Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 168-173
Клинические проявления нарушений функций тромбомодулина
https://doi.org/10.24287/1726-1708-2024-23-4-168-173Аннотация
Тромбомодулин (ТМ) обладает многообразием функций: участвует в регуляции гемостатического ответа, играет роль в разнообразных воспалительных реакциях, а также в пролиферации клеток и ангиогенезе. Изучение клинических проявлений нарушений в работе ТМ помогает лучше понять его роль в различных физиологических процессах и предложить новые терапевтические подходы, связанные с его использованием. В данном обзоре мы постарались подойти к этой проблеме со стороны генетических нарушений: здесь представлено описание некоторых патологических мутаций в гене ТМ, а также их клинические проявления. В обзоре также рассмотрен опыт применения ТМ в диагностике и терапии, обсуждаются перспективы его использования для коррекции различных жизнеугрожающих состояний.
Список литературы
1. Amiral J., Seghatchian J. Revisiting the activated protein C-protein S-thrombomodulin ternary pathway: Impact of new understanding on its laboratory investigation. Transfus Apher Sci 2019; 58 (4): 538–44.
2. Marar T.T., Matzko C.N., Wu J., Esmon C.T., Sinno T., Brass L.F., et al. Thrombin spatial distribution determines protein C activation during hemostasis and thrombosis. Blood 2022; 139 (12): 1892–902.
3. Conway E.M. Thrombomodulin and its role in inflammation. Semin Immunopathol 2012; 34 (1): 107–25.
4. Suzuki K. Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C. Nihon Ketsueki Gakkai Zasshi 1988; 51 (8): 1655–64.
5. Watanabe-Kusunoki K., Nakazawa D., Ishizu A., Atsumi T. Thrombomodulin as a Physiological Modulator of Intravascular Injury. Front Immunol 2020; 11: 1–12.
6. Martinod K., Wagner D.D. Thrombosis: Tangled up in NETs. Blood 2014; 123 (18): 2768–76.
7. Abeyama K., Stern D.M., Ito Y., Kawahara K.I., Yoshimoto Y., Tanaka M., et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115 (5): 1267–74.
8. Shi C.S., Shi G.Y., Hsiao S.M., Kao Y.C., Kuo K.L., Chih-Yuan M., et al. Lectin-like domain of thrombomodulin binds to its specific ligand Lewis y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 2008; 112 (9): 3661–70.
9. Wang H., Vinnikov I., Shahzad K., Bock F., Ranjan S., Wolter J., et al. The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. Thromb Haemost 2012; 108(6): 1141–53.
10. Delvaeye M., Noris M., De Vriese A., Esmon C.T., Esmon N.L., Ferrell G., et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N Engl J Med 2009; 361 (4): 345–57.
11. Geudens N., Van De Wouwer M., Vanaudenaerde B.M., Vos R., Van De Wauwer C., Verleden G.M., et al. The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury. Eur Respir J 2008; 32 (4): 862–70.
12. Hemker H.C., Kessels H. Feedback mechanisms in coagulation. Pathophysiol. Haemost Thromb 1991; 21(4): 189–96.
13. Пантелеев М.А., Котова Я.Н., Токарев А.А., Атауллаханов Ф.И. Механизмы регуляции свертывания крови. Терапевтический архив 2008; 80 (7): 88–91.
14. Pozzi N., Barranco-Medina S., Chen Z., Di Cera E. Exposure of R169 controls protein C activation and autoactivation. Blood 2012; 120 (3): 664–70.
15. Kokame K., Zheng X., Sadler J.E. Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomodulin and is inhibited competitively by protein C. J Biol Chem 1998; 273 (20): 12135–9.
16. Kuo C.H., Huang Y.H., Chen P.K., Lee G.H., Tang M.J., Conway E.M., et al. VEGF-Induced Endothelial Podosomes via ROCK2-Dependent Thrombomodulin Expression Initiate Sprouting Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1657–71.
17. Alonso F., Dong Y., Génot E. Thrombomodulin, an Unexpected New Player in Endothelial Cell Invasion During Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1672–4.
18. Langdown J., Luddington R.J., Huntington J.A., Baglin T.P. A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop). Blood 2014; 124 (12): 1951–6.
