PDF icon PDF herunterladen
Thromb Haemost
DOI: 10.1055/a-2641-6568
Invited Editorial Focus

Monocyte/Macrophages: Unexpected Allies in the Fight Against Arterial Thrombosis?

Gemma Vilahur    *
1   Sant Pau Research Institute (IR-SANT PAU), Barcelona, Spain
2   CIBERCV, Madrid, Spain
,
María Borrell-Pagés   *
1   Sant Pau Research Institute (IR-SANT PAU), Barcelona, Spain
2   CIBERCV, Madrid, Spain
› Institutsangaben
Funding This work was supported by Grant PID2021-128891OB-I00 (to G.V.), PLEC2021–007664- Unión Europea Next GenerationEU/PRTR (to G.V.), and Grant M-ERA-NET-3/PCI2023-143431 - EU Horizon 2020 (to G.V.) funded by MCIN/AEI/10.13039/501100011033 and Fondo Europeo de Desarrollo Regional (FEDER) A way of making Europe; CIBERCV-CB16/11/00411 (to G.V.), ERA-CVD JTC 202-023/AC20/00054 (to M.B.P.) and PI23-00589 ISCIII (to M.B.P.); and the Generalitat of Catalunya-Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat [2021SGR01006 to G.V.] and 2016PROD00043 (Agencia Gestión Ayudas Universitarias Investigación: AGAUR).
› Weitere Informationen
   Lizenzen und Reprints
Preview

Venous and arterial thrombosis share common cardiovascular risk factors, yet their underlying pathophysiological mechanisms and clinical presentations differ.[1] Venous thrombosis is often associated with stasis, endothelial injury, and hypercoagulability—commonly referred to as Virchow's triad. In contrast, arterial thrombosis is primarily driven by the exposure of the blood to prothrombogenic components at sites where atherosclerotic plaques have eroded or ruptured.[2] [3] Although in both conditions the roles of activated platelets, tissue factor (TF)-driven activation of the coagulation cascade, neutrophils/NETs, and inflammation are well-established, the particular contribution of monocytes/macrophages to thrombus formation remains less understood. So far, evidence shows that circulating monocytes interact with platelets and neutrophils (via various mechanistic pathways) in thrombus formation.[4] [5] [6] Yet, monocytes/macrophages have recently emerged as key players in gradual venous thrombus resolution.[7] In the setting of arterial thrombosis data are scarce. So far, higher monocyte TF-like activity and higher TF expression have been detected in patients who had recently suffered an acute coronary syndrome compared to healthy controls,[8] yet the role of monocyte/macrophages in the evolving arterial thrombi remains to be explored.

In this article of Thrombosis and Haemostasis, Lee et al[9] provide compelling data on the dynamic contribution of monocytes/macrophages in carotid arterial thrombosis and identify an association between the amount of monocyte/macrophage thrombus infiltration and improved outcome in stroke patients. First, the authors conduct a study using a mouse model of FeCl3-induced complete thrombotic occlusion of the carotid artery followed by distal ligation at several time points (0.5, 1, 2, 3, 6, 24, 48, and 72 hours) to characterize thrombus evolution over time. Immunohistochemical analyses reveal a time-dependent rise of monocyte/macrophage infiltration from 3 h post-occlusion onwards, peaking at 24 h and starting to decline at 48 h. Recent data on the same animal model have proven acute systemic monocytosis upon arterial thrombosis induction.[10] Changes in circulating leukocyte levels were evident within 30 minutes post carotid thrombosis induction and persisted for up to 4 days. These data suggest a potential temporal pattern of monocyte synthesis and release, either from the bone marrow or extramedullary sources,[11] which may sustain the continued recruitment of monocyte/macrophages to the developing thrombi within the first day post-event ([Fig. 1]). Macrophages are tissue-resident or infiltrated immune cells with a high plasticity.[12] Their phenotype and functions are heterogeneous and critically depend on the surrounding microenvironment.[13] It is considered that macrophages can polarize into two different phenotypes, M1 and M2. M1 macrophages produce pro-inflammatory cytokines (release IL-1β, IL-6, IL-12, IL-23, and TNF-α) whereas M2 macrophages display an anti-inflammatory and a pro-reparative phenotype (release IL-10 and TGF-β among others). Interestingly, Lee and colleagues detected M2 macrophages at early time points (30 min post-occlusion), reaching a maximal detection at 6 h and starting to decline at 48 h. Yet, whether monocytes exhibit a reparative phenotype upon reaching the culprit artery or if they undergo a phenotypic shift upon infiltrating the thrombus deserves to be investigated.

Zoom
Fig. 1 Potential thrombotic-resolving roles of monocytes and macrophages in atherothrombotic cardiovascular disease. Created in BioRender. Vilahur, G. (2025) https://BioRender.com/24g5dxc

The authors expand their investigations in the clinical setting by characterizing thrombi retrieved during endovascular thrombectomy from 102 stroke patients. For this purpose, they determine the cellular composition of thrombus (monocyte/macrophage, neutrophils, platelets and erythrocytes content) and extracellular components (fibrin[ogen]) and combine their observations with clinical data (patient characteristics and outcomes). Interestingly, the authors found a higher content of monocytes/macrophages in the thrombi removed from patients with fewer occurrences of parenchymal hematoma and greater rates of functional independence, supporting that monocyte/macrophage-rich thrombi predict improved outcomes. Hence, this study highlights the potential pro-resolving effects of M2 macrophages in the arterial bed, which likely contributes to the observed positive outcomes. Assessing the quantity and dynamics of pro-inflammatory macrophages would help rule out any potential counteractive effects on the anticipated benefits of M2 macrophages. Furthermore, the development of arterial thrombosis is primarily initiated by macrophage-derived TF exposure following atherosclerotic plaque disruption.[2] [3] Experimental evidence from the same thrombotic mouse model has established a direct correlation between TF activity and thrombotic occlusion.[14] [15] Evaluating TF expression and activity within the evolving thrombi could provide valuable functional insights into the infiltrating monocyte/macrophage populations, with significant clinical implications.[5] [16]

Finally, this study also provides the first evidence of the dynamics of monocytes/macrophages in arterial thrombus formation. As such, monocytes/macrophages infiltrate the evolving thrombus in a time-dependent manner, reaching a maximal amount at later stages of thrombus maturation (1–2 days) rather than acutely in the initial triggering phase. This experimental data in a model of vascular-injury-induced thrombosis is supported by human data in which the authors classify thrombi as fresh or old based on hematoxylin–eosin staining. Fresh thrombi are characterized by active coagulation, ongoing platelet aggregation, and enhanced inflammatory response. In contrast, older thrombi exhibit signs of fibrinolysis and structural remodeling, becoming more stable and less susceptible to embolization.[17] Notably, old thrombi are more prevalent in stroke patients who display high monocyte/macrophage content and consequently better outcomes further supporting a macrophage pro-resolving phenotype.

Overall, this study supports that infiltrated monocyte/macrophages may act as unexpected allies in the fight against arterial thrombosis. It remains to be determined whether a similar response applies to coronary-induced arterial thrombosis and its potential to limit myocardial damage in the setting of myocardial infarction ([Fig. 1]). Most importantly, these findings also underscore the necessity of considering the broader implications of modulating the innate immune response in ischemic diseases, extending beyond their anticipated effects on the target organ.

* These authors contributed equally to this work.




Publikationsverlauf

Eingereicht: 13. Juni 2025

Angenommen: 23. Juni 2025

Artikel online veröffentlicht:
04. Juli 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany