Uticaj tkivnog aktivatora plazminogena, inhibitora aktivatora plazminogena-1 i trombinom aktiviranog fibrinoliznog inhibitora na rizik od nastanka venske tromboze
Fibrinoliza i venska tromboza
Ključne reči:
fibrinoliza, tromboza dubokih vena, t-PA, PAI-a, TAFI
Sažetak
Cilj: Uloga fibrinoliznog mehanizma u riziku za nastanak venske tromboze i dalje je kontroverzna. Cilj rada bio je da se ispita uticaj tkivnog aktivatora plazminogena (t-PA), inhibitora aktivatora plazminogena-1 (PAI-1) i trombinom aktiviranog fibrinoliznog inibitora (TAFI) na rizik od nastanka prve epizode venske tromboze.
Metode: Istraživanje je obuvatilo 100 ispitanika sa trombozom dubokih vena i 100 ispitanika bez pretodne istorije venske tromboze. Globalna fibrinolizna aktivnost je procenjivana euglobulinskim vremenom lize koaguluma (EVLK). Za određivanje koncentracija t-PA i TAFI korištena je ELISA metoda. Za određivanje koncentracije PAI-1 korišten je metod hromogenog supstrata.
Rezultati: Nije dobijena statistički značajna razlika pri poređenju t-PA i PAI-1 između pacijenata i kontrola. Pacijenti su imali značajno veću koncentraciju TAFI u poređenju sa kontrolama. Analizom relativnog rizika uočeno je trostruko povećanje rizika od venske tromboze povezano sa suprimiranom fibrinoliznom aktivnošću. Osnovni OR bio je 2.70 (95% CI 1.22-5.98) a nakon prilagođavanja za confounding OR je iznosio 3.02 (95% CI 1.26-7.22). Povišene koncentracije TAFI pokazale su uticaj na rizik od nastanka venske tromboze, obizom na osnovni OR od 2.18 (95% CI 1.19-3.99) i prilagođeni OR od 2.25 (95% CI 1.16-4.35), što ukazuje na dvostruko povećanje rizika od nastanka venske tromboze povezano sa povišenom koncentracijom TAFI.
Zaključak: Suprimirana funkcionalnost fibrinoliznog mehanizma trostruko povećava rizik od nastanka tromboze dubokih vena, dok povišen nivo TAFI dvostruko povećava ovaj rizik. Nivo plazminogena, t-PA i PAI-1 nema uticaj na rizik od nastanka venske tromboze.
Reference
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27. Meltzer ME, Lisman T, deGroot PG, et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-a. Blood. 2010; 116:113-21.
28. Folsom AR, Aleksic N, Park E, et al. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol. 2001; 21:611-617.
29. Juan-Vague I, Pyke SD, Alessi MC, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation. 1996; 94:2057-2063.
30. Jenkins GR, Saiffert D, Parmer RJ, et al. Regulation of plasminogen gene expression by interleukin-6. Blood. 1997; 89:2394-2403.
31. Meltzer ME, Doggen CJM, deGroot PG, et al. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood. 2010; 116:529-36.
32. Ridker PM, Vaughan DE, Stampfer MJ, et al. Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator-inhibitor. Circulation. 1992; 85:1822-7.
33. Sartori MT, Wiman B, Vettore S, et al. 4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost. 1998; 80:956-60.
34. Swiatkiewicz A, Jurkowski P, Kotschy M, et al. Level of antitrombin III, protein C, protein S and other selected parameters of coagulation and fibrinolysis in the blood of the patients with reccurent deep venous thrombosis. Med Sci Monit. 2002; 8:CR263-CR268.
35. Bombeli T, Jutzi M, De CE, et al. In patients with deep-vein thrombosis elevated levels of factor VIII correlate only with von Willebrand factor but not other endothelial cell-derived coagulation and fibrinolysis proteins. Blood Coagul Fibrinol. 2002; 13:577-581.
36. van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor (TAFI) and the risk for deep vein thrombosis. Blood. 2000; 95:2855-9.
