Charly Kusch, David Štegner, Lukas Johannes Weiss, Paquita Nurden, Philipp Burkard, Denise F. Johnson, Wolfgang Bergmeier, Ceylan Onursal, Stefano Navarro, Christian Hackenbroch, Dennis Pfeiffer, Sabrina Ivana Bonfiglio, Mara Meub, Carina Gross, Joachim Schenk, Valeria Fumagalli, Kristina Mott, Markus Bender, Matteo Iannacone, Oliver Andrés, W. Kastenmüller, Katrin G. Heinze, Markus Sauer, Harald Schulze, Klaus Ley, Alan T. Nurden, Bernhard Nieswandt
Platelet integrin αIIbβ3 is essential for hemostasis, thrombosis, and inflammation. We found that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow triggered its accumulation in plasma membrane extensions or "platelet-derived integrin- and tetraspanin-enriched tethers" (PITTs). PITTs remained anchored to leukocytes or endothelial cells, whereas the partially αIIbβ3-deficient platelet body detached. Although still responsive to stimuli, αIIbβ3-deficient platelets did not support thrombus formation. PITTs promoted leukocyte activation and vascular inflammation in mouse models of infection and endotoxemia, and αIIbβ3 blockade reduced immune-mediated tissue damage. In patients with sepsis, COVID-19, or severe infections, PITT formation and platelet αIIbβ3 loss correlated with disease severity and adverse outcomes. We propose that PITTs are proinflammatory structures that amplify immune responses while contributing to platelet dysfunction in thrombo-inflammatory disease.