Platelet-Red Blood Cell Interactions in Thrombosis: Integrating Hemodynamic, Molecular, and Clinical Evidence-A Systematic Review.

Abstract There is growing recognition that red blood cells (RBCs) play a role in thrombosis beyond their traditional role as passive cellular components. This systematic review synthesizes contemporary evidence on RBC-platelet interactions in the mechanistic, structural, and clinical domains. A comprehensive search of PubMed, Scopus, Web of Science, and ScienceDirect from January 2014 to March 2026 identified 45 eligible studies, predominantly experimental and in vitro studies, with fewer animal, computational, and clinical/translational studies. Available evidence suggests that RBCs may contribute to thrombosis through several partially overlapping pathways, including shear-dependent platelet margination, phosphatidylserine-associated thrombin generation, direct RBC-platelet adhesion, and EV-associated procoagulant activity. In addition, the biophysical properties of RBCs influence thrombus architecture, density, and stability. Clinical studies have suggested an association between altered RBC function and thrombotic risk in conditions such as polycythemia, diabetes mellitus, and sickle cell disease. However, despite consistent mechanistic evidence, clinical validation remains limited, particularly in large-scale human studies. Overall, these findings support a more integrated cellular framework of thrombosis, in which RBCs may modulate platelet behavior, coagulation dynamics, and thrombus architecture. However, because most of the included studies were experimental or mechanistic, clinical translation remains limited. Future research should prioritize standardized experimental platforms, harmonized outcome measures, and prospective multicenter clinical studies before RBC-related parameters can be considered for biomarker development and therapeutic targeting.