Современные представления о системе фибринолиза и методах диагностики ее нарушений

Фибринолиз - важный биохимический процесс, отвечающий за разрушение фибриновых сгустков, образующихся в результате работы системы свертывания. Сбои в работе системы фибринолиза могут приводить к состояниям, угрожающим жизни, - тромбозам и неконтролируемым кровотечениям. Наблюдается стремительный прогресс в понимании молекулярных механизмов работы системы фибринолиза, детально описаны все основные участники и реакции процесса, тем не менее вопросы регуляции и оценки состояния системы фибринолиза изучены слабо. В данном обзоре представлен анализ накопленной информации о работе системы фибринолиза и сопутствующей патологии. Подробно рассмотрены методы оценки и диагностики состояния системы фибринолиза.

фибринолиз, свертывание крови, плазмин, методы исследования фибринолиза

1. Meltzer M.E., Doggen C.J., de Groot P.G., Rosendaal F.R., Lisman T. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Hemost. 2009;35(5):468-477.

2. Gorog D.A. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol. 2010;55(24):2701-2709.

3. Chesebro J.H., Knatterud G., Roberts R., Borer J., Cohen L.S., Dalen J. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;76(1):142-154.

4. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970;214(12):2163-2172.

5. Meneveau N., Schiele F., Vuillemenot A., Valette B., Grollier G., Bernard Y. et al. Streptokinase vs alteplase in massive pulmonary embolism. A randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J. 1997;18(7):1141-1148.

6. Heemskerk J.W., Bevers E.M., Lindhout T. Platelet activation and blood coagulation. Thromb Haemost. 2002;88(2):186-193.

7. Carson S.D., Brozna J.P. The role of tissue factor in the production of thrombin. Blood Coagul Fibrinolysis. 1993;4(2):281-292.

8. Morrison S.A., Jesty J. Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma. Blood. 1984;63(6):1338-1347.

9. van Dieijen G., Tans G., Rosing J., Hemker H.C. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem. 1981;256(7):3433-3442.

10. Wu J.R., Zhou C., Majumder R., Powers D.D., Weinreb G., Lentz B.R. Role of procoagulant lipids in human prothrombin activation. 1. Prothrombin activation by factor X(a) in the absence of factor V(a) and in the absence and presence of membranes. Biochemistry. 2002;41(3):935-949.

11. Monkovic D.D., Tracy P.B. Activation of human factor V by factor Xa and thrombin. Biochemistry. 1990;29(5):1118-1128.

12. Lollar P., Knutson G.J., Fass D.N. Activation of porcine factor VIII:C by thrombin and factor Xa. Biochemistry. 1985;24(27):8056-8064.

13. Mathur A., Zhong D., Sabharwal A.K., Smith K.J., Bajaj S.P. Interaction of factor IXa with factor VIIIa. Effects of protease domain Ca2+ binding site, proteolysis in the autolysis loop, phospholipid, and factor X. J Biol Chem. 1997;272(37):23418-23426.

14. Weisel J.W., Litvinov R.I. Mechanisms of fibrin polymerization and clinical implications. Blood. 2013;121(10):1712-1719.

15. Rijken D.C. Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator. J Biol Chem. 1982;257(6):2920-2925.

16. Bajzar L., Manuel R., Nesheim M.E. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1995;270(24):14477-14484.

17. Levin E.G., Marzec U., Anderson J., Harker L.A. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest. 1984;74(6):1988-1995.

18. Sidelmann J.J., Gram J., Jespersen J., Kluft C. Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost. 2000;26(6):605-618.

19. Muszbek L., Bereczky Z., Bagoly Z., Komaromi I., Katona E. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011;91(3):931-972.

20. Samis J.A., Ramsey G.D., Walker J.B., Nesheim M.E., Giles A.R. Proteolytic processing of human coagulation factor IX by plasmin. Blood. 2000;95(3):943-951.

21. Prins M.H., Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med. 1991;151(9):1721-1731.

22. Reed G.L., Matsueda G.R., Haber E. Platelet factor XIII increases the fibrinolytic resistance of platelet-rich clots by accelerating the crosslinking of alpha 2-antiplasmin to fibrin. Thromb Haemost. 1992;68(3):315-320.

