Portal de investigación
High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2-induced prothrombotic state.
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Payá M
- Alcahut-Rodríguez C
- Barbella-Aponte RA
- Hernández-Fernández F
- Molina-Nuevo JD
- Barroso-García G
- Castro-Robles B
- López-López S
- Arias-Salazar L
- Ayo-Martín Ó
- García-García J
- Yélamos-Sanz B
- García-Flores N
- Arandilla AG
- Moreno-Luna R
- Serrano-Heras G
- Segura T
Grupos
Abstract
The pathophysiological mechanisms underlying the hypercoagulable state and thrombotic events associated with COVID-19 remain incompletely understood. To investigate prothrombotic alterations during SARS-CoV-2 infection, we performed an exploratory and integrated analysis of cerebral thrombi retrieved, during the first wave of the pandemic, by mechanical thrombectomy from stroke patients with (n=6) and without (n=6) COVID-19. We combined histological and ultrastructural assessment with quantitative proteomics and elemental profiling to identify differences in cellular organization and in protein and metal composition. Immunohistochemical quantification revealed a trend toward increased macrophage abundance, a more diffuse CD68? staining pattern, and reduced platelet content in COVID-19 thrombi. In contrast, neutrophil extracellular traps (NETs) burden, neutrophil number, and erythrocyte content did not differ significantly between groups. Transmission electron microscopy showed a disorganized ultrastructural fibrillar network in thrombi from COVID-19 stroke patients, consistent with the irregular and less densely packed extracellular matrix observed by Masson's trichrome staining. Furthermore, quantitative proteomics by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 48 differentially expressed proteins among 720 shared proteins, with marked upregulation of hemoglobin subunits (a, ß, ?, and d), haptoglobin, biliverdin reductase and redox-regulating proteins, alongside downregulation of platelet-related proteins in COVID-19 thrombi. Total reflection X-ray fluorescence (TXRF) confirmed increased iron levels in COVID-19-associated thrombi. Notably, glycophorin A immunostaining did not indicate increased erythrocyte abundance, and erythrocyte structural proteins were not differentially expressed in proteomic analysis, suggesting that hemoglobin and iron were largely present in a cell-free form within the retrieved thrombi of COVID-19 stroke patients. In addition, acute-phase reactants, classical complement components, and immunoglobulins were detected exclusively in COVID-19 samples, consistent with a distinctive immune-inflammatory and oxidative signature. Overall, these findings support a novel pathophysiological mechanism underlying COVID-19-associated hypercoagulability and thrombosis, involving elevated circulating cell-free hemoglobin and increased iron content. Furthermore, this study highlights the potential contribution of hemoglobin/iron-related processes to the COVID-19 prothrombotic state and may provide molecular targets for future therapeutic strategies.
© 2026. The Author(s).
Datos de la publicación
- ISSN/ISSNe:
- 0001-6322, 1432-0533
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 42667425
- Factor de Impacto:
- 5,203 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
ACTA NEUROPATHOLOGICA SPRINGER
Documentos
- No hay documentos
Filiaciones
Keywords
- COVID-19; Hemoglobin; Hypercoagulability; Iron; Prothrombotic state; Quantitative proteomics; Stroke
Cita
Payá M,Alcahut C,Barbella RA,Hernández F,Molina JD,Barroso G,Castro B,López S,Arias L,Ayo Ó,García J,Yélamos B,García N,Arandilla AG,Moreno R,ALIENA A,VIELBA I,TEMBL JI,SALOM JB,Serrano G,Segura T. High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2-induced prothrombotic state. Acta Neuropathol. 2026. 152. (1):26. IF:10,300. (1).