Platelets mediate the clearance of senescent red blood cells by forming prophagocytic platelet-cell complexes

Dian C. Ningtyas, Florentina Leitner, Huma Sohail, Yee Lin Thong, Sarah M. Hicks, Sidra Ali, Megan Drew, Kiran Javed, Jiwon Lee, Enny Kenangalem, Jeanne R. Poespoprodjo, Nicholas M. Anstey, Melanie Rug, Philip Y.I. Choi, Steven Kho, Elizabeth E. Gardiner, Brendan J. McMorran

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In humans, ∼0.1% to 0.3% of circulating red blood cells (RBCs) are present as platelet-RBC (P-RBC) complexes, and it is 1% to 2% in mice. Excessive P-RBC complexes are found in diseases that compromise RBC health (eg, sickle cell disease and malaria) and contribute to pathogenesis. However, the physiological role of P-RBC complexes in healthy blood is unknown. As a result of damage accumulated over their lifetime, RBCs nearing senescence exhibit physiological and molecular changes akin to those in platelet-binding RBCs in sickle cell disease and malaria. Therefore, we hypothesized that RBCs nearing senescence are targets for platelet binding and P-RBC formation. Confirming this hypothesis, pulse-chase labeling studies in mice revealed an approximately tenfold increase in P-RBC complexes in the most chronologically aged RBC population compared with younger cells. When reintroduced into mice, these complexes were selectively cleared from the bloodstream (in preference to platelet-free RBC) through the reticuloendothelial system and erythrophagocytes in the spleen. As a corollary, patients without a spleen had higher levels of complexes in their bloodstream. When the platelet supply was artificially reduced in mice, fewer RBC complexes were formed, fewer erythrophagocytes were generated, and more senescent RBCs remained in circulation. Similar imbalances in complex levels and senescent RBC burden were observed in humans with immune thrombocytopenia (ITP). These findings indicate that platelets are important for binding and clearing senescent RBCs, and disruptions in platelet count or complex formation and clearance may negatively affect RBC homeostasis and may contribute to the known risk of thrombosis in ITP and after splenectomy.

Original languageEnglish
Pages (from-to)1-36
Number of pages36
Publication statusE-pub ahead of print - 22 Nov 2023


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