Thrombotic memory-linking a break in tolerance to platelets to rethrombosis
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.