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

ABSTRACT: 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.

Patients with Waldenström macroglobulinemia have impaired platelet and coagulation function.

ABSTRACT: Clinical features in patients with the B-cell lymphoma, Waldenström macroglobulinemia (WM), include cytopenias, immunoglobulin M (IgM)-mediated hyperviscosity, fatigue, bleeding, and bruising. Therapeutics such as Bruton's tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal hemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not yet been investigated in patients with WM. Therefore, this study aimed to evaluate hemostatic dysfunction in samples from these patients. Whole blood (WB) samples were collected from 14 patients with WM not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs). Platelet receptor levels and reticulation were measured by flow cytometry, plasma thrombin generation with or without platelets by fluorescence resonance energy transfer assay, WB clotting potential by rotational thromboelastometry, and plasma soluble glycoprotein VI (sGPVI) and serum thrombopoietin (TPO) by enzyme-linked immunosorbent assay. Donor platelet spreading, aggregation, and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed. WM platelet receptor levels, responses to physiological agonists, and plasma sGPVI were within normal ranges. WM platelets had reduced reticulation (P = .0012) whereas serum TPO levels were increased (P = .0040). WM plasma displayed slower thrombin generation (P = .0080) and WM platelets contributed less to endogenous thrombin potential (ETP; P = .0312). HD plasma or platelets incubated with IgM (50-60 mg/mL) displayed reduced spreading (P = .0002), aggregation (P < .0001), and ETP (P = .0081). Thus, alterations to thrombin potential and WB coagulation were detected in WM samples. WM IgM significantly impaired hemostasis in vitro. Platelet and coagulation properties are disturbed in patients with well-managed WM.