19. Rehill A.M., Preston R.J.S. A new thrombomodulin-related coagulopathy. J Thromb Haemost 2020; 18 (9): 2123–5.
20. Dargaud Y., Scoazec J.Y., Wielders S.J.H., Trzeciak C., Hackeng T.M., Négrier C., et al. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood 2015; 125 (9): 1497–501.
21. Burley K., Whyte C.S., Westbury S.K., Walker M., Stirrups K.E., Turro E., et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood 2016; 128 (14): 1879–83.
22. Morrow G.B., Beavis J., Harper S., Bignell P., Laffan M.A., Curry N. Characterisation of a novel thrombomodulin c.1487delC,p.(Pro496Argfs*10) variant and evaluation of therapeutic strategies to manage the rare bleeding phenotype. Thromb Res 2021; 197: 100–8.
23. Turro E., Astle W.J., Megy K., Gräf S., Greene D., Shamardina O., et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 2020; 583 (7814): 96–102.
24. Osada M., Maruyama K., Kokame K., Denda R., Yamazaki K., Kunieda H., et al. A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder. Blood Adv 2021; 5 (19): 3830–8.
25. Tang L., Wang H.F., Lu X., Jian X.R., Jin B., Zheng H., et al. Common genetic risk factors for venous thrombosis in the chinese population. Am J Hum Genet 2013; 92 (2): 177–87.
26. Razzaq S. Hemolytic uremic syndrome: An emerging health risk. Am Fam Physician 2006; 74 (6): 991–6.
27. Noris M., Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16 (4): 1035–50.
28. Doggen C.J.M., Kunz G., Rosendaal F.R., Lane D.A., Vos H.L., Stubbs P.J., et al. A mutation in the thrombomodulin gene, 127G to a coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost 1998; 80 (5): 743–8.
29. Maga T.K., Nishimura C.J., Weaver A.E., Frees K.L., Smith R.J.H. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 2010; 31 (6): 1445–60.
30. Le Clech A., Simon-Tillaux N., Provôt F., Delmas Y., Vieira-Martins P., Limou S., et al. Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Kidney Int 2019; 95 (6): 1443–52.
31. Matsumoto T., Fan X., Ishikawa E., Ito M., Amano K., Toyoda H., et al. Analysis of patients with atypical hemolytic uremic syndrome treated at the Mie University Hospital: Concentration of C3 p.I1157T mutation. Int J Hematol 2014; 100 (5): 437–42.
32. Zhao W., Ding Y., Lu J., Zhang T., Chen D., Zhang H., et al. Genetic analysis of the complement pathway in C3 glomerulopathy. Nephrol Dial Transplant 2018; 33 (11): 1919– 27.
33. Kunz G., Ireland H.A., Stubbs P.J., Kahan M., Coulton G.C., Lane D.A. Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction. Blood 2000; 95 (2): 569–76.
34. Wu C., Dwivedi D.J., Pepler L., Lysov Z., Waye J., Julian J., et al. Targeted gene sequencing identifies variants in the protein c and endothelial protein c receptor genes in patients with unprovoked venous thromboembolism. Arterioscler Thromb Vasc Biol 2013; 33 (11): 2674–81.
35. Mahmood I., Hamdan F., Al-Tameemi W. Role of endothelial dysfunction in relation to prothrombogenesis in polycythemia vera. Iraqi J Hematol 2018; 7 (1): 8.
36. Page A.V., Liles W.C. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence 2013; 4 (6): 507–16.
37. Salomaa V., Matei C., Aleksic N., Sansores-Garcia L., Folsom A.R., Juneja H., et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: A case-cohort study. Lancet 1999; 353 (9166): 1729–34.
38. Kampoli A.M., Tousoulis D., Antoniades C., Siasos G., Stefanadis C. Biomarkers of premature atherosclerosis. Trends Mol Med 2009; 15 (7): 323–32.
39. Wada H., Mori Y., Shimura M., Hiyoyama K., Ioka M., Nakasaki T., et al. Poor outcome in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with severe vascular endothelial cell injuries. Am J Hematol 1998; 58 (3): 189–94.
40. Lin S.M., Wang Y.M., Lin H.C., Lee K.Y., Huang C. Da, Liu C.Y., et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med 2008; 36 (3): 683–9.
