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A team from Würzburg has fundamentally changed our understanding of platelet biology with a study published in Science. The researchers demonstrate that the surface protein integrin αIIbβ3 is not only a key molecule in blood clotting, but can also act as a pro-inflammatory effector during severe disease processes. Under these conditions, αIIbβ3 switches function and becomes a structural component of a previously unknown organelle: PITT (Platelet-derived Integrin- and Tetraspanin-rich Tether). PITTs are released by platelets, remain deposited at the inflamed vessel wall, and further drive inflammatory processes. Blocking αIIbβ3 with monoclonal antibodies reduces PITT formation.
Würzburg. Platelets are small, anucleate blood cells that play an essential role in hemostasis. Their primary task is to recognize vascular injury, become activated, and aggregate via their surface receptor integrin αIIbβ3. This leads to the formation of a stable platelet plug that seals the wound and stops bleeding. When this process becomes dysregulated, however, it can result in vessel-occluding clots – so-called thromboses – which may cause myocardial infarction or stroke.
A surprising platelet mechanism beyond classical activation
The classical role of platelets in hemostasis and thrombosis has been well understood for decades. However, a team from the Institute of Experimental Biomedicine at the University Hospital Würzburg (UKW) and the Rudolf Virchow Center (RVZ) of Julius-Maximilians-Universität Würzburg (JMU) has now uncovered a surprising cellular mechanism, published in Science, that fundamentally changes our view of platelet biology. During severe pathological conditions such as infections or infarction, platelets can switch to a completely different functional program. In this context, integrin αIIbβ3 serves as a building block of a novel organelle that is released by platelets and drives damaging inflammatory processes.
The researchers observed that under such conditions, platelets form and shed tiny, filamentous membrane extensions—so-called PITTs. PITT stands for Platelet-derived Integrin- and Tetraspanin-rich Tethers and refers to integrin- and tetraspanin-enriched membrane structures released from platelets. These PITTs bind to immune cells and the vessel wall and activate them, while the detaching platelets themselves remain weakened and less adhesive in the bloodstream.
Professor Bernhard Nieswandt, senior author of the study and Chair of Experimental Biomedicine I at UKW, explains:
“Normally, platelets become activated only upon vascular injury. They change shape, release signaling molecules, and form a thrombus. With PITTs, the opposite happens: platelets do not undergo classical activation. Instead, they shed comet-tail-like organelles from their membrane network that are rich in αIIbβ3 and the tetraspanin co-receptor CD9, while other surface molecules remain on the platelet. This is a completely novel mechanism that has not been observed in any other cell type and raises fundamental questions about membrane organization and regulated protein mobility.”
From patient blood samples to mouse models
PITT formation was first discovered in blood samples from patients with severe sepsis, serious bacterial infections, and COVID-19. The researchers detected the filamentous tethers in blood smears and simultaneously observed a loss of αIIbβ3 from the platelet surface. Further studies in animal models and using intravital microscopy demonstrated that PITTs form directly within blood vessels during inflammation or infection and attach to immune cells and the vessel wall. This leads to activation of these cells and amplification of vascular inflammation.
“That platelets redistribute αIIbβ3 in this way and thereby lose their normal clotting function was completely unexpected,” emphasizes Professor David Stegner, group leader at the RVZ and co-first author of the study alongside Charly Kusch. “This may explain why many critically ill patients suffer simultaneously from tissue-damaging inflammation and an increased risk of bleeding.”
New therapeutic perspectives
The researchers further showed that blocking αIIbβ3 with monoclonal antibodies significantly reduced PITT formation and, consequently, severe inflammatory responses and tissue damage in disease models. This opens new therapeutic avenues to specifically target so-called thrombo-inflammatory disease mechanisms without impairing vital hemostasis.
Funding and international collaboration
The study was conducted within the framework of the Collaborative Research Center (SFB) 1525 “Cardio-Immune Interfaces,” funded by the German Research Foundation (DFG), and was additionally supported by the ERC Advanced Grant “PITT-Inflame” from the European Union.
In addition to several Würzburg-based research groups, collaborators from France, Italy, and the United States were involved.
Figure
A single platelet forming pro-inflammatory PITTs in an inflamed blood vessel.
Intravital microscopy image from the liver of a mouse model: a platelet (turquoise) adheres to the inflamed vessel wall (yellow dashed outline) and sheds a long, filamentous membrane extension—a so-called PITT (magenta). These platelet-derived integrin- and tetraspanin-rich tethers remain deposited at the vessel wall and promote inflammatory responses, while the platelet itself re-enters the bloodstream. Scale bar: 1 μm.
Prof. Dr. Bernhard Nieswandt Nieswandt_B@ukw.de
Prof. Dr. David Stegner david.stegner@uni-wuerzburg.de
Institute of Experimental Biomedicine – Chair I, University Hospital Würzburg & Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg
Kusch C.*, Stegner D.*, Weiß L.J., Nurden P., Burkard P., Johnson D., Bergmeier W., Onursal C., Navarro S., Hackenbroch C., Pfeiffer D., Bonfiglio S.I., Meub M., Groß C., Schenk J., Fumagalli V., Mott K., Bender M., Iannacone M., Andres O., Kastenmüller W., Heinze K.G., Sauer S., Schulze H., Ley K., Nurden A.T. & Nieswandt B. “Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation.” Science 391, eadu2825 (2026). https://doi.org/10.1126/science.adu2825
https://www.platelets.eu/biomed/nieswandt/pitt-inflame-erc/ ERC Advanced Grant “PITT-Inflame” from the European Union
https://www.ukw.de/forschung-lehre/sfb-1525/startseite/ Collaborative Research Center (SFB) 1525 “Cardio-Immune Interfaces
A single platelet forming pro-inflammatory PITTs in an inflamed blood vessel.
Copyright: Institute of Experimental Biomedicine – Chair I, University Hospital Würzburg
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