IN VIVO THROMBOSIS

Interaction between major pathways for platelet activation in mouse models of arterial thrombosis

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 Obiettivo del progetto (Objective)

'Platelets play a central role in arterial thrombosis, causing life-threatening and disabling diseases like myocardial infarction and ischemic stroke. Despite antiplatelet therapies have been proven efficacious for primary and secondary prevention of cardio- and cerebrovascular diseases, arterial thrombosis remains a major healthy problem. A better understanding of the multiple mechanisms by which platelets can be activated is the basis for the rationale development of new antithrombotic drugs. The “outgoing” host institution involved in this project has previously demonstrated that protease-activated receptor (PAR) signaling in platelets is necessary for platelet activation by thrombin and important for hemostasis and thrombosis in mouse models. These results have greatly contributed to the development of a PAR1 antagonist, that has been recently used as antithrombotic drug in a phase II trial . The objectives of this proposal are to better define the role of thrombin signaling in vivo and to explore how the thrombin-PARs pathway relates to other effectors of hemostasis and thrombosis. This study will make use of mouse models of hemostasis and thrombosis. In the partner institution the generation of knockout mice for multiple platelet receptors (glycoprotein VI, FcγR, P2Y12 ) and other relevant molecules for hemostasis and thrombosis (vonWillebrand factor, FIX, FXI, fibrinogen) is ongoing. On those mice the following endpoints will be evaluated 1) hemostasis (bleeding time, neonatal hemorrhage, placentation, maternal hemorrhage, anemia) 2) thrombosis (by using a ferric chloride injury to induce carotid or mesenteric thrombosis). This project will allow the researcher to gain knowledge and experience on the in vivo models of hemostasis and thrombosis. This will be relevant for the fellowship program since the in vivo models will be set up during the return phase in the host institution.'

Introduzione (Teaser)

Arterial thrombosis is the first cause of death and ill health in the western world. The aggregation of platelets plays a major role in the development of this pathology, which can lead to heart attacks and strokes.

Descrizione progetto (Article)

Although anti-platelet therapies are effectively used for primary and secondary prevention of cardiovascular and cerebrovascular diseases, arterial thrombosis remains a severe health problem. To develop new anti-thrombotic drugs that will lessen associated health risks, we need a better understanding of how platelets are activated.

The 'Interaction between major pathways for platelet activation in mouse models of arterial thrombosis' (In vivo thrombosis) project aimed to better define the role of thrombin signalling and to explore how relevant pathways influence a disruption in normal blood flow and thrombosis. This study employed advanced genetic engineering techniques and mouse models of haemostasis and thrombosis.

Thrombin is a protease protein that is active in guiding a wide range of coagulation-related reactions. Protease-activated receptor 4 (PAR4) is a protein receptor and powerful mediator of platelet activation and inflammation, especially when alerted to elevated concentrations of thrombin. The objectives of this EU-funded study included identifying pathways triggering the platelet thrombi formation in the absence of PAR4 function.

Project partners focused on the interplay between the PAR4-thrombin pathway and the Glycoprotein (GP) VI-collagen pathway. Study results revealed that PAR4 deficiency alone comes with higher bleeding risk, albeit better protection against thrombosis. Combined GPVI and PAR4 deficiency offers better protection against thrombosis but still carries a risk of increased bleeding.

Following the logic of combining two anti-platelet drugs, currently standard practice for antithrombotic therapies, project outcomes resulted in greater understanding of bleeding risk and protection against thrombosis. Such new information is significant for professionals working to manage cardiac and neurological diseases.