37. Verdu J, Marco P, Benlloch S, et al. Thrombin activatable fibrinolysis inhibitor (TAFI) polymorphisms and plasma TAFI levels measured with an ELISA insensitive to isoforms in patients with venous thromboembolic disease (VTD). Thromb Haemost. 2006; 95:585-6.
38. Eichinger S, Schonauer V, Weltermann A, et al. Thrombin-activatable fibrinolysis inhibitor and the risk for reccurent venosu thromboembolism. Blood. 2004; 103:3773-6.
39. de Brujine EL. Thrombin Avtivatable Fibrinolysis Inhibitor in Venous and Arterial Thrombosis. PhD Thesis. Erasmus Universiteit Rotterdam 2011.
40. Henry M, Aubert H, Morange PE, et al. Identification of polymorphisms in the promoter and the 3’ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood. 2001; 97:2053–2058.
41. Franco RF, Fagundes MG, Meijers JC, et al. Identification of polymorphisms in the 5’-untranslated region of the tafi gene: relationship with plasma tafi levels and risk of venous thrombosis. Haematologica. 2001; 86:510–517.
42. Martini CH, Branolts A, de Brujine EL, et all. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. BJH. 2006; 134:92-4.
2. Lurie F, Sullivan P. Classification of chronic venous disorders of thw lower limbs. Handbook of Venous and Lymphatic Disorders. CRC Press. 2024. Ch 6.
3. Eck RJ, Hulshof L, Wiersema R, et al. Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: data from two prospective cohort studies. Crit Care. 2021; 25:27.
4. Pastori D, Cormaci VM, Marucci S, et al. A Comprehensive Review of Risk Factors for Venous Tromboembolism: From Epidemiology to Pathopysiology. Int J Mol Sci. 2023; 24:3169.
5. Khialani D, leCessie S, Lijfering WM, et al. The joint effect of genetic risk factors and different types of combined oral contraceptives on venous thrombosis risk. Br J Haematol. 2020; 191:90-97.
6. Zöller B, Svensson PJ, Dahlbäck B, et al. Genetic risk factors for venous thromboembolism. Exp Rev Hematol. 2020; 13(9):971-981.
7. Duffett L. Deep Vein Thrombosis. Ann Intern Med. 2022; 175:129-144.
8. Ward SE, O'Sullivan JM, O'Donnell JS. The relationship between ABO blood group, von Willebrand factor, and primary hhemostasis. Blood. 2020; 136(25):2864-2874.
9. Klemen DN, Feingold PL, Hashimoto B. Mortality risk associated with venous thromboembolism: a systematic review and Bayesian meta-analysis. Lancet. 2020; 7(8):583-593.
10. Khan F, Tritschler T, Kahn SR, et al. Venous thromboembolism. Lancet. 2021; 398(10294):64-77.
11. Mulder FI, Horváth-Puhó N, vanEs HWM, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021; 137(14):1959-1969.
12. Makedonov I, Kahn SR, Galanaud JP, et al. Prevention and Management of the PostThrombotic Syndrome. J Clin Med. 2020; 9:923.
13. Kyrle PA, Eichinger S. Is Virchow's triad complete? Blood. 2009; 114(6):1138-1139.
14 Bagot CN, Arya R. Virchow and his triad: a question of attribution. Brit J Haematol. 2008; 143:180-190.
15. Kwaan HC. The role of Fibrinolytic System in Health and Disease. Int J Mol Sci. 2022; 23:5262.
16. Francini M, Xaffanello M, Manucci PM. Bleeding Disorders in Primary Fibrinolysis. Int J Mol Sci. 2021. 22:7027
17. Keragala CB, Medcalf RL. Plasminogen: an enigmatic zymogen. Blood. 2021; 137(21):2881-2889.
18. Sharma S, Uppal V, Senee HK, et al. Assessment of fibrinolytic markers in patients with deep vein thrombosis. Blood Coagul Fibrinol. 2022; 33(2):113-118.
19. Vilar R, Fish RJ, Casini A, et al. Fibrin(ogen) in human disease: both friend and foe. Haematologica. 2020; 105(2):284-296.
