In my project I was able to define a novel function of platelets that are recruited to sites of tissue inflammation: They actively move – migrate – on the vascular surface. This movement follows substrate densities, helping platelets to identify sites of vascular injury. This re-positioning is important for platelets to find sites of vessel injury and prevent bleeding in the inflamed microvasculature. Moreover, platelets migrate to find and collect invading bacteria, and therefore prevent dissemination of bacteria in the blood stream. I also revealed that this process depends on a cytoskeletal regulator actin related protein. Platelets sense and react to the local micro-environment and form sheet-like lamellipodia; lamellipodia formation is dispensable for classical thrombosis and haemostasis. Further, I dissected the contribution of immunothrombosis to cardiovascular diseases. I investigated the contribution of platelet migration in atherosclerosis using a novel mouse model and uncovered that platelet migration-deficient mice are partially protected from the development of atherosclerotic lesions. In a model of deep vein thrombosis (DVT) I showed that antibodies of the IgG and IgM subtypes are critically involved in venous thrombogenesis triggering platelet and endothelial interaction and activation. In addition, using mouse models with platelet-specific deficiency in central pathways of procoagulant activation of platelets, my group identified an essential role of platelet procoagulant transformation in DVT and revealed novel pharmacological strategies targeting procoagulant platelets for DVT treatment and prevention. Using multi-omics approaches I identified distinct systemic immune states in the blood of patients with acute and chronic coronary syndromes and provided a unique data resource for analysing the immune landscape of thrombi collected from stroke patients. In addition, I discovered the interactions between megakaryocytes and immune cells as a previously unknown regulatory mechanism of platelet production. First, I was able to demonstrate that physical interactions of neutrophils with proplatelet protrusions are key to efficient platelet release (thrombopoiesis). Second, I identified plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate the proliferation of megakaryocyte progenitors. When pDCs encounter mature megakaryocytes that undergo thrombopoiesis they release INF-alpha which in turn drives the proliferation of megakaryocyte progenitors (megakaryopoiesis). This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis. I was also able to show an important contribution of IMMUNOTHROMBOSIS to the pathology of severe COVID-19. In cooperation with multiple partners at the hospital we collected and analysed blood and tissue samples of patients with COVID-19 pneumonia. We were able to show that platelets become activated in severe disease and interact with neutrophils. This interaction leads to neutrophil activation which release so called neutrophil extracellular traps (NETs). NETs then form clots in the smaller blood vessels of patients. Interestingly, this is not limited to the lung, but also occurs in the liver, kidney and heart of individuals with severe disease. Finally, my group also spearheaded a focus on resilience mechanisms that operate in mammals to protect from immunothrombosis. Through an international collaboration, we explored thromboprotective mechanisms protecting hibernating bears from deep vein thrombosis during hibernation-related immobilization. Applying this innovative model system, we found that the downregulation of HSP47 in platelets correlates with thrombosis protection not only in bears but across different mammalian species (Thienel et al, Science, 2023). I showed that HSP47 is involved in regulating NETosis, consequently, downregulation of HSP47 reduces formation of prothrombotic NETs. Together, these results identify HSP47 as a novel druggable immunothrombotic mechanism. We published these results in high-ranking international journals including Nature, Science, Nature Medicine, Immunity, Nature Communications, Circulation, and Blood to disseminate the findings. Moreover, I presented the results at conferences, for example during my invited Gus Born Lecture at the International Society of Thrombosis and Hemostasis (ISTH) annual meeting.
