Journal Club

Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation

Science 22 Jan 2026 Vol 391, Issue 6783

INTRODUCTION

Integrins are a family of heterodimeric transmembrane receptors that link the extracellular matrix to the cytoskeleton and regulate adhesion, migration, and signaling in many cell types. The platelet integrin αIIbβ3 (also designated GPIIb/IIIa) is among the best-studied integrins and is indispensable for hemostasis and thrombosis. Beyond their established role in clotting, platelets contribute to immune-mediated tissue damage in inflammatory and infectious disease.

RATIONALE

Because the platelet effector mechanisms that mediate thrombo-inflammation were unclear, we sought to understand the role of αIIbβ3 and how its engagement contributes to altered platelet function.

RESULTS

In blood smears and tissue samples from patients with severe COVID-19, sepsis, or bacterial infection, we observed alterations in platelet morphology and integrin expression. Specifically, we noted the presence of elongated platelet-derived membrane tethers that stained strongly for αIIbβ3 and its associated tetraspanin CD9. We called these structures platelet-derived integrin- and tetraspanin-enriched tethers (PITTs). Indicators of an increased abundance of PITT formation correlated with reduced αIIbβ3/CD9 surface levels in circulating platelets. Flow cytometry confirmed selective loss of these receptors, whereas other major glycoproteins were preserved. Using human and murine platelets, we demonstrated that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow was sufficient to trigger rapid integrin clustering and tether formation, independent of classical platelet activation. PITTs remained attached to leukocytes or endothelium, whereas the platelet body detached, partially depleted of αIIbβ3/CD9. We generated Itga2b-GFP (green fluorescent protein) knock-in mice and performed live imaging of PITT formation in vitro and confirmed αIIbβ3/CD9 enrichment in PITTs and their detachment from platelet bodies and deposition in inflamed lungs during endotoxemia, bacterial pneumonia, or SARS-CoV-2 infection using in vivo mouse studies.

PITTs formed without detectable platelet degranulation, phosphatidylserine exposure, or integrin activation, distinguishing them from classical extracellular vesicles or activation-induced protrusions. In vivo, PITTs decorated neutrophils, inducing calcium fluxes and up-regulation of activation markers, suggesting that PITTs could promote inflammatory signaling. In models of acute lung injury, genetic deletion of von Willebrand factor or pharmacologic blockade of αIIbβ3 decreased PITT formation, neutrophil infiltration, and tissue damage. In patients with sepsis, reduced platelet CD41a expression—reflecting PITT release—correlated with higher sequential organ failure assessment (SOFA) scores, acute respiratory distress syndrome, and mortality. Stratification by CD41a levels revealed that patients in the lowest quartile had substantially increased odds for adverse outcomes.

CONCLUSION

We propose that PITTs act as platelet-derived structures that redistribute the αIIbβ3/CD9 pool during severe infection and inflammation. By anchoring to leukocytes and endothelial cells, PITTs may amplify vascular inflammation and immune activation while leaving behind platelets with impaired adhesive function. This mechanism may explain the paradoxical coexistence of thrombo-inflammation and bleeding in critical illness. Beyond hemostasis, αIIbβ3 may serve as a proinflammatory effector that shapes immune responses and clinical outcome in inflammatory and infectious disease. Targeting PITT formation may offer new opportunities to modulate thrombo-inflammation without impairing platelet viability.