23. Di Stasio E., Nagaswami C., Weisel J.W., Di Cera E. Cl-regulates the structure of the fibrin clot. Biophys J. 1998;75(4):1973-1979.

24. Bates S.M. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Hemost. 2012;38(7):673-682.

25. Di Nisio M., Squizzato A., Rutjes A.W., Buller H.R., Zwinderman A.H., Bossuyt P.M. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost. 2007;5(2):296-304.

26. Bates S.M., Jaeschke R., Stevens S.M., Goodacre S., Wells P.S., Stevenson M.D. et al. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):418.

27. Collen D., de Maeyer L. Molecular biology of human plasminogen. I. Physiochemical properties and microheterogeneity. Thromb Diath Haemorrh. 1975;34(2):396-402.

28. Drew A.F., Kaufman A.H., Kombrinck K.W., Danton M.J., Daugherty C.C., Degen J.L. et al. Ligneous conjunctivitis in plasminogen-deficient mice. Blood. 1998;91(5):1616-1624.

29. Brandt J.T. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med. 2002;126(11):1376-1381.

30. Schuster V., Hugle B., Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12):2315-2322.

31. Tait R.C., Walker I.D., Conkie J.А., Islam S.I., McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb Haemost. 1996;76(6):1004-1008.

32. Tefs K., Gueorguieva M., Klammt J., Allen C.M., Aktas D., Anlar F.Y. еt аl. Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients. Blood. 2006;108(9):3021-3026.

33. Stalder M., Hauert J., Kruithof E.K., Bachmann F. Release of vascular plasminogen activator (v-PA) after venous stasis: electrophoretic-zymographic analysis of free and complexed v-PA. Br J Haematol. 1985;61(1):169-176.

34. Madison E.L., Goldsmith E.J., Gerard R.D., Gething M.J., Sambrook J.F. Serpin-resistant mutants of human tissue-type plasminogen activator. Nature. 1989;339(6227):721-724.

35. Paoni N.F. A slow clearing, fibrin-specific, PAI-1 resistant variant of tPA (T103N, KHRR 296-299 AAAA). Thromb Haemost. 1993;70(2):307-312.

36. Kooistra T., Opdenberg J.P., Toet K., Hendriks H.F., van den Hoogen R.M., Emeis J.J. Stimulation of tissue-type plasminogen activator synthesis by retinoids in cultured human endothelial cells and rat tissues in vivo. Thromb Haemost. 1991;65(5):565-572.

37. Medh R.D., Santell L., Levin E.G. Stimulation of tissue plasminogen activator production by retinoic acid: synergistic effect on protein kinase C-mediated activation. Blood. 1992;80(4):981-987.

38. Tanswell P., Seifried E., Su P.C., Feuerer W., Rijken D.C. Pharmacokinetics and systemic effects of tissue-type plasminogen activator in normal subjects. Clin Pharmacol Ther. 1989;46(2):155-162.

39. Carmeliet P., Schoonjans L., Kieckens L., Ream B., Degen J., Bronson R. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368(6470):419-424.

40. Meltzer M.E., Doggen C.J., de Groot P.G., Rosendaal F.R., Lisman T. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Hemost. 2009;35(5):468-477.

41. Meltzer M.E., Doggen C.J., de Groot P.G., Rosendaal F.R., Lisman T. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood. 2010;116(4):529-536.

42. Grimaudo V., Hauert J., Bachmann F., Kruithof E.K. Diurnal variation of the fibrinolytic system. Thromb Haemost. 1988;59(3):495-499.

43. Smith A., Patterson C., Yarnell J., Rumley A., Ben-Shlomo Y., Lowe G. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study. Circulation. 2005;112(20):3080-3087.

44. Folsom A.R., Aleksic N., Park E., Salomaa V., Juneja H., Wu K.K. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol. 2001;21(4):611-617.

45. Meltzer M.E., Lisman T., de Groot P.G., Meijers J.C., le Cessie S., Doggen C.J. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood. 2010;116(1):113-121.

46. Husain S.S., Gurewich V., Lipinski B. Purification and partial characterization of a single-chain high-molecular-weight form of urokinase from human urine. Arch Biochem Biophys. 1983;220(1):31-38.

