Periodic Reporting for period 2 - T-MEMORE (Thrombotic MEMOry-Linking a break in tolerance to platelets to REthrombosis)
Reporting period: 2022-06-01 to 2023-11-30
The projects investigates mechanisms of recurrent venous thrombosis, which is a major health care issue with growing incidence. By understanding this disease, health care costs can be reduced and patient morbidity and mortality can be prevented.
For WP1 I dissected the immune response to platelets in venous thrombosis. In this setting antibodies are deposited on platelets in a fibrin-dependent manner. The interaction of IgG with fibrin on the platelet surface is independent from antigen binding, as IgGs directed against irrelevant antigens is able to bind as well, which I confirmed in mouse models (KL25 mice) and is independent from natural antibodies (CR2-/- mice). This antibody-fibrin interaction is sufficient to expose the C1q binding side of IgG and to activate the classical complement pathway. There, I found that the complement factors C1q, C3, and C4 are involved in platelet activation, but not the terminal pathway as analysed in specific knockout mice and by using complement inhibitors. The complement system triggers the activation of neutrophils, but also IL-8 is involved in this process in COVID-19 depending on the disease severity (Kaiser et al. 2021; Pekayvaz et al. 2022)
For WP2 I investigated the role of the spleen in coordinating the removal of activated platelets. Here, I show that splenectomy had no major impact on thrombus formation itself, but it was involved in the removal of activated platelets. In the liver only very few activated platelets are found after induction of venous thrombosis excluding a major role of this organ in platelet removal. However, in the context of vaccine associated thrombocytopenia I found that a vaccine vector binds to platelets in the setting of intravenous injection resulting in platelet activation and their removal by spleen macrophages (Nicolai et al., Blood 2022). Moreover, I have established an intravital microscopy setup as well as bioinformatic analysis approach to dissect platelet-leukocyte interactions by calcium imaging (Mehari et al, Science signaling, accepted)
The current understanding of the factors leading to thrombosis and its relapse are summarized in my recent review article in Nature Reviews Cardiology (Stark et al., Nat Rev Cardiol. 2021)
For WP2 I investigated the role of the spleen in coordinating the removal of activated platelets. Here, I show that splenectomy had no major impact on thrombus formation itself, but it was involved in the removal of activated platelets. In the liver only very few activated platelets are found after induction of venous thrombosis excluding a major role of this organ in platelet removal. However, in the context of vaccine associated thrombocytopenia I found that a vaccine vector binds to platelets in the setting of intravenous injection resulting in platelet activation and their removal by spleen macrophages (Nicolai et al., Blood 2022). Moreover, I have established an intravital microscopy setup as well as bioinformatic analysis approach to dissect platelet-leukocyte interactions by calcium imaging (Mehari et al, Science signaling, accepted)
The current understanding of the factors leading to thrombosis and its relapse are summarized in my recent review article in Nature Reviews Cardiology (Stark et al., Nat Rev Cardiol. 2021)
I expect that that new mechanisms of venous thrombosis will de identified, which are beyond the state-of-the-art in the prevention and therapy of venous thrombosis. This involves inflammatory mechanisms of venous thrombosis, which are a promising target for preventive and therapeutic approaches.