Preferential and sustained platelet activation in COVID-19 survivors with mental disorders, 2024, Maugeri et al.

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Preferential and sustained platelet activation in COVID-19 survivors with mental disorders
Maugeri, Norma; De Lorenzo, Rebecca; Mazza, Mario Gennaro; Palladini, Mariagrazia; Ciceri, Fabio; Rovere-Querini, Patrizia; Manfredi, Angelo A.; Benedetti, Francesco

Pre-existing mental disorders are considered a risk factor for severe COVID-19 outcomes, possibly because of higher vascular burden. Moreover, an unconventional platelet activation characterizes COVID-19 and contributes to inflammatory and thrombotic manifestations. In the light of the inflammation theory of mental disorders, we hypothesized that patients with mental disorders could be sensitive to the SARS-CoV-2 elicited platelet activation.

We investigated platelet activation in 141 COVID-19 survivors at one month after clearance of the virus, comparing subjects with or without an established pre-existing diagnosis of mental disorder according to the DSM-5. We found that platelets from patients with a positive history of psychiatric disorder underwent unconventional activation more frequently than conventional activation or no activation at all. Such preferential activation was not detected when platelets from patients without a previous psychiatric diagnosis were studied. When testing the effects of age, sex, and psychiatric history on the platelet activation, GLZM multivariate analysis confirmed the significant effect of diagnosis only.

These findings suggest a preferential platelet activation during acute COVID-19 in patients with a pre-existing psychiatric disorder, mediated by mechanisms associated with thromboinflammation. This event could have contributed to the higher risk of severe outcome in the psychiatric population.

Link | PDF (Nature Scientific Reports) [Open Access]

 

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This is the first study to report a significantly higher rate of platelet activation after SARS-CoV-2 infection patients with a pre-existing DSM-5 psychiatric diagnosis. This effect was explained by a higher rate of unconventional platelet activation, which in previous studies has been shown to be exquisitely dependent on the CD147 receptor on the platelet surface, and specifically triggered by the SARS-CoV-2 infection.

The integral plasma membrane glycoprotein CD147 (cluster of differentiation 147), also known as basigin, or extracellular matrix metalloproteinase inducer (EMMPRIN), is a member of the immunoglobulin superfamily of proteins that are involved in the recognition, binding, or adhesion processes of cells. CD147 mediates inflammatory activation in several cells, including macrophages, and the expression of inflammatory cytokines and chemokines in endothelial cells, which may contribute to the pathogenesis of inflammatory diseases. CD147 is widely expressed in many cell types, including haematopoietic, epithelial, endothelial cells and leukocytes. In the normal brain, it is expressed in neurons, astrocytes, vascular endothelial cells, microglia, and it is suggested to play a major role in the pathogenetic mechanisms involved in ischemic stroke, brain injury, multiple sclerosis, Alzheimer's disease.

Although CD147 was never studied in psychiatric conditions, indirect evidence suggests its involvement. CD147 is the main stimulator of matrix metalloproteinases, which are key enzymes in maintaining the integrity of the extracellular matrix, and in modulating inflammation and innate immunity, to regulate barrier function, inflammatory cytokine and chemokine activity, and to generate chemokine gradients. Matrix metalloproteinases are upregulated in several psychiatric conditions including MDD and BD, correlating with anxiety, and thus suggesting a possible upregulation of CD147.

In proposing a mechanism for the enhanced CD147-dependent platelet activation in patients with psychiatric conditions, it is then tempting to hypothesize that it might be due to a higher expression of CD147, or to a higher responsivity of the CD147 signaling pathway, linked with the psychiatric diagnosis, and/or with a higher sensitivity to the effects of stress associated with the pandemic and with the life-threatening experience of COVID-19 pneumonia. This mechanistic hypothesis needs to be tested in further studies.

See also —

AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4 (2024, Viruses)

Unconventional CD147‐dependent platelet activation elicited by SARS‐CoV‐2 in COVID‐19 (2022, Journal of Thrombosis and Haemostasis)

SARS-CoV-2 Entry: At the Crossroads of CD147 and ACE2 (2021, Cells)

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells (2020, Nature Signal Transduction and Targeted Therapy)