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Свертывание крови в XXI веке: новые знания, методы и перспективы для терапии

https://doi.org/10.24287/1726-1708-2020-19-1-139-157

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Аннотация

Нарушения в системе свертывания крови – лидирующая причина смертности и инвалидности в современном мире. В связи с этим как никогда актуальным становится поиск новых препаратов, способных предотвращать патологическое тромбообразование, не влияя при этом на нормальный гемостаз. Исследования последних десятилетий произвели переворот в понимании принципов работы и регуляции свертывания крови. Кроме того, появились новые, более эффективные подходы к разработке лекарств, в том числе методы компьютерного моделирования, позволяющие значительно сократить затраты времени и ресурсов на поиск новых молекул-кандидатов. В данном обзоре рассмотрены система свертывания крови, природа тромбоза, показана важная роль факторов Xa и XIa и причины, по которым их все чаще выбирают в качестве мишеней для разработки новых антикоагулянтов, а также представлены наиболее интересные из уже существующих ингибиторов, факторов свертывания Xa и XIa.

Об авторах

Н. А. Подоплелова
ФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России; ФГБУН «Центр теоретических проблем физико-химической фармакологии» РАН
Россия


В. Б. Сулимов
Научно-исследовательский вычислительный центр ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»; ООО «Димонта»
Россия


А. С. Тащилова
Научно-исследовательский вычислительный центр ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»; ООО «Димонта»
Россия


И. С. Ильин
Научно-исследовательский вычислительный центр ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»; ООО «Димонта»
Россия


М. А. Пантелеев
ФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России; ФГБУН «Центр теоретических проблем физико-химической фармакологии» РАН; ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»; ФГБОУ ВО «Московский физико-технический институт (государственный университет)»
Россия

д-р физ.-мат. наук, профессор, зав. лабораторией клеточного гемостаза и тромбоза,

117997, Москва, ГСП-7, ул. Саморы Машела, 1 



И. В. Ледeнева
ФГБОУ ВО «Воронежский государственный университет»
Россия


Х. С. Шихалиев
ФГБОУ ВО «Воронежский государственный университет»
Россия


Список литературы

1. Macfarlane R.G. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 1964; 202: 498–99.

2. Matafonov A., Cheng Q., Geng Y., Verhamme I.M., Umunakwe O., Tucker E.I., et al. Evidence for factor IX-independent roles for factor XIa in blood coagulation. J Thromb Haemost 2013; 11: 2118–27.

3. Zakharova N.V., Artemenko E.O., Podoplelova N.A., Sveshnikova A.N., Demina I.A., Ataullakhanov F.I., et al. Platelet surface-associated activation and secretion-mediated inhibition of coagulation factor XII. PLoS One 2015; 10: e0116665.

4. Meijers J.C.M. Feedback controversy stops here. Blood 2009; 114: 235.

5. Gailani D., Bane C.E., Gruber A. Factor XI and contact activation as targets for antithrombotic therapy. J Thromb Haemost 2015; 13: 1383–95.

6. Panteleev M.A., Dashkevich N.M., Ataullakhanov F.I. Hemostasis and thrombosis beyond biochemistry: Roles of geometry, flow and diffusion. Thromb Res 2015; 136: 699–711.

7. Panteleev M.A., Ovanesov M.V., Kireev D.A., Shibeko A.M., Sinauridze E.I., Ananyeva N.M., et al. Spatial propagation and localization of blood coagulation are regulated by intrinsic and protein C pathways, respectively. Biophys J 2006; 90: 1489–500.

8. Dashkevich N.M., Ovanesov M.V., Balandina A.N., Karamzin S.S., Shestakov P.I., Soshitova N.P., et al. Thrombin activity propagates in space during blood coagulation as an excitation wave. Biophys J 2012; 103: 2233–40.

9. Sinauridze E.I., Panteleev M.A., Ataullakhanov F.I. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis 2012; 23: 482–93.

10. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914–18.

11. Shibeko A.M., Lobanova E.S., Panteleev M.A., Ataullakhanov F.I. Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa. BMC Syst Biol 2010; 4: 5.

12. Tokarev A.A., Butylin A.A., Ataullakhanov F.I. Platelet Adhesion from Shear Blood Flow Is Controlled by Near-Wall Rebounding Collisions with Erythrocytes. Biophys J 2011; 100: 799–808.

13. Sveshnikova A.N., Balatskiy A.V., Demianova A.S., Shepelyuk T.O., Shakhidzhanov S.S., Balatskaya M.N., et al. Systems biology insights into the meaning of the platelet’s dual-receptor thrombin signaling. J Thromb Haemost 2016; 14: 2045–57.

14. Podoplelova N.A., Sveshnikova A.N., Kotova Y.N., Eckly A., Receveur N., Nechipurenko D.Y., et al. Blood coagulation factors bound to procoagulant platelets are concentrated in their cap structures to promote clotting. Blood 2016; 128: 1745–56.

