Research of adaptation mechanisms of regulation of microcirculatory beds in patients with hemophilia

Introduction. Frequent bleeding with hemophilia significantly worsens the quality of life of patients. The pathogenesis of hemorrhage in hemophilia has not been studied enough, especially at the vascular level, so it is necessary to study microcirculation in this disease.
The purpose of the study is to assess the mechanisms of regulation of blood tissue perfusion and the adaptive reserves of the microcirculation system in patients with hemophilia.
Materials and methods. Total microcirculation was assessed by laser Doppler flowmetry in 44 patients with hemophilia A between the ages of 14 and 20 years. Severe form of the disease was in 59 % of patients, the average – in 32 %, light – in 9 % of patients. The control group included 26 healthy men aged 14 to 19 years. The sensors recorded blood flow in the index fingers on both sides. In 20 patients with hemophilia А, an occlusion test was performed.
The results of the study. In patients with hemophilia, asymmetric changes in microcirculation parameters were detected when measured in the area of the index fingers. At rest in patients with hemophilia, the prevalence of vasospasm was revealed: a decrease in the perfusion index M, an increased blood bypass due to the predominance of myogenic tone. However, neurogenic tone indicators tended to decrease. During occlusive ischemia, vasospasm is slowed down in the first seconds after the onset of exposure to the stress factor.
Conclusion. The study revealed a dysregulation of the vascular tone of the microvasculature in young hemophilia patients at rest and under the influence of a stress factor in the form of short-term ischemia. Therefore, with hemophilia from a young age, control of microcirculation is necessary for the timely prevention of both bleeding and cardiovascular pathology associated with vasospasm.

1. Beby A.T., Haarmann H. Comparison of annual cost of recombinant factor VIII (full-length vs. B-domain deleted) for treatment of haemophilia A in The Netherlands. Haemophilia 2014;20(Issue 2):34–5.

2. Astermark J., Dolan G., Hilberg T., Jiménez-Yuste V., Laff an M., Lassila R., Lobet S., Martinoli C., Perno C.F. Managing haemophilia for life: 4th Haemophilia Global Summit. Haemophilia 2014;20(5):1–20. doi: 10.1111/hae.12468.

3. Davydkin I.L., Andreeva T.A., Zorenko V.Yu., Konstantinova V.N., Zalepukhina O.E., Klimova N.I., Kurtov I.V., Noskova M.S., Gusyakova O.A., Mishin G.V., Severova T.V., Shuster A.M., Kudlay D.A., Luk’yanov S.V., Borozinets A.Yu. 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. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2013;12(3):29–37. (In Russ.)

4. .Andreeva T.A., Zorenko V.Yu., Davydkin I.L., Konstantinova V.N., Zalepukhina O.E., Klimova N.I., Kurtov I.V., Avdoshina M.S., Gusyakova O.A., Mishin G.V., Severova T.V., Shuster A.M., Kudlay D.A., Luk’yanov S.V., Borozinets A.Yu. Effi ciency 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. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2013;12(4):31–7. (In Russ.)

5. Zorenko V.Yu., Mishin G.V., Severova T.V., Kudlay D.A., Borozinets A.Yu. Pharmacokinetics, safety, and tolerability of Octofactor in patients with hemophilia A: Results of phase I clinical study. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2013;12(2):30–7. (In Russ.)

6. Andreeva T.A., Zorenko V.Yu., Davydkin I.L., Konstantinova V.N., Zalepukhina O.E., Klimova N.I., Mishin G.V., Krechetova A.V., Kurtov I.V., Shamina M.S., Fatenkova E.S., Gusyakova O.A., Shuster A.M., Kudlay D.A., Luk’yanov S.V., Borozinets A.Yu. Effi ciency 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. Voprosy gematologii/ onkologii i immunopatologii v pediatrii = Pediatric Hematology/ Oncology an Immunopathology 2015;14(1):65–75. (In Russ.)

7. Kuznik B.I., Sturov V.G., Levshin N.Yu., Maksimova O.G., Kudlay D.A. Hemorrhagic and thrombotic diseases and syndromes in children and adolescents: Pathogenesis, clinic, diagnosis, therapy and prevention. 2nd ed. Novosibirsk: Nauka Publishing House, 2018. 524 p. (In Russ.)

8. Vorobiev A.I. Hematology Guide: in 3 volumes. Vol. 3. M: Newdiamed, 2005. (In Russ.)

9. Holme P.A., Combescure C., Berntorp E., Moerloose P.D.E., Tait C. A cross-sectional study of comorbidities and hypertension in patients with hemophilia A and B in Europe – interim results from the H3 study. Haemophilia 2014;20(Issue 2):63.

10. Pocoski J., Ma A., Kessler C.M., Boklage S., Humphries T.J. Cardiovascular comorbidities are increased in US patients with haemophilia A: a retrospective database analysis. Haemophilia 2014;20(Issue 4):472–8.

11. Stepanova T.Yu., Kosyakova Yu.A., Gavrilova O.I. Vascular link of the hemostatic system. In: Fundamentals of clinical hemostasiology: monograph; I.L. Davydkin, V.A. Kondurtsev, T.Yu. Stepanova, S.A. Bobylev, eds. Samara, 2009. (In Russ.)

12. Krupatkin A.I., Sidorov V.V. Laser Doppler flowmetry of blood microcirculation: a manual for doctors. M.: Meditsina, 2005. (In Russ.)

13. Mikhaylichenko L.A. Endothelial component in the mechanisms of regulation of vascular tone of paired formations according to laser Doppler flowmetry. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation 2008;4(28):71–80. (In Russ.)

14. Tyurenkov I.N., Voronkov A.V., Petrova E.V., Sliecans A.A., Robertus A.I., Volotova E.V. Comparative evaluation of vasodilating endothelial function in pathologies of various origins. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation 2011;4(40):87–90. (In Russ.)

15. Tikhonova I.V., Tankanag A.V., Chemeris N.K. The dynamics of the amplitudes of fluctuations in peripheral blood flow in the development of post-occlusive reactive hyperemia in healthy volunteers. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation 2009;1(29):31–5. (In Russ.)

16. Mamaev A.N., Kudlay D.A. Data visualization in presentations, reports and studies. М.: Prakticheskaya meditsina, 2011. 39 p. (In Russ.)

17. Kosyakova Yu.A., Davydkin I.L., Gergel N.I. Determination of pathogenetic variants of hemophilic arthropathy using a functional assessment of microcirculation. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation 2017;2(62):44–9. (In Russ.)

18. Al-Nuvayirah A.A., Tyrenkov V.V., Kachnov V.A., Koltsov A.V. Study of endothelial function in patients with gout in combination with metabolic syndrome. Regionarnoye krovoobrashcheniye i mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation 2011;1(37):53–8. (In Russ.)

19. Antonova L.V., Matveeva V.G., Panasenko A.V., Golovkin A.S., Artymuk N.V., Trishkin A.G., Bikmetova E.S. Change in proliferative activity and viability of human endothelial cells during hypoxia and further reoxygenation. Fundamental’nyye issledovaniya = Basic Research 2012;7-2:273–7. (In Russ.)