47. Dano K., Andreasen P.A., Grondahl-Hansen J., Kristensen P., Nielsen L.S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139-266.

48. Pannell R., Gurewich V. Activation of plasminogen by single-chain urokinase or by two-chain urokinase-a demonstration that single-chain urokinase has a low catalytic activity (pro-urokinase). Blood. 1987;69(1):22-26.

49. van der Kaaden M.E. Plasma clearance of urokinase-type plasminogen activator. Fibrinolysis Proteolysis. 1998;12:251-258.

50. Manchanda N., Schwartz B.S. Single chain urokinase. Augmentation of enzymatic activity upon binding to monocytes. J Biol Chem. 1991;266(22):14580-14584.

51. McGuinness C.L., Humphries J., Waltham M., Burnand K.G., Collins M., Smith A. Recruitment of labelled monocytes by experimental venous thrombi. Thromb Haemost. 2001;85(6):1018-1024.

52. Carmeliet P. Targeted gene manipulation and transfer of the plasminogen and coagulation systems in mice. Fibrinolysis. 1996;10:195-213.

53. Carmeliet P. Urokinase but not tissue type plasminogen activator mediates arterial neointima formation in mice. Circ Res. 1997;81:829-839.

54. Deindl E., Ziegelhoffer T., Kanse S.M., Fernandez B., Neubauer E., Carmeliet P. et al. Receptor-independent role of the urokinase-type plasminogen activator during arteriogenesis. FASEB J. 2003;17(9):1174-1176.

55. Nicoloso G., Hauert J., Kruithof E.K., van Melle G., Bachmann F. Fibrinolysis in normal subjects - comparison between plasminogen activator inhibitor and other components of the fibrinolytic system. Thromb Haemost. 1988;59(2):299-303.

56. Hekman C.M., Loskutoff D.J. Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem. 1985;260(21):11581-11587.

57. Konkle B.A., Schick P.K., He X., Liu R.J., Mazur E.M. Plasminogen activator inhibitor-1 mRNA is expressed in platelets and megakaryocytes and the megakaryoblastic cell line CHRF-288. Arterioscler Thromb. 1993;13(5):669-674.

58. van Mourik J.A., Lawrence D.A., Loskutoff D.J. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem. 1984;259(23):14914-14921.

59. Cwikel B.J., Barouski-Miller P.A., Coleman P.L., Gelehrter T.D. Dexamethasone induction of an inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem. 1984;259(11):6847-6851.

60. Robbie L.A., Bennett B., Croll A.M., Brown P..A, Booth N.A. Proteins of the fibrinolytic system in human thrombi. Thromb Haemost. 1996;75(1):127-133.

61. Dieval J., Nguyen G., Gross S., Delobel J., Kruithof E.K. A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1. Blood. 1991;77(3):528-532.

62. Lee M.H., Vosburgh E., Anderson K., McDonagh J. Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. Blood. 1993;81(9):2357-2362.

63. Vaughan D.E. Plasminogen activator inhibitor-1: a common denominator in cardiovascular disease. J Investig Med. 1998;46(8):370-376.

64. Carroll V.A., Binder B.R. The role of the plasminogen activation system in cancer. Semin Thromb Hemost. 1999;25(2):183-197.

65. Scarabin P.Y., Aillaud M.F., Amouyel .P, Evans A., Luc G., Ferrieres J. et al. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction-the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost. 1998;80(5):749-756.

66. Kawano T., Morimoto K., Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta. J Biochem. 1970;67(3):333-342.

67. Risse B.C., Brown H., Lavker R.M., Pearson J.M., Baker M.S., Ginsburg D. et al. Differentiating cells of murine stratified squamous epithelia constitutively express plasminogen activator inhibitor type 2 (PAI-2). Histochem Cell Biol. 1998;110(6):559-569.

68. Kruithof E.K., Tran-Thang C., Gudinchet A., Hauert J., Nicoloso G., Genton C. et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69(2):460-466.

69. Scherrer A., Kruithof E.K., Grob J.P. Plasminogen activator inhibitor-2 in patients with monocytic leukemia. Leukemia. 1991;5(6):479-486.