41. Mori Y., Wada H., Okugawa Y., Tamaki S., Nakasaki T., Watanabe R., et al. Increased Plasma Thrombomodulin as a Vascular Endothelial Cell Marker in Patients With Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome. Clin Appl Thromb 2001; 7 (1): 5–9.
42. Shimizu M., Kuroda M., Inoue N., Konishi M., Igarashi N., Taneichi H., et al. Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine 2014; 66 (1): 1–6.
43. Budzyń M., Iskra M., Turkiewicz W., Krasiński Z., Gryszczyńska B., Kasprzak M.P. Plasma concentration of selected biochemical markers of endothelial dysfunction in women with various severity of chronic venous insufficiency (CVI) – A pilot study. PLoS One 2018; 13 (1): 1–17.
44. Mihajlovic D.M., Lendak D.F., Draskovic B.G., Mikic A.S.N., Mitic G.P., Cebovic T.N., et al. Thrombomodulin is a Strong Predictor of Multiorgan Dysfunction Syndrome in Patients With Sepsis. Clin Appl Thromb 2015; 21 (5): 469–74.
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46. Budzyń M., Gryszczyńska B., Majewski W., Krasiński Z., Kasprzak M.P., Formanowicz D., et al. The association of serum thrombomodulin with endothelial injuring factors in abdominal aortic aneurysm. Biomed Res Int 2017; 2017: 2791082.
47. Folsom A.R., Yao L., Alonso A., Lutsey P.L., Missov E., Lederle F.A., et al. Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence. Circulation 2015; 132 (7): 578–85.
48. Che X.Y., Hao W., Wang Y., Di B., Yin K., Xu Y.C., et al. Nucleocapsid protein as early diagnostic marker for SARS. Emerg Infect Dis 2004; 10 (11): 1947–9.
49. Subirana I., Fitó M., Diaz O., Vila J., Francés A., Delpon E., et al. Prediction of coronary disease incidence by biomarkers of inflammation, oxidation, and metabolism. Sci Rep 2018; 8 (1): 1–7.
50. Lyons T.J., Basu A. Biomarkers in diabetes: Hemoglobin A1c, vascular and tissue markers. Transl Res 2012; 159 (4): 303–12.
51. Arishima T., Ito T., Yasuda T., Yashima N., Furubeppu H., Kamikokuryo C., et al. Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin. Thromb J 2018; 16 (1): 1–7.
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Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 168-173
Clinical manifestations of thrombomodulin dysfunction
https://doi.org/10.24287/1726-1708-2024-23-4-168-173Abstract
Thrombomodulin (TM) performs a wide variety of functions: it is involved in the regulation of hemostatic answer, inflammation, cell proliferation and angiogenesis. Studying clinical manifestations of thrombomodulin dysfunction helps to better understand its role in various physiological processes and develop new treatment strategies involving the use of thrombomodulin. Here, we focused on genetic causes of this problem, describing some pathological mutations in the TM gene as well as their clinical manifestations. We also reported on TM use in disease diagnosis and treatment and discussed the prospects for its application in the management of various life-threatening conditions.
References
1. Amiral J., Seghatchian J. Revisiting the activated protein C-protein S-thrombomodulin ternary pathway: Impact of new understanding on its laboratory investigation. Transfus Apher Sci 2019; 58 (4): 538–44.
2. Marar T.T., Matzko C.N., Wu J., Esmon C.T., Sinno T., Brass L.F., et al. Thrombin spatial distribution determines protein C activation during hemostasis and thrombosis. Blood 2022; 139 (12): 1892–902.
3. Conway E.M. Thrombomodulin and its role in inflammation. Semin Immunopathol 2012; 34 (1): 107–25.
4. Suzuki K. Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C. Nihon Ketsueki Gakkai Zasshi 1988; 51 (8): 1655–64.
5. Watanabe-Kusunoki K., Nakazawa D., Ishizu A., Atsumi T. Thrombomodulin as a Physiological Modulator of Intravascular Injury. Front Immunol 2020; 11: 1–12.
6. Martinod K., Wagner D.D. Thrombosis: Tangled up in NETs. Blood 2014; 123 (18): 2768–76.
7. Abeyama K., Stern D.M., Ito Y., Kawahara K.I., Yoshimoto Y., Tanaka M., et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115 (5): 1267–74.
