Aging platelets shift their hemostatic properties to inflammatory functions
Abstract
Abstract Platelets are crucial players in hemostasis and thrombosis but also contribute to immune regulation and host defense, using different receptors, signaling pathways, and effector functions, respectively. Whether distinct subsets of platelets specialize in these diverse tasks is insufficiently understood. Here, we used a pulse-labeling method in Mus musculus models for tracking in vivo platelet aging and its functional implications. Using in vitro and in vivo assays, we reveal that young, reticulated platelets show heightened responses in the setting of clot formation, with corresponding, increased responses to agonists, adhesion, and retractile function. Unexpectedly, aged platelets lose their hemostatic proficiency but are more prone to react to inflammatory challenge: compared with reticulated platelets, this cohort was more likely to form platelet-leukocyte aggregates and showed increased adhesion to neutrophils in vitro, as well as enhanced bactericidal function. In vivo, this was reflected in increased pulmonary recruitment of aged platelets in an acute lung injury model. Proteomic analyses confirmed the upregulation of immune pathways in this cohort, including enhanced procoagulant function. In mouse models of prolonged platelet half-life, this resulted in increased pulmonary leukocyte infiltration and inflammation upon acute lung injury. Similarly, human platelet concentrates decreased their hemostatic function and elevated their putative immunomodulatory potential in vitro over time, and in a mouse model of platelet transfusion, aged platelet concentrates resulted in augmented inflammation. In summary, we show that platelets exhibit age-dependent phenotypic shifts, allowing them to fulfill their diverse tasks in the vasculature. Because functional alterations of aging platelets extend to platelet concentrates, this may hold important implications for transfusion medicine.
Article Details
Authors (29)
Afra Anjum
1Medizinische Klinik und Poliklinik I, University Hospital Ludwig Maximilian University, Munich, Germany
Magdalena Mader
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Shaan Mahameed
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Abhinaya Muraly
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Frederik Denorme
Department of Emergency Medicine, School of Medicine, Washington University
Fabian P. Kliem
4Institute of Medical Psychology and Biomedical Center, Faculty of Medicine, Ludwig Maximilian University Munich, Munich, Germany
Dario Rossaro
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Sezer Agköl
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Lea Di Fina
8Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany
Maité Mulkers
1University Hospital of Ludwig Maximilian University
Lisa Laun
Institute for Evaluation of Labour Market and Education Policy (IFAU)
Lukas Li
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Nadja Kupper
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Keyang Yue
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Marie-Louise Hoffknecht
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Anastassia Akhalkatsi
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Quentin Loew
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Joachim Pircher
Raphael Escaig
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Erwin Strasser
5Division of Transfusion Medicine, Cell Therapeutics, and Hemostaseology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Christian Wichmann
Ludwig Maximilian University Hospital, Munich, Germany
Kami Pekayvaz
1Department of Medicine I, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Bernhard Nieswandt
9Institute of Experimental Biomedicine I, Würzburg, Germany
Christian Schulz
Maria S. Robles
Rainer Kaiser
Ludwig Maximilian University Hospital, Munich, Germany
Steffen Massberg
Robert Campbell
Leo Nicolai
1Medizinische Klinik und Poliklinik I, University Hospital Ludwig Maximilian University, Munich, Germany