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


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.    


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ISSN: 2518-6140 (on-line version)