8. Shi C.S., Shi G.Y., Hsiao S.M., Kao Y.C., Kuo K.L., Chih-Yuan M., et al. Lectin-like domain of thrombomodulin binds to its specific ligand Lewis y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 2008; 112 (9): 3661–70.
9. Wang H., Vinnikov I., Shahzad K., Bock F., Ranjan S., Wolter J., et al. The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. Thromb Haemost 2012; 108(6): 1141–53.
10. Delvaeye M., Noris M., De Vriese A., Esmon C.T., Esmon N.L., Ferrell G., et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N Engl J Med 2009; 361 (4): 345–57.
11. Geudens N., Van De Wouwer M., Vanaudenaerde B.M., Vos R., Van De Wauwer C., Verleden G.M., et al. The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury. Eur Respir J 2008; 32 (4): 862–70.
12. Hemker H.C., Kessels H. Feedback mechanisms in coagulation. Pathophysiol. Haemost Thromb 1991; 21(4): 189–96.
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14. Pozzi N., Barranco-Medina S., Chen Z., Di Cera E. Exposure of R169 controls protein C activation and autoactivation. Blood 2012; 120 (3): 664–70.
15. Kokame K., Zheng X., Sadler J.E. Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomodulin and is inhibited competitively by protein C. J Biol Chem 1998; 273 (20): 12135–9.
16. Kuo C.H., Huang Y.H., Chen P.K., Lee G.H., Tang M.J., Conway E.M., et al. VEGF-Induced Endothelial Podosomes via ROCK2-Dependent Thrombomodulin Expression Initiate Sprouting Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1657–71.
17. Alonso F., Dong Y., Génot E. Thrombomodulin, an Unexpected New Player in Endothelial Cell Invasion During Angiogenesis. Arterioscler Thromb Vasc Biol 2021; 41 (5): 1672–4.
18. Langdown J., Luddington R.J., Huntington J.A., Baglin T.P. A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop). Blood 2014; 124 (12): 1951–6.
19. Rehill A.M., Preston R.J.S. A new thrombomodulin-related coagulopathy. J Thromb Haemost 2020; 18 (9): 2123–5.
20. Dargaud Y., Scoazec J.Y., Wielders S.J.H., Trzeciak C., Hackeng T.M., Négrier C., et al. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood 2015; 125 (9): 1497–501.
21. Burley K., Whyte C.S., Westbury S.K., Walker M., Stirrups K.E., Turro E., et al. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy. Blood 2016; 128 (14): 1879–83.
22. Morrow G.B., Beavis J., Harper S., Bignell P., Laffan M.A., Curry N. Characterisation of a novel thrombomodulin c.1487delC,p.(Pro496Argfs*10) variant and evaluation of therapeutic strategies to manage the rare bleeding phenotype. Thromb Res 2021; 197: 100–8.
23. Turro E., Astle W.J., Megy K., Gräf S., Greene D., Shamardina O., et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 2020; 583 (7814): 96–102.
24. Osada M., Maruyama K., Kokame K., Denda R., Yamazaki K., Kunieda H., et al. A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder. Blood Adv 2021; 5 (19): 3830–8.
25. Tang L., Wang H.F., Lu X., Jian X.R., Jin B., Zheng H., et al. Common genetic risk factors for venous thrombosis in the chinese population. Am J Hum Genet 2013; 92 (2): 177–87.
26. Razzaq S. Hemolytic uremic syndrome: An emerging health risk. Am Fam Physician 2006; 74 (6): 991–6.
27. Noris M., Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16 (4): 1035–50.
28. Doggen C.J.M., Kunz G., Rosendaal F.R., Lane D.A., Vos H.L., Stubbs P.J., et al. A mutation in the thrombomodulin gene, 127G to a coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost 1998; 80 (5): 743–8.
29. Maga T.K., Nishimura C.J., Weaver A.E., Frees K.L., Smith R.J.H. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 2010; 31 (6): 1445–60.
30. Le Clech A., Simon-Tillaux N., Provôt F., Delmas Y., Vieira-Martins P., Limou S., et al. Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Kidney Int 2019; 95 (6): 1443–52.
31. Matsumoto T., Fan X., Ishikawa E., Ito M., Amano K., Toyoda H., et al. Analysis of patients with atypical hemolytic uremic syndrome treated at the Mie University Hospital: Concentration of C3 p.I1157T mutation. Int J Hematol 2014; 100 (5): 437–42.
