Scientists discover a non-classical platelet mechanism linked to severe infections

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.

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."

Bernhard Nieswandt, Professor and Chair, Experimental Biomedicine I, UKW

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.