T-MEMORE Thrombotic MEMOry-Linking a break in tolerance to platelets to REthrombosis

Summary

Thrombotic diseases like venous thromboembolism (VTE) are leading causes of mortality worldwide, due to their unpredictable, relapsing occurrence. The strongest predictor of a thrombotic event is a previous thrombosis, implicating that VTE has systemic memory effects beyond local clot formation triggering thrombotic relapse. In T-MEMORE, I will go beyond the state-of-the art of thrombosis research by testing the ground-breaking concept that VTE is not only a local event, but a chronic, systemic disease caused by an immune response to platelets mimicking a break in tolerance.
My recent research revealed that venous thrombosis is the outcome of a sterile inflammation primarily directed against one target: activated platelets. I found that platelet-directed immunity in turn fosters platelet activation and thrombotic vessel occlusion. The systemic and long-term thrombotic memory effects of platelet-directed immunity are unknown, but have important implications for unmet clinical needs: (1) identification of patients at risk of rethrombosis; (2) personalisation of the duration and type of secondary prevention; (3) discovery of new approaches for VTE prophylaxis beyond anticoagulants with their inherent bleeding risk.
The thrombotic memory effect caused by a local thrombosis will be deciphered by innovative functional in vivo imaging in the bone marrow – as the site of platelet production – as well as spleen and liver – as sites of platelet removal (objective 1). The potential of manipulating platelet-directed immunity to prevent thrombotic relapse will be tested in a clinically relevant model of rethrombosis (objective 2). In a translational approach, I aim to uncover a platelet-directed immune profile in patients with recurrent VTE, which would be a key step towards a personalized, molecular-guided therapy (objective 3). The overarching aim of T-MEMORE is to prove the concept of thrombotic memory as an innovative approach for the targeted prevention of VTE recurrence.

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Web resources:	https://cordis.europa.eu/project/id/947611
Start date:	01-12-2020
End date:	30-11-2025
Total budget - Public funding:	1 483 145,00 Euro - 1 483 145,00 Euro

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Original description

Thrombotic diseases like venous thromboembolism (VTE) are leading causes of mortality worldwide, due to their unpredictable, relapsing occurrence. The strongest predictor of a thrombotic event is a previous thrombosis, implicating that VTE has systemic memory effects beyond local clot formation triggering thrombotic relapse. In T-MEMORE, I will go beyond the state-of-the art of thrombosis research by testing the ground-breaking concept that VTE is not only a local event, but a chronic, systemic disease caused by an immune response to platelets mimicking a break in tolerance.
My recent research revealed that venous thrombosis is the outcome of a sterile inflammation primarily directed against one target: activated platelets. I found that platelet-directed immunity in turn fosters platelet activation and thrombotic vessel occlusion. The systemic and long-term thrombotic memory effects of platelet-directed immunity are unknown, but have important implications for unmet clinical needs: (1) identification of patients at risk of rethrombosis; (2) personalisation of the duration and type of secondary prevention; (3) discovery of new approaches for VTE prophylaxis beyond anticoagulants with their inherent bleeding risk.
The thrombotic memory effect caused by a local thrombosis will be deciphered by innovative functional in vivo imaging in the bone marrow as the site of platelet production as well as spleen and liver as sites of platelet removal (objective 1). The potential of manipulating platelet-directed immunity to prevent thrombotic relapse will be tested in a clinically relevant model of rethrombosis (objective 2). In a translational approach, I aim to uncover a platelet-directed immune profile in patients with recurrent VTE, which would be a key step towards a personalized, molecular-guided therapy (objective 3). The overarching aim of T-MEMORE is to prove the concept of thrombotic memory as an innovative approach for the targeted prevention of VTE recurrence.