Jornal Vascular Brasileiro
https://jvascbras.org/article/doi/10.1590/1677-5449.202401022
Jornal Vascular Brasileiro
Innovation

Evaluation of expression of genes associated with post-thrombotic syndrome

Avaliação da expressão de genes associados à síndrome pós-trombótica

Ricardo André Viana Barros; Erika Mota Herenio; Mariana Rocha Maximiano; Julia Hellena Mendes Ribeiro; Octávio Luiz Franco; Robert Edward Pogue

Downloads: 0
Views: 13

Abstract

Prediction of the development of post-thrombotic syndrome (PTS) among patients with deep venous thrombosis (DVT) is currently based on clinical characteristics alone; no reliable biomarkers are available. Coagulation Factor XIII A chain (F13A1) of the clotting cascade stabilizes the thrombus; myeloperoxidase (MPO) interacts with the endothelium; and Fms-related tyrosine kinase 4 (FLT4), also known as Vascular Endothelial Growth Factor Receptor-3, encodes a vascular endothelium-derived growth factor receptor that participates in angiogenesis. In this study, MPO, FLT4, and F13A1 gene expression was evaluated to identify novel biomarkers of PTS. This study evaluated nine patients allocated to three different groups. The control group included three healthy patients (group I); the second group included three patients with DVT without PTS (group II); and the third group included three patients with PTS (group III). Expression of MPO, FLT4, and F13A1 was evaluated in all three groups. A decrease in FLT4 expression was observed in group II (ΔCt -2.71; gene expression 0.03, p=0.11) and a significant decrease was observed in group III (ΔCt -2.44; gene expression 0.01, p=0.05). A nonsignificant difference in MPO gene expression was found among the three groups. There was a notable and progressive increase in F13A1 expression in group III (ΔCt 6.54; gene expression 3.5, p=0.02). Despite the low sampling rate in the present study, the decreased FLT4 expression and increased of F13A1 expression may represent biomarkers of PTS in group III.

 

Keywords

post-thrombotic syndrome; gene expression; coagulation factor XIII; myeloperoxidase; vascular endothelial growth factor receptor-3

Resumo

A previsão do desenvolvimento da síndrome pós-trombótica (SPT) em pacientes com trombose venosa profunda (TVP) baseia-se, atualmente, apenas em características clínicas, pois biomarcadores confiáveis não estão disponíveis. A cadeia alfa do fator XIII (F13A1) da cascata de coagulação estabiliza o trombo; a mieloperoxidase (MPO) interage com o endotélio; e a tirosina quinase 4 (FLT4), também conhecida como receptor-3 do fator de crescimento endotelial vascular, é um receptor do fator de crescimento derivado do endotélio vascular envolvido na angiogênese. Avaliar a expressão gênica de MPO, FLT4 e F13A1 para identificar novos biomarcadores de SPT. Este estudo incluiu nove pacientes estratificados em três grupos diferentes. O grupo-controle incluiu três pacientes saudáveis (grupo I); o segundo grupo incluiu três pacientes com TVP sem SPT (grupo II); e o terceiro grupo incluiu três pacientes com SPT (grupo III). A expressão gênica de MPO, FLT4 e F13A1 foi avaliada nos três grupos. Observou-se uma redução significativa na expressão de FLT4 (ΔCt -2,71; expressão gênica 0,03, p = 0,11 no grupo II; ΔCt -2,44; expressão gênica 0,01, p = 0,05 no grupo III) e uma diferença não significativa na expressão do gene MPO entre os grupos. No entanto, houve um aumento progressivo notável na expressão de F13A1 no grupo III (ΔCt 6,54; expressão gênica 3,5, p = 0,02). Apesar da baixa taxa de amostragem no presente estudo, a diminuição da expressão de FLT4 e o aumento da expressão de F13A1 podem representar biomarcadores de SPT no grupo III.

Palavras-chave

 síndrome pós-trombótica; expressão gênica; fator de coagulação XIII; mieloperoxidase; receptor-3 do fator de crescimento endotelial vascular

References

1 Sobreira ML, Rogatto SR, Dos Santos RM, Santos IT, Ferrari IC, Yoshida WB. An unexpectedly high rate of thrombophilia disorders in patients with superficial vein thrombosis of the lower extremities. Ann Vasc Surg. 2017;43:272-7. PMid:28501666.

2 Galanaud JP, Monreal M, Kahn SR. Epidemiology of the post-thrombotic syndrome. Thromb Res. 2018;164:100-9. PMid:28844444.

3 Guanella R, Ducruet T, Johri M, et al. Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation. J Thromb Haemost. 2011;9(12):2397-405. PMid:21951970.

4 Urbanek T, Labropoulos N. Can we predict and prevent post-thrombotic syndrome? Vasa. 2021;50(1):11-21. PMid:33393384.

5 Engeseth M, Enden T, Sandset PM, Wik HS. Predictors of long-term postthrombotic syndrome following high proximal deep vein thrombosis: a crosssectional study. Thromb J. 2021;19(1):3. PMid:33419441.

6 Ndrepepa G. Myeloperoxidase–A bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta. 2019;493:36-51. PMid:30797769.

7 Elaskalani O, Abdol Razak NB, Metharom P. Neutrophil extracellular traps induce aggregation of washed human platelets independently of extracellular DNA and histones. Cell Commun Signal. 2018;16(1):24. PMid:29843771.

