnost' preparata Oktofaktor pri profilakticheskom lechenii podrostkov s tjazheloj gemofiliej A. Rossijskij zhurnal detskoj gematologii i onkologii. 2017; 4 (1): 61–70 [Vdovin V.V., Andreeva T.A., Davydkin I.L. et al. The efficacy and safety of the drug Octofactor in prophylactic treatment of adolescents with severe hemophilia A. Russian Journal of Pediatric Hematology and Oncology. 2017; 4 (1): 61–70 (in Russ.)]. https://doi.org/10.17650/2311-1267-2017-4-1-61-70
  32. Zozulja N.I., Jastrubenetskaja O.I., Beljaeva S.S. i dr. Rezul'taty nabljudatel'nogo issledovanija effektivnosti i bezopasnosti preparata Oktofaktor. Rossijskij zhurnal detskoj gematologii i onkologii. 2019; 6 (2): 30–47 [Zozulya N.I., Yastrubinetskaya O.I., Belyaeva S.S. et al. The results of the use of Octofactor in patients with moderate and severe hemophilia A (data from a prospective, multicenter, open-label, observational study). Russian Journal of Pediatric Hematology and Oncology. 2019; 6 (2): 30–47 (in Russ.)]. https://doi.org/10.21682/2311-1267-2019-6-2-30-47
  33. Shiller E., Petrov V., Svirin P. et al. Long-term prophylaxis with activated recombinant FVII in children with hemophilia A and inhibitor, receiving treatment with ITI protocol. Blood. 2016; 128 (22): 4980.
  34. Volkova S.A. Opyt primenenija i otsenka gemostaticheskogo dejstvija preparata Koagil-VII v domashnem lechenii u patsienta s ingibitornoj gemofiliej A posle total'nogo endoprotezirovanija kolennogo sustava. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2015; 14 (2): 59–62 [Volkova S.A. Experience gained in the use of Coagil-VII and evaluation of its hemostatic activity in a patient with inhibitory hemophilia A, receiving the drug in the home treatment setting after total knee arthroplasty. Pediatric Hematology/Oncology and Immunopathology. 2015; 14 (2): 59–62 (in Russ.)]. https://doi.org/10.24287/1726-1708-2015-14-2-59-62
  35. Andreeva T.A., Zorenko V.Ju., Davydkin I.L. i dr. Effektivnost' i bezopasnost' preparata Innonafaktor pri profilakticheskom lechenii bol'nyh s tjazheloj i srednetjazheloj formoj gemofilii V (rezul'taty 1-j chasti klinicheskogo issledovanija II–III fazy). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2015; 14 (1): 65–75 [Andreeva T.A., Zorenko V.Yu., Davydkin I.L. et al. Efficiency and safety of Innonafactor in prevention of bleeding episodes in patients with severe and moderate hemophilia B: Results of part 1 of phase II–III clinical trial. Pediatric Hematology/Oncology and Immunopathology. 2015; 14 (1): 65–75 (in Russ.)]. https://doi.org/10.24287/1726-1708-2015-14-1-65-75
  36. Davydkin I.L., Zorenko V.Ju., Andreeva T.A. i dr. Effektivnost' i bezopasnost' preparata Innonafaktor v lechenii bol'nyh s tjazheloj i srednetjazheloj formoj gemofilii B (rezul'taty 2-j chasti klinicheskogo issledovanija II–III fazy). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2015; 14 (2): 50–8 [Davydkin L.I., Zorenko V.Yu., Andreeva T.A. et al. Efficacy and safety of Innonafactor in on-demand treatment of patients with severe and moderate hemophilia B: Results of part 2 of phase II–III clinical trial. Pediatric Hematology/Oncology and Immunopathology. 2015; 14 (2): 50–8 (in Russ.)]. https://doi.org/10.24287/1726-1708-2015-14-2-50-58
  37. Zorenko V.Ju., Mishin G.V., Severova T.V. i dr. Farmakokineticheskie svojstva, bezopasnost' i perenosimost' preparata Innonafaktor (rezul'taty I fazy klinicheskogo issledovanija u bol'nyh s tjazheloj i srednetjazheloj formoj gemofilii B). Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2014; 13 (4): 39–49 [Zorenko V.Yu., Mishin G.V., Severova T.V. et al. Pharmacokinetics, safety, and tolerability of Innonafactor: results of phase i clinical study in patients with severe and moderate hemophilia B. Pediatric Hematology/Oncology and Immunopathology. 2014; 13 (4): 39–49 (in Russ.)]. Andreeva T.A., Davydkin I.L., Mamaev A.N. i dr. Rezul'taty mnogotsentrovogo, prospektivnogo, otkrytogo, nekontroliruemogo issledovanija effektivnosti i bezopasnosti preparata Innonafaktor u patsientov v vozraste 12 let i starshe s tjazheloj i srednetjazheloj gemofiliej V. Russkij zhurnal detskoj gematologii i onkologii. 2017; 4 (1): 20–32 [Andreeva T.A., Davydkin I.L., A.N. Mamaev A.N. et al. Results of a multicenter, prospective, open, uncontrolled study of the efficacy and safety of the drug Innonafactor in patients aged 12 years and older with severe and moderate hemophilia B. Russian Journal of Pediatric Hematology and Oncology. 2017; 4 (1): 20–32. (in Russ.)]. DOI: 10.17650/2311-1267-2017-4-4-20-32
  38. Rajpurkar M., Croteau S., Boggio L. et al. Thrombotic events with recombinant activated factor VII (rFVIIa) in approved indications are rare and associated with older age, cardiovascular disease, and concomitant use of activated prothrombin complex concentrates (aPCC). J Blood Med. 2019; 10: 335–40. DOI: 10.2147/JBM.S219573