15. Podoplelova N.A., Sveshnikova A.N., Kurasawa J.H., Sarafanov A.G., Chambost H., Vasil’ev S.A., et al. Hysteresis-like binding of coagulation factors X/Xa to procoagulant activated platelets and phospholipids results from multistep association and membrane-dependent multimerization. Biochim Biophys Acta 2016; 1858: 1216–27.

16. Panteleev M.A., Ananyeva N.M., Greco N.J., Ataullakhanov F.I., Saenko E.L. Two subpopulations of thrombin-activated platelets differ in their binding of the components of the intrinsic factor X-activating complex. J Thromb Haemost 2005; 3: 2545–53.

17. Davì G., Patrono C. Platelet Activation and Atherothrombosis. N Engl J Med 2007; 357: 2482–94.

18. Bonaca M.P., Bhatt D.L., Steg P.G., Storey R.F., Cohen M., Im K., et al. Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y 12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54. Eur Heart J 2016; 37: 1133–42.

19. Hiatt W.R., Fowkes F.G.R., Heizer G., Berger J.S., Baumgartner I., Held P., et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N Engl J Med 2017; 376: 32–40.

20. Rothberg M.B., Celestin C., Fiore L.D., Lawler E., Cook J.R. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143: 241–50.

21. Mega J.L., Braunwald E., Wiviott S.D., Bassand J.-P., Bhatt D.L., Bode C., et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9–19.

22. Virchov R.L.K. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. Frankfurt am Main: 1856.

23. Friedman M.H., Brinkman A.M., Qin J.J., Seed W.A. Relation between coronary artery geometry and the distribution of early sudanophilic lesions. Atherosclerosis 1993; 98: 193–9.

24. von Brühl M.-L., Stark K., Steinhart A., Chandraratne S., Konrad I., Lorenz M., et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819–35.

25. Swystun L.L., Liaw P.C. The role of leukocytes in thrombosis. Blood 2016; 128: 753–62.

26. Moosbauer C., Morgenstern E., Cuvelier S.L., Manukyan D., Bidzhekov K., Albrecht S., et al. Eosinophils are a major intravascular location for tissue factor storage and exposure. Blood 2007; 109: 995–1002.

27. Uderhardt S., Ackermann J.A., Fillep T., Hammond V.J., Willeit J., Santer P., et al. Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. J Exp Med 2017; 214: 2121–38.

28. Longstaff C., Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13: S98–105.

29. Longstaff C., Varjú I., Sótonyi P., Szabó L., Krumrey M., Hoell A., et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem 2013; 288: 6946–56.

30. Reimers R.C., Sutera S.P., Joist J.H. Potentiation by red blood cells of shear-induced platelet aggregation: relative importance of chemical and physical mechanisms. Blood 1984; 64: 1200–6.

31. Goel M.S., Diamond S.L. Adhesion of normal erythrocytes at depressed venous shear rates to activated neutrophils, activated platelets, and fibrin polymerized from plasma. Blood 2002; 100: 3797–803.

32. Whelihan M.F., Lim M.Y., Mooberry M.J., Piegore M.G., Ilich A., Wogu A., et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost 2016; 14: 1941–52.

33. Kwaan H.C. Microvascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 2011; 37: 961–78.

34. Levi M., Schultz M., van der Poll T. Sepsis and thrombosis. Semin. Thromb. Hemost 2013; 39: 559–66.

35. May F., Krupka J., Fries M., Thielmann I., Pragst I., Weimer T., et al. FXIIa inhibitor rHA-Infestin-4: Safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis. Br J Haematol 2016; 173: 769–78.

36. Larsson M., Rayzman V., Nolte M.W., Nickel K.F., Björkqvist J., Jämsä A., et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6: 222ra17.

37. David T., Kim Y.C., Ely L.K., Rondon I., Gao H., O’Brien P., et al. Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis. Sci Transl Med 2016; 8: 353ra112.

38. Büller H.R., Bethune C., Bhanot S., Gailani D., Monia B.P., Raskob G.E., et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372: 232–40.

39. Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., et al. The Protein Data Bank. Nucleic Acids Res 2000; 28: 235–42.

40. Садовничий В.А., Сулимов В.Б. Суперкомпьютерные технологии в медицине. Суперкомпьютерные технологии в науке, образовании и промышленности. – М.: Изд-во Московского университета 2009; 1: 16–23.

41. Gupta M., Sharma R., Kumar A. Docking techniques in pharmacology: How much promising? Comput Biol Chem 2018; 76: 210–17.

42. Сулимов В.Б., Сулимов А.В. Докинг: молекулярное моделирование для разработки лекарств. – М.: ИИнтелл, 2017.