70. Robbie L.A., Dummer S., Booth N.A., Adey G.D., Bennett B.Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br J Haematol. 2000;109(2):342-348.

71. Torr-Brown S.R., Sobel B.E. Attenuation of thrombolysis by release of plasminogen activator inhibitor type-1 from platelets. Thromb Res. 1993;72(5):413-421.

72. Cushman M., Lemaitre R.N., Kuller L.H., Psaty B.M., Macy E.M., Sharrett A.R. et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 1999;19(3):493-498.

73. Mast A.E., Enghild J.J., Pizzo S.V., Salvesen G. Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry. 1991;30(6):1723-1730.

74. Collen D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb Haemost. 1980;43(2):77-89.

75. Ostrowski S.R., Sorensen A.M., Larsen C.F., Johansson P.I. Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study. Scand J Trauma Resusc Emerg Med. 2011;19:64.

76. Favaloro E.J. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost. 2010;36(4):458-467.

77. Breen K.A., Grimwade D., Hunt B.J. The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia. Br J Haematol. 2012;156(1):24-36.

78. Sakurai Y., Takahashi T. Trypsin-like endopeptidase(s) naturally entrapped in human blood < 2-macroglobulin. Biomed Res. 1996;17:347-350.

79. Nesheim M. Fibrinolysis and the plasma carboxypeptidase. Curr Opin Hematol. 1998;5(5):309-313.

80. Stromqvist M., Schatteman K., Leurs J., Verkerk R., Andersson J.O., Johansson T. еt al. Immunological assay for the determination of procarboxypeptidase U antigen levels in human plasma. Thromb Haemost. 2001;85(1):12-17.

81. Bajzar L., Nesheim M., Morser J., Tracy P.B. Both cellular and soluble forms of thrombomodulin inhibit fibrinolysis by potentiating the activation of thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1998;273(5):2792-2798.

82. Silveira A., Schatteman K., Goossens F., Moor E., Scharpe S., Stromqvist M. еt al. Plasma procarboxypeptidase U in men with symptomatic coronary artery disease. Thromb Haemost. 2000;84(3):364-368.

83. van Tilburg N.H., Rosendaal F.R., Bertina R.M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood. 2000;95(9):2855-2859.

84. Heylen E., Willemse J., Hendriks D. An update on the role of carboxypeptidase U (TAFIa) in fibrinolysis. Front Biosci (Landmark Ed). 2011;16:2427-2450.

85. Osterud B., Laake K., Prydz H. The activation of human factor IX. Thromb Diath Haemorrh. 1975;33(3):553-563.

86. Lee C.D., Mann K.G. Activation/inactivation of human factor V by plasmin. Blood. 1989;73(1):185-190.

87. Rick M.E., Krizek D.M. Platelets modulate the proteolysis of factor VIII:C protein by plasmin. Blood. 1986;67(6):1649-1654.

88. Myles T., Nishimura T., Yun T.H., Nagashima M., Morser .J, Patterson A.J. еt al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem. 2003;278(51):51059-51067.

89. Plow E.F., Ploplis V.A., Busuttil S., Carmeliet P., Collen D. A role of plasminogen in atherosclerosis and restenosis models in mice. Thromb Haemost. 1999;82 Suppl 1:4-7.

90. Moons L., Shi C., Ploplis V., Plow E., Haber E., Collen D. еt al. Reduced transplant arteriosclerosis in plasminogen-deficient mice. J Clin Invest. 1998;102(10):1788-1797.

91. van Hinsbergh V.W., Kooistra T., Emeis J.J., Koolwijk P. Regulation of plasminogen activator production by endothelial cells: role in fibrinolysis and local proteolysis. Int J Radiat Biol. 1991;60(1-2):261-272.

92. Kowalski E., Kopec M., Niewiarowski. An evaluation of the euglobulin method for the determination of fibrinolysis. J Clin Pathol. 1959;12(3):215-218.

93. Mandle R.J. Jr, Kaplan A.P. Hageman-factor-dependent fibrinolysis: generation of fibrinolytic activity by the interaction of human activated factor XI and plasminogen. Blood. 1979;54(4):850-862.