Bivalirudin Inhibits Thrombin-Mediated Tissue Factor Expression in Human Endothelial Cells

Plinio Cirillo, Grazia Pellegrino, Stefano Conte, Giovanni Cimmino, Giusi Barra, Raffaele De Palma, Bruno Trimarco

Abstract


Thrombosis is the main pathophysiological mechanism in Acute Coronary Syndromes (ACS), and involves the activation of platelets and of Tissue Factor (TF)-dependent extrinsic coagulation pathway. TF-mRNA and antigen are detectable in the adventitia of normal vessels. On the contrary, little TF immunoreactivity is measurable in the smooth muscle cells of uninjured vessels and unperturbed endothelial cells, being in contact with circulating blood, usually do not express TF activity. However, several stimuli are able to induce TF in endothelial cells, including thrombin. Thus in an acute "scenario", thrombin might be responsible for creating a prothombotic milieau. Bivalirudin (BIVA) is a synthetic, reversible direct thrombin inhibitor actually considered a valuable alternative to heparins in patients who need anticoagulation in the setting of ACS and percutaneous coronary intervention to avoid acute thrombotic events. In the present study we have investigated whether BIVA, by inhibiting thrombin, might have effects on TF expression and procoagulant activity in endothelial cells. Human Umbilical Endothelial Cells (HUVEC) were stimulated with thrombin or with the activated coagulation factors FVIIa/FXa for 2 hrs to evaluate TF-mRNA transcription by real-time PCR and for 6 hrs to measure TF expression/activity  on cell surface by FACs analysis and procoagulant activity. In additional experiments HUVEC were  pre-treated with BIVA for 1 hr before being stimulated and processed as above. Thrombin induced TF-mRNA transcription as well TF expression/activity on HUVEC shifting them to a procoagulant phenotype. On the contrary, the activated coagulation factors FVIIa/FXa did not affect TF expression/activity, indicating that thrombin plays a pivotal role in mediating this phenomenon. BIVA was able to prevent these thrombin deleterious effects. Data of the present study, although in vitro, suggest that BIVA, in the context of ACS, might significantly reduce thrombogenicity not only by acting as direct thrombin inhibitor but through its effects on TF expression/activity too.    


References


Abbate R, Cioni G, Ricci I, Miranda M, Gori AM. Thrombosis and acute coronary syndrome. Thromb Res. 2012; 129:235-40. DOI: 10.1016/j.thromres.2011.12.026

Tatsumi K, Mackman N. Tissue Factor and Atherothrombosis. J Atheroscler Thromb. 2015; 22:543-9. DOI:10.5551/jat.30940

Bartha K, Brisson C, Archipoff G, de la Salle C, Lanza F, Cazenave JP, Beretz A. Thrombin regulates tissue factor andthrombomodulin mRNA levels and activites in human saphenous vein endothelial cells by distinct mechanisms. J Biol Chem 1993; 268: 421-29.

Capodanno D, De Caterina R. Bivalirudin for acute coronary syndromes: premises, promises, and doubts. Thromb Haemost 2015; 113: 698-707. DOI: 10.1160/TH14-09-0765

Cirillo P, Angri V, De Rosa S, Calì G, Petrillo G, Maresca F, D'Ascoli GL, Maietta P, Brevetti L, Chiariello M. Pro atherothrombotic effects of leptin in human coronary endothelial cells. Thromb Haemost. 2010;103:1065-75. DOI: 10.1160/TH09-06-0392

Rezaie AR. Protease-activated receptor signaling by coagulation proteases in endothelial cells. Thromb Haemost. 2014;112:876-82. DOI: 10.1160/TH14-02-0167

Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A. 2000; 97: 5255-60.

Pepke W, Eisenreich A, Jaster M, Ayral Y, Bobbert P, Mayer A, Schultheiss HP, Rauch U. Bivalirudin inhibits periprocedural platelet function and tissue factor expression of human smooth muscle cells. Cardiovasc Ther. 2013; 31:115-23. DOI: 10.1111/j.1755-5922.2011.00305.x.

Gertz SD, Fallon JT, Gallo R, Taubman MB, Banai S, Barry WL, Gimple LW, Nemerson Y, Thiruvikraman S, Naidu SS, Chesebro JH, Fuster V, Sarembock JJ, Badimon JJ. Hirudin reduces tissue factor expression in neointima after baloon injury in rabbit femoral and porcine coronary arteries. Circulation 1998: 580-87.

Shewan LG, Coats AJS, Henein M. Requirements for ethical publishing in

biomedical journals. International Cardiovascular Forum Journal 2015;2:2

DOI: 10.17987/icfj.v2i1.




DOI: https://doi.org/10.17987/jatamis.v2i0.363

Refbacks

  • There are currently no refbacks.


Copyright (c) 2017 Plinio Cirillo, Grazia Pellegrino, Stefano Conte, Giovanni Cimmino, Giusi Barra, Raffaele De Palma, Bruno Trimarco

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

ISSN: 2518-6140 (on-line version)