43. Сулимов А.В., Кутов Д.К., Каткова Е.В., Кондакова О.А., Сулимов В.Б. Поиск подходов к улучшению точности расчетов энергии связывания белок-лиганд с помощью докинга. Известия Академии наук. Серия химическая 2017: 1913–24.

44. Chen Y.C. Beware of docking! Trends Pharmacol Sci 2015; 36: 78–95.

45. Yuriev E., Holien J., Ramsland P.A. Improvements, trends, and new ideas in molecular docking: 2012–2013 in review. J Mol Recognit 2015; 28: 581–604.

46. Pagadala N.S., Syed K., Tuszynski J. Software for molecular docking: a review. Biophys Rev 2017; 9: 91–102.

47. Sulimov V.B., Kutov D.C., Sulimov A.V. Advances in Docking. Curr Med Chem 2019; 26: 1–25.

48. Сулимов А.В., Кутов Д.К., Тащилова А.С., Ильин И.С., Подоплелова Н.А. Пантелеев М.А. и др. Современные методы разработки новых лекарственных средств, влияющих на систему гемостаза. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2019; 18: 136–52.

49. Sulimov A.V., Kutov D.C., Oferkin I.V., Katkova E.V., Sulimov V.B. Application of the docking program SOL for CSAR benchmark. J Chem Inf Model 2013; 53: 1946–56.

50. Patel N.R., Patel D.V., Murumkar P.R., Yadav M.R. Contemporary developments in the discovery of selective factor Xa inhibitors: A review. Eur J Med Chem 2016; 121: 671–98.

51. Кабанкин А.С., Синауридзе Е.И., Липец Е.Н., Атауллаханов Ф.И. Компьютерный дизайн низкомолекулярных ингибиторов факторов системы свертывания крови. Биохимия 2019; 84: 191–211.

52. Lagos C.F., Segovia G.F., Nuñez-Navarro N., Faúndez M.A., Zacconi F.C. Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches. Molecules 2017; 22: 1588.

53. Pu Y., Liu H., Zhou Y., Peng J., Li Y., Li P., et al. In silico Discovery of Novel FXa Inhibitors by Pharmacophore Modeling and Molecular Docking. Nat Products Bioprospect 2017; 7: 249–56.

54. Xing J., Yang L., Li H., Li Q., Zhao L., Wang X., et al. Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation. Eur J Med Chem 2015; 95: 388–99.

55. Sulimov V.B., Gribkova I.V., Kochugaeva M.P., Katkova E.V., Sulimov A.V., Kutov D.C., et al. Application of Molecular Modeling to Development of New Factor Xa Inhibitors. Biomed Res Int 2015; 2015: 120802.

56. Ilin I., Lipets E., Sulimov A., Kutov D., Shikhaliev K., Potapov A., et al. New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling. J Mol Graph Model 2019; 89: 215–24.

57. Levy J.H., Douketis J., Weitz J.I. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 2018; 15: 273–81.

58. Quan M.L., Wong P.C., Wang C., Woerner F., Smallheer J.M., Barbera F.A., et al. Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors. J Med Chem 2014; 57: 955–69.

59. Wong P.C., Quan M.L., Watson C.A., Crain E.J., Harpel M.R., Rendina A.R., et al. In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa. J Thromb Thrombolysis 2015; 40: 416–23.

60. Pinto D.J.P., Orwat M.J., Smith L.M., Quan M.L., Lam P.Y.S., Rossi K.A., et al. Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212). J Med Chem 2017; 60: 9703–23.

61. Fjellström O., Akkaya S., Beisel H.-G., Eriksson P.-O., Erixon K., Gustafsson D., et al. Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design. PLoS One 2015; 10: e0113705.

62. Pinto D.J.P., Smallheer J.M., Corte J.R., Austin E.J.D., Wang C., Fang T., et al. Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Bioorg Med Chem Lett 2015; 25: 1635–42.

63. Hu Z., Wang C., Han W., Rossi K.A., Bozarth J.M., Wu Y., et al. Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors. Bioorg Med Chem Lett 2018; 28: 987–92.

64. Corte J.R., Fang T., Hangeland J.J., Friends T.J., Rendina A.R., Luettgen J.M., et al. Pyridine and pyridinone-based factor XIa inhibitors. Bioorg Med Chem Lett 2015; 25: 925–30.

65. Corte J.R., Fang T., Pinto D.J.P., Orwat M.J., Rendina A.R., Luettgen J.M., et al. Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group. Bioorg Med Chem 2016; 24: 2257–72.

66. Smith L.M., Orwat M.J., Hu Z., Han W., Wang C., Rossi K.A., et al. Novel phenylalanine derived diamides as Factor XIa inhibitors. Bioorg Med Chem Lett 2016; 26: 472–8.