32. Zhao W., Ding Y., Lu J., Zhang T., Chen D., Zhang H., et al. Genetic analysis of the complement pathway in C3 glomerulopathy. Nephrol Dial Transplant 2018; 33 (11): 1919– 27.
33. Kunz G., Ireland H.A., Stubbs P.J., Kahan M., Coulton G.C., Lane D.A. Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction. Blood 2000; 95 (2): 569–76.
34. Wu C., Dwivedi D.J., Pepler L., Lysov Z., Waye J., Julian J., et al. Targeted gene sequencing identifies variants in the protein c and endothelial protein c receptor genes in patients with unprovoked venous thromboembolism. Arterioscler Thromb Vasc Biol 2013; 33 (11): 2674–81.
35. Mahmood I., Hamdan F., Al-Tameemi W. Role of endothelial dysfunction in relation to prothrombogenesis in polycythemia vera. Iraqi J Hematol 2018; 7 (1): 8.
36. Page A.V., Liles W.C. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence 2013; 4 (6): 507–16.
37. Salomaa V., Matei C., Aleksic N., Sansores-Garcia L., Folsom A.R., Juneja H., et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: A case-cohort study. Lancet 1999; 353 (9166): 1729–34.
38. Kampoli A.M., Tousoulis D., Antoniades C., Siasos G., Stefanadis C. Biomarkers of premature atherosclerosis. Trends Mol Med 2009; 15 (7): 323–32.
39. Wada H., Mori Y., Shimura M., Hiyoyama K., Ioka M., Nakasaki T., et al. Poor outcome in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with severe vascular endothelial cell injuries. Am J Hematol 1998; 58 (3): 189–94.
40. Lin S.M., Wang Y.M., Lin H.C., Lee K.Y., Huang C. Da, Liu C.Y., et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med 2008; 36 (3): 683–9.
41. Mori Y., Wada H., Okugawa Y., Tamaki S., Nakasaki T., Watanabe R., et al. Increased Plasma Thrombomodulin as a Vascular Endothelial Cell Marker in Patients With Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome. Clin Appl Thromb 2001; 7 (1): 5–9.
42. Shimizu M., Kuroda M., Inoue N., Konishi M., Igarashi N., Taneichi H., et al. Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome. Cytokine 2014; 66 (1): 1–6.
43. Budzyń M., Iskra M., Turkiewicz W., Krasiński Z., Gryszczyńska B., Kasprzak M.P. Plasma concentration of selected biochemical markers of endothelial dysfunction in women with various severity of chronic venous insufficiency (CVI) – A pilot study. PLoS One 2018; 13 (1): 1–17.
44. Mihajlovic D.M., Lendak D.F., Draskovic B.G., Mikic A.S.N., Mitic G.P., Cebovic T.N., et al. Thrombomodulin is a Strong Predictor of Multiorgan Dysfunction Syndrome in Patients With Sepsis. Clin Appl Thromb 2015; 21 (5): 469–74.
45. Faust S.N., Levin M., Harrison O.B., Goldin R.D., Lockhart M.S., Kondaveeti S., et al. Dysfunction of Endothelial Protein C Activation in Severe Meningococcal Sepsis. N Engl J Med 2001; 345 (6): 408–16.
46. Budzyń M., Gryszczyńska B., Majewski W., Krasiński Z., Kasprzak M.P., Formanowicz D., et al. The association of serum thrombomodulin with endothelial injuring factors in abdominal aortic aneurysm. Biomed Res Int 2017; 2017: 2791082.
47. Folsom A.R., Yao L., Alonso A., Lutsey P.L., Missov E., Lederle F.A., et al. Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence. Circulation 2015; 132 (7): 578–85.
48. Che X.Y., Hao W., Wang Y., Di B., Yin K., Xu Y.C., et al. Nucleocapsid protein as early diagnostic marker for SARS. Emerg Infect Dis 2004; 10 (11): 1947–9.
49. Subirana I., Fitó M., Diaz O., Vila J., Francés A., Delpon E., et al. Prediction of coronary disease incidence by biomarkers of inflammation, oxidation, and metabolism. Sci Rep 2018; 8 (1): 1–7.
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