8 Lee KH, Cavanaugh L, Leung H, et al. Quantification of NETs-associated markers by flow cytometry and serum assays in patients with thrombosis and sepsis. Int J Lab Hematol. 2018;40(4):392-9. PMid:29520957.

9 Metz AK, Diaz JA, Obi AT, Wakefield TW, Myers DD, Henke PK. Venous thrombosis and post-thrombotic syndrome: from novel biomarkers to biology. Methodist DeBakey Cardiovasc J. 2018;14(3):173-81. PMid:30410646.

10 Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298-307. PMid:21593862.

11 Drosos I, Pavlaki M, Ortega Carrillo MDP, et al. Increased lymphangiogenesis and lymphangiogenic growth factor expression in perivascular adipose tissue of patients with coronary artery disease. J Clin Med. 2019;8(7):1000. PMid:31324038.

12 Schmitz T, Bäuml CA, Imhof D. Inhibitors of blood coagulation factor XIII. Anal Biochem. 2020;605:113708. PMid:32335064.

13 Satsangi J, Jewell DP, Welsh K, Bunce M, Bell JI. Effect of heparin on polymerase chain reaction. Lancet. 1994;343(8911):1509-10. http://doi.org/10.1016/S0140-6736(94)92622-0. PMid:7911214.

14 Zhao S, Fernald RD. Comprehensive algorithm for quantitative real-time polymerase chain reaction. J Comput Biol. 2005;12(8):1047-64. PMid:16241897.

15 Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002;30(9):e36. PMid:11972351.

16 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T). Method. Methods. 2001;25(4):402-8. PMid:11846609.

17 Miot HA. Tamanho da amostra em estudos clínicos e experimentais. J Vasc Bras. 2011;10(4):275-8. PMid:30787944.

18 Beckmann L, Dicke C, Spath B, et al. Myeloperoxidase is a negative regulator of phospholipid-dependent coagulation. Thromb Haemost. 2017;117(12):2300-11. http://doi.org/10.1160/TH17-04-0266. PMid:29212118.

19 Türker FS, Malbora A, Erisir M. Oxidative status and antioxidant enzyme levels in deep venous thrombosis patients. Am J Cardiovasc Dis. 2021;11(1):176-83. PMid:33815933.

20 Giaglis S, Sur Chowdhury C, van Breda SV, et al. Circulatory neutrophils exhibit enhanced neutrophil extracellular trap formation in early puerperium: NETs at the nexus of thrombosis and immunity. Int J Mol Sci. 2021;22(24):13646. http://doi.org/10.3390/ijms222413646. PMid:34948443.

21 Cedervall J, Hamidi A, Olsson AK. Platelets, NETs and cancer. Thromb Res. 2018;164(Suppl 1):S148-52. http://doi.org/10.1016/j.thromres.2018.01.049. PMid:29703474.

22 Iding AFJ, Witten A, Isaacs A, et al. Leukocyte gene expression in postthrombotic syndrome. Thromb Res. 2021;202:40-2. http://doi.org/10.1016/j.thromres.2021.03.007. PMid:33713866.

23 Bittar LF, Silva LQD, Orsi FLA, et al. J. M. Increased inflammation and endothelial markers in patients with late severe post-thrombotic syndrome. PLoS One. 2020;15(1):e0227150. http://doi.org/10.1371/journal.pone.0227150. PMid:31945777.

24 Monaghan RM, Page DJ, Ostergaard P, Keavney BD. The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases. Cardiovasc Res. 2021;117(8):1877-90. http://doi.org/10.1093/cvr/cvaa291. PMid:33067626.

25 Jerafi-Vider A, Bassi I, Moshe N, et al. VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells. Cell Rep. 2021;35(11):109255. http://doi.org/10.1016/j.celrep.2021.109255. PMid:34133928.

26 Bereczky Z, Muszbek L. Factor XIII and venous thromboembolism. Semin Thromb Hemost. 2011;37(3):305-14. http://doi.org/10.1055/s-0031-1273094. PMid:21455864.

27 Ambroziak M, Kuryłowicz A, Budaj A. Increased coagulation factor XIII activity but not genetic variants of coagulation factors is associated with myocardial infarction in young patients. J Thromb Thrombolysis. 2019;48(3):519-27. http://doi.org/10.1007/s11239-019-01856-3. PMid:30972713.

28 von Meijenfeldt FA, Havervall S, Adelmeijer J, et al. COVID-19 is associated with an acquired factor XIII deficiency. Thromb Haemost. 2021;121(12):1668-9. http://doi.org/10.1055/a-1450-8414. PMid:33742434.

29 Yu T, Shen R, You G, et al. Machine learning-based prediction of the postthrombotic syndrome: Model development and validation study. Front Cardiovasc Med. 2022;9:990788. http://doi.org/10.3389/fcvm.2022.990788. PMid:36186967.
 


Submitted date:
08/05/2024

Accepted date:
12/23/2024

Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV)"> Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV)">
68360f19a95395700802a435 jvb Articles
Links & Downloads

J Vasc Bras

Share this page
Page Sections