Splenic regulation of systemic platelet activation state
Platelets are essential to prevent blood loss and to orchestrate inflammation. Thrombotic complications of vascular disease and hyperresponsive platelets are associated with adverse outcomes, yet physiological mechanisms counteracting systemic platelet activation are poorly defined. In mice, we found that the spleen filters activated platelets in thrombotic and inflammatory conditions, limiting pathology by maintaining platelet quiescence. Glycoprotein VI-dependent activation of platelets initiated by extracellular matrix components in the splenic red pulp was counterbalanced by G6b-B-immunoreceptor tyrosine-based inhibitory motif signaling triggered by perlecan in quiescent platelets, allowing them to recirculate. By contrast, threshold activation signals in preactivated platelets could override inhibition, leading to splenic capture through inside-out signaling and β1-integrin engagement. Thus, the spleen acts as a modulator of platelet responsiveness and thrombo-inflammatory risk.
Authors
- Craig Balmforth (ORCID: https://orcid.org/0009-0005-1991-0017)
- Zoltán Nagy (ORCID: https://orcid.org/0000-0001-6517-2071)
- Florian Gaertner (ORCID: https://orcid.org/0000-0001-6120-3723)
- Konstantin Hoffmann (ORCID: https://orcid.org/0000-0003-2268-5816)
- Steffen Maßberg (ORCID: https://orcid.org/0000-0001-7387-3986)
- Bernhard Nieswandt (ORCID: https://orcid.org/0000-0003-1454-7413)
- Matthias P. Fabritius (ORCID: https://orcid.org/0000-0002-3471-4701)
- Rainer Kaiser (ORCID: https://orcid.org/0000-0003-1750-3395)
- Marie‐Louise Hoffknecht (ORCID: https://orcid.org/0000-0002-5894-0308)
- Dario Rossaro (ORCID: https://orcid.org/0000-0003-1301-8739)
- Filip K. Świrski (ORCID: https://orcid.org/0000-0002-3163-9152)
- Alexander Leunig (ORCID: https://orcid.org/0000-0002-9179-9203)
- Gabriel H. M. Araujo (ORCID: https://orcid.org/0000-0002-2859-9364)
- Johanna Knechtel
- Konstantin Stark (ORCID: https://orcid.org/0000-0002-5369-8399)
- Frederick Klauschen (ORCID: https://orcid.org/0000-0002-9131-2389)
- Alexandra Mazharian (ORCID: https://orcid.org/0000-0002-0204-3325)
- Afra Anjum (ORCID: https://orcid.org/0000-0002-1976-4102)
- Jean Solarz (ORCID: https://orcid.org/0000-0003-3282-2976)
- Lisa Laun (ORCID: https://orcid.org/0000-0002-1525-5685)
- Leo Nicolai (ORCID: https://orcid.org/0000-0003-0776-5885)
- David E. Newby (ORCID: https://orcid.org/0000-0001-7971-4628)
- Magdalena Mader
- Yotis A. Senis (ORCID: https://orcid.org/0000-0002-0947-9957)
- Sezer Akgöl (ORCID: https://orcid.org/0000-0002-3154-3214)
- Raphael Escaig
- Robin Dewender (ORCID: https://orcid.org/0009-0003-1192-3791)
- Shaan Mahameed (ORCID: https://orcid.org/0009-0002-8372-6562)
- Michael Schmid (ORCID: https://orcid.org/0009-0003-5012-4159)
- Lennart Kreutz
- Maité Mulkers (ORCID: https://orcid.org/0009-0003-4402-2682)
- Nellie M. Kwabla (ORCID: https://orcid.org/0009-0003-1173-9855)
- Felix Zhang (ORCID: https://orcid.org/0009-0005-9984-9163)
- Heiko Schulz
- Justus Reittinger (ORCID: https://orcid.org/0009-0007-2033-324X)
- Hannah Niederdorfer (ORCID: https://orcid.org/0009-0009-7164-2602)
- Nathalie Mackert
Institutions
- University of Würzburg (DE)
- Edinburgh Cancer Research (GB)
- LMU Klinikum (DE)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Universitätsklinikum Würzburg (DE)
- German Centre for Cardiovascular Research (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Edinburgh (GB)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2026-09-17
- DOI
- https://doi.org/10.1126/science.aec7230
- Primary Topic
- Platelet Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
- European Research Council
- H2020 European Research Council