Platelets mediate the clearance of senescent red blood cells by forming pro-phagocytic platelet-cell complexes.

In humans approximately 0.1-0.3% of circulating red blood cells (RBC) are present as platelet-RBC (P-RBC) complexes, and 1-2% in mice. Excessive P-RBC complexes are found in diseases that compromise RBC health (e.g. 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, RBC nearing senescence exhibit physiological and molecular changes akin to platelet-binding RBC in sickle cell disease and malaria. We therefore hypothesized that RBC nearing senescence are targets for platelet binding and P-RBC formation. Confirming this hypothesis, pulse-chase labelling studies in mice revealed an approximately ten-fold increase in P-RBC complexes in the most chronologically aged RBC population compared to 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 RBC remained in the 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 RBC, 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 post-splenectomy.