67. Buchanan M.S., Carroll A.R., Wessling D., Jobling M., Avery V.M., Davis R.A., et al. Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa. J Med Chem 2008; 51: 3583–7.

68. Obaidullah A.J., Al-Horani R.A. Discovery of Chromen-7-yl Furan-2-Carboxylate as a Potent and Selective Factor XIa Inhibitor. Cardiovasc. Hematol. Agents Med Chem 2017; 15: 40–8.

69. Shi J., Ewing W.R., Nielsen L., Hu Z., Quan M.L. US20170283403A1 – Diamide macrocycles that are fxia inhibitors. 2017.

70. Shi J., Ewing W.R., Pinto D.J.P. WO2017151746A1 – Diamide macrocycles having factor xia inhibiting activity. 2017.

71. Pinto D.J.P., Clarke C.G., Smith I.L.M., Orwat M.J., Jeon Y., Corte J.R. US20160145263A1 – Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors. 2016.

72. Pinto D.J.P., Smallheer J.M., Corte J.R., Hu Z., Cavallaro C.L., Gilligan P.J., et al. US20120270853A1-Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors. 2012.

73. Corte J.R., Gilligan P.J., Wang Y., Yang W., Ewing W.R., Pinto D.J.P. MX2015000919A – Dihydropyridone p1 as factor xia inhibitors. 2015.

74. Quan M.L., Pinto D.J.P., Smallheer J.M., Ewing W.R., Rossi K.A., Luettgen J.M., et al. Factor XIa Inhibitors as New Anticoagulants. J Med Chem 2018; 61: 7425–47.

75. Bane C.E., Gailani D. Factor XI as a target for antithrombotic therapy. Drug Discov Today 2014; 19: 1454–8.

76. Al-Horani R.A., Desai U.R. Factor XIa inhibitors: A review of the patent literature. Expert Opin Ther Pat 2016; 26: 323–45.

77. Al-Horani R.A., Desai U.R. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. J Med Chem 2014; 57: 4805–18.

78. Al-Horani R.A., Gailani D., Desai U.R. Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants. Thromb Res 2015; 136: 379–87.

79. Wong P.C., Crain E.J., Watson C.A., Schumacher W.A. A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits. J Thromb Thrombolysis 2011; 32: 129–37.

80. Hanessian S., Larsson A., Fex T., Knecht W., Blomberg N. Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa. Bioorg Med Chem Lett 2010; 20: 6925–8.

81. Sakai M., Hagio T., Koyama S., Gohda M., Suzuki K., Ono T., et al. Antithrombotic effect of ONO-8610539, a new, potent and selective small molecule factor XIa inhibitor, in a monkey model of arteriovenous shunt. J Thromb Haemost 2015; 13 (Suppl. 2): 230–1.

82. Mori M., Goto T., Shintome M., Toda M., Taga S., Matsushita K., et al. DSR130787, a novel orally-active factor XIA inhibitor with low risk of bleeding: PO173-TUE. J Thromb Haemost 2015; 13 (Suppl. 2): 570–1.

83. Bethune C., Walsh M., Jung B., Yu R., Geary R.S., Bhanot S. Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis. Blood 2017; 130: 1116.

84. Buchmuller A., Wilmen A., Strassburger J., Schmidt M.V., Laux V. The antifactor XIa antibody BAY 1213790 is a novel anticoagulant that shows strong antithrombotic efficacy without an increased risk of bleeding in rabbit models. Res. Pr Thromb Haemost 2017; 1 (Suppl. 1): 355.

85. Cheng Q., Tucker E.I., Pine M.S., Sisler I., Matafonov A., Sun M., et al. A role for factor XIIa–mediated factor XI activation in thrombus formation in vivo. Blood 2010; 116: 3981–9.

86. Lazarova T.I., Jin L., Rynkiewicz M., Gorga J.C., Bibbins F., Meyers H.V., et al. Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa. Bioorg Med Chem Lett 2006; 16: 5022–2.


Для цитирования:


Подоплелова Н.А., Сулимов В.Б., Тащилова А.С., Ильин И.С., Пантелеев М.А., Ледeнева И.В., Шихалиев Х.С. Свертывание крови в XXI веке: новые знания, методы и перспективы для терапии. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2020;19(1):139-157. https://doi.org/10.24287/1726-1708-2020-19-1-139-157

For citation:


Podoplelova N.A., Sulimov V.B., Ilin I.S., Tashilova A.S., Panteleev M.A., Ledeneva I.V., Shikhaliev K.S. Blood coagulation in the 21st century: existing knowledge, current strategies for treatment and perspective. Pediatric Hematology/Oncology and Immunopathology. 2020;19(1):139-157. (In Russ.) https://doi.org/10.24287/1726-1708-2020-19-1-139-157

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ISSN 1726-1708 (Print)
ISSN 2414-9314 (Online)