E. Tarantino
Università degli Studi di Milano, 2016-01-12

Background: Deep vein thrombosis (DVT) is a serious national health problem, and pulmonary thromboembolism (PE) represents the life-threatening most common complication. Venous thromboembolism (VTE), including both these conditions, is traditionally treated with anticoagulant drugs. In particular, vitamin K antagonists and heparins are usually used in the reduction of thrombus development and in secondary prevention. However, the use of these drugs has several limitations: wide variability dose/response relationship between patients and in the same patient, multiple interactions with other drugs/foods, variability of daily doses, need of periodic withdrawals of blood during therapy, problems of overdosing. Then, the discovery of new drugs for VTE needs. The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyse the formation of prostaglandins and, thromboxane from arachidonic acid, and play a critical role in thrombosis. Recent meta-analysis suggests that low-dose aspirin (ASA) reduces the rate of VTE recurrence. In contrast, the clinical use of COX-2 inhibitors seems associated with increased risk of venous thrombosis. However, the role of COX-1 and COX-2 in venous thrombosis remain unclear. Aim: We investigated the impact of COX-1 and COX-2 enzymes in venous thrombosis in order to identify the molecular mechanisms responsible for this effect and develop new therapeutic strategies to prevent venous thrombosis. In particular, we focused on the impact of inhibition of COX-pathway on leukocyte activation, important regulators of formation and propagation of venous thrombus. Methods and Results: Using in vivo and in vitro approaches, we provide evidence that: a) thromboxane, produced by platelets, triggers activation of leukocytes, with consequent development and propagation of venous thrombus induced by inferior vena cava ligation. In particular, we showed that ASA, by inhibiting irreversibly platelet COX-1, prevents platelet thromboxane production resulting in decreased venous thrombosis. b) COX-2 deletion induces platelet hyper-activity and hyper-coagulation state, associated with a reduced fibrinolysis and formation of bigger thrombi. In this scenario, the high levels of tissue factor observed in leukocytes of COX-2KO mouse may explain the positive association observed between administration of COX-2 inhibitors and VTE. Thanking advantage of an accurate, and clinically relevant, technique such as ultrasonography, we are setting a method helpful to monitor thrombus growing and to better understand the pathophysiology of venous thromboembolism. Conclusion: In conclusion, data obtained show that the inhibition of COX-1 and COX-2 in a venous thrombosis mouse model could lead to opposite effect on the thrombus development, stabilization and resolution. In particular, COX-1 inhibition is responsible of an impairment development and growth of venous thrombus, with a mechanism most likely dependent of TXA2/TP pathway. In contrast, COX-2 inhibition caused an increased in thrombus development, growing accompanied with reduction in the thrombus resolution. All data obtained support evidences that both COX-1 and COX-2 play a key role in DVT, opening the way to novel therapeutic approaches.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/2434/353697
tutor: E. Tremoli ; co-tutor: S.S.Barbieri ; coordinatore: A. Corsini
Settore BIO/14 - - Farmacologia

Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18002330