20. Sillen M, Decklerck PJ. Trombin Activatable Fibrinolysis Inhibitor (TAFI): An Updated Narrative Review. Int J Mol Sci. 2021; 22:3670.
21. Memtsas VP, Arachchillage DRJ, Gorog DA. Role, Laboratory Assessment and Clinical Relevance of Fibrin, Factor XIII and Endogenous Fibrinolysis in Arterial and Venous Thrombosis. Int J Mol Sci. 2021;22:1472.
22. Kanji R, Kubica J, Navarese EP, et al. Endogenous fibrinolysis-Relevance to clinical thrombosis risk assessment. Eur J Clin Invest. 2021;51:e13471.
23. Prins MH, Hirsh J. A critical review of the evidence supporting relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 191; 151:1721-1731.
24. Crowther MA, Roberts J, Roberts R, et al. Fibrinolytic variables in patients with reccurent venous thrombosis: a prospective cohort study. Thromb Haemost. 2001; 85:390-394.
25. Meltzer ME, Lisman T, Doggen CJ, et al. Synergistic effects of hypofibrinolysis and genetic and acquired risk factors on the risk of a first venous thrombosis. PLoS Med 2008; 5:e97.
26. Okamoto A, Sakata T, Mannami T, et al. Population-based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study. J Thromb Haemost. 2003; 1:2397-403.
27. Meltzer ME, Lisman T, deGroot PG, et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-a. Blood. 2010; 116:113-21.
28. Folsom AR, Aleksic N, Park E, et al. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol. 2001; 21:611-617.
29. Juan-Vague I, Pyke SD, Alessi MC, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation. 1996; 94:2057-2063.
30. Jenkins GR, Saiffert D, Parmer RJ, et al. Regulation of plasminogen gene expression by interleukin-6. Blood. 1997; 89:2394-2403.
31. Meltzer ME, Doggen CJM, deGroot PG, et al. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood. 2010; 116:529-36.
32. Ridker PM, Vaughan DE, Stampfer MJ, et al. Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator-inhibitor. Circulation. 1992; 85:1822-7.
33. Sartori MT, Wiman B, Vettore S, et al. 4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost. 1998; 80:956-60.
34. Swiatkiewicz A, Jurkowski P, Kotschy M, et al. Level of antitrombin III, protein C, protein S and other selected parameters of coagulation and fibrinolysis in the blood of the patients with reccurent deep venous thrombosis. Med Sci Monit. 2002; 8:CR263-CR268.
35. Bombeli T, Jutzi M, De CE, et al. In patients with deep-vein thrombosis elevated levels of factor VIII correlate only with von Willebrand factor but not other endothelial cell-derived coagulation and fibrinolysis proteins. Blood Coagul Fibrinol. 2002; 13:577-581.
36. van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor (TAFI) and the risk for deep vein thrombosis. Blood. 2000; 95:2855-9.
37. Verdu J, Marco P, Benlloch S, et al. Thrombin activatable fibrinolysis inhibitor (TAFI) polymorphisms and plasma TAFI levels measured with an ELISA insensitive to isoforms in patients with venous thromboembolic disease (VTD). Thromb Haemost. 2006; 95:585-6.
38. Eichinger S, Schonauer V, Weltermann A, et al. Thrombin-activatable fibrinolysis inhibitor and the risk for reccurent venosu thromboembolism. Blood. 2004; 103:3773-6.
39. de Brujine EL. Thrombin Avtivatable Fibrinolysis Inhibitor in Venous and Arterial Thrombosis. PhD Thesis. Erasmus Universiteit Rotterdam 2011.
40. Henry M, Aubert H, Morange PE, et al. Identification of polymorphisms in the promoter and the 3’ region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood. 2001; 97:2053–2058.
41. Franco RF, Fagundes MG, Meijers JC, et al. Identification of polymorphisms in the 5’-untranslated region of the tafi gene: relationship with plasma tafi levels and risk of venous thrombosis. Haematologica. 2001; 86:510–517.
42. Martini CH, Branolts A, de Brujine EL, et all. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. BJH. 2006; 134:92-4.
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