Red Blood Cells in Hemostasis and Thrombosis: Mechanisms, Interactions, and Clinical Implications

Thrombus formation is a highly coordinated and complex process involving coagulation pathways, cellular components, and hemodynamic forces. Shaped by local flow conditions and the vascular environment, clot development is inherently heterogeneous, producing thrombi with regionally distinct composition and mechanical properties. For decades, red blood cells (RBCs) have occupied a peripheral position in models of hemostasis and thrombosis, defined largely within a reductionist framework emphasizing oxygen transport and bulk rheological effects. Within this paradigm, mechanistic models have focused on platelet and coagulation pathways, with erythrocytes viewed as passive bystanders.[ 1 ] In recent years, advances in high-resolution intravital imaging, microfluidic systems, and systems-level approaches have revealed more active roles for erythrocytes in thrombosis, including effects on platelet behavior, coagulation, and clot organization.[ 2 ] [ 3 ] Despite these advances, erythrocyte-driven mechanisms remain underrepresented in prevailing models, reflecting a persistent disconnect between emerging experimental evidence and established frameworks. Accordingly, more integrative models are required to fully account for the complexity and heterogeneity of thrombi observed in vivo. In this special issue of the journal, we bring together complementary perspectives that situate RBCs across the full continuum of hemostasis and thrombosis, from initiation through propagation, stabilization, and resolution. First, Kim et al. characterize erythrocytes as context-dependent amplifiers of thrombus initiation under flow, enhancing platelet accumulation at sites of vascular injury in a manner dependent on both hematocrit and platelet availability.[ 4 ] This effect persists under normal and moderately reduced platelet counts but is absent in severe thrombocytopenia, indicating that erythrocyte-mediated enhancement of platelet deposition is ultimately constrained by platelet levels. In parallel, reductions in hematocrit produce a disproportionately greater impairment in hemostatic efficiency than comparable reductions in platelet count, reinforcing the contribution of erythrocytes to effective clot formation. This finding aligns with the increased bleeding tendency observed in anemia and the hemostatic effects of RBC transfusion in cytopenic states. Next, Alamin et al. link erythrocyte properties to thrombotic outcomes through coordinated effects on blood viscosity, platelet interactions, and incorporation into the fibrin network, influencing thrombus formation and stability.[ 5 ] These relationships extend across clinical contexts, where alterations in erythrocyte count, deformability, and turnover are associated with increased thrombotic risk, including in conditions such as sickle cell disease, polycythemia vera, and following transfusion or storage-related changes. Phosphatidylserine exposure is identified as a procoagulant feature that may enhance thrombin generation, reinforcing the association between erythrocyte alterations and procoagulant activity. Subsequent contributions delineate distinct yet interconnected mechanisms through which erythrocytes acquire prothrombotic phenotypes. Borghi et al. describe oxidative stress-driven remodeling characterized by reduced deformability, membrane reorganization, and enhanced adhesive properties.[ 6 ] Noubouossie and Key identify erythrocyte-derived extracellular vesicles as mediators of thromboinflammatory signaling, linking altered red cell states to coordinated activation of coagulation and inflammatory pathways.[ 7 ] Bucciol et al. further emphasize intrinsic erythrocyte heterogeneity, demonstrating how intercellular variability translates into spatial and mechanical heterogeneity within thrombi, with implications for clot architecture, stability, and therapeutic responsiveness.[ 8 ] Ilbawi and Othman[ 9 ] and Alamin and Yahia[ 10 ] extend this framework by positioning erythrocyte biomechanics as a central determinant of flow-dependent cellular organization that shapes thrombus formation across pathological settings. In cancer-associated thrombosis, Ilbawi and Othman describe disease-driven alterations in deformability and aggregation, promoting microvascular flow disturbance and thrombotic susceptibility.[ 9 ] Alamin and Yahia describe how erythrocytes regulate platelet margination under flow and contribute to thrombus architecture through effects on clot structure and fibrin organization.[ 10 ] Together, these reports demonstrate how erythrocyte mechanical properties govern cellular distribution under flow and the structural organization of thrombi across diverse physiological and pathological contexts. Next, Wohner et al. examine the interaction between erythrocytes and tranexamic acid (TXA), providing evidence that its effects extend beyond plasmin inhibition to include modulation of fibrin structure.[ 11 ] Through factor XIII-mediated cross-linking and progressive incorporation of erythrocytes into the fibrin scaffold, TXA influences fibrin compaction and mechanical stability, thereby altering resistance to fibrinolysis. These findings suggest that erythrocytes contribute not only to thrombus susceptibility to lysis, but also to the structural evolution of the fibrin matrix, offering a potential mechanistic basis for the variability in TXA response among women, under conditions of altered hematocrit. The final contribution in this issue of Seminars in Thrombosis and Hemostasis (STH) , by Asghariastanehei et al. examines activation of the mechanosensitive ion channel Piezo1 and its effects on erythrocyte function and coagulation.[ 12 ] Pharmacologic activation disrupts ionic homeostasis, resulting in potassium efflux, sodium influx, cellular dehydration, and reduced deformability. These biophysical alterations are associated with changes in coagulation dynamics and thrombus architecture, including reduced clot compaction, underscoring the contribution of erythrocyte mechanical properties to thrombus formation and structure. Together, these contributions reflect a shift in how erythrocytes are viewed in the context of hemostasis and thrombosis, from passive rheological elements to active participants influencing thrombus formation, structure, and stability through complementary mechanisms. Across contexts, RBCs emerge as regulators of clot organization, interacting with fibrin, platelets, and flow-dependent forces to shape thrombus architecture and mechanical properties throughout clot evolution. This special issue, therefore, situates erythrocytes within the framework of platelet- and plasma-driven thrombosis, in which cellular composition and the mechanical environment jointly govern thrombus behavior. Collectively, these contributions support erythrocytes as active participants in thrombus formation and stability, while also highlighting remaining uncertainties regarding their function under physiological flow conditions. We anticipate this work will stimulate future research to clarify these processes and generate stronger evidence with meaningful clinical translation. We would like to sincerely thank all contributing authors for their high-quality work, the reviewers for their constructive feedback, and the Editorial Board of STH for the opportunity to assemble this special issue. We hope our readers find this collection useful and enjoyable. Authors' Contributions R.B.: conceptualization, writing—original draft, writing—review and editing. M.O.: conceptualization, writing—review and editing. Publication History Received: 06 May 2026 Accepted after revision: 12 May 2026 Article published online: 23 June 2026 © 2026. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA