Long COVID cognitive issues linked to clotting proteins


By Selina Wellbelove

10 Sep 2023

High levels of fibrinogen or D-dimer in the blood have been linked to common symptoms of long COVID such as brain fog and fatigue, new data from the PHOSP-COVID trial shows.

The two distinct blood biomarker profiles predicted cognitive deficits at six and twelve months after COVID-19, the researchers from the Universities of Oxford and Leicester reported.

The research team analysed the blood tests and cognitive outcomes of 1,837 patients in the PHOSP-COVID cohort who had been hospitalised for COVID-19 in the UK during the first wave of the pandemic, in a bid to discover the underlying mechanisms for cognitive issues after the acute phase of infection.

They found one subset of patients who had raised fibrinogen but normal levels of C reactive protein, thus indicating a state of hypercoagulation, who had both objective and subjective cognitive issues six and 12 months post infection.

A second subset patients had raised D-dimer levels relative to CRP.  These patients experienced only subjective cognitive deficits but also reported a reduced ability to work, with additional symptoms of fatigue and shortness of breath.

“Both fibrinogen and D-dimer are involved in blood clotting, and so the results support the hypothesis that blood clots are a cause of post-COVID cognitive problems,” said co-lead author Dr Max Taquet, NIHR Academic Clinical Fellow in Psychiatry, University of Oxford.

“Fibrinogen may be directly acting on the brain and its blood vessels, whereas D-dimer often reflects blood clots in the lungs and the problems in the brain might be due to lack of oxygen. In line with this possibility, people who had high levels of D-dimer were not only at a higher risk of brain fog, but also at a higher risk of respiratory problems,” he noted.

Interestingly, the team also found evidence to suggest that raised fibrinogen is a common mechanism by which people develop cognitive issues, as cognitive deficits at six months were identified in those with raised levels of the protein regardless of whether they had COVID or not.

[The finding] “might reflect immunothrombotic events with potential direct effects of fibrinogen on the brain,” the researchers suggested in their paper published in Nature Medicine (link here).

However, this was not seen with the D-dimer profile; the data showed that people without COVID but raised levels of this protein were not at increased risk of developing cognitive issues after six months compared to those with normal levels, thus showing some specificity to the COVID virus.

Study limitations

Limitations include that the data are based on hospitalised patients and so it remains unknown whether they also apply to people with milder forms of COVID-19, who can also experience cognitive issues after infection, and also whether these symptoms persist beyond one year.

Also, as Professor Beverley Hunt told the limbic: “It is not clear when cognitive deterioration in the patients studied occurred, and it could have been as a result of cerebral damage at the time of acute infection.

“Secondly we need to remember that most cases of ‘long Covid’ had an initial mild infection and don’t have significantly raised levels of fibrinogen and D-dimer,” she added.

Nevertheless, the authors believe the mechanistic insights provided in their trial might help suggest further studies and treatment evaluations.

“For instance, investigations of brain imaging in people with post-COVID cognitive deficits might identify whether there is evidence of cerebral ischemia. If this is so, then evaluation of anticoagulants during the acute illness in a population at risk might be worthwhile”, they wrote.

The researchers also stressed that the mechanisms are speculative and more research was needed. In the meantime, the biomarker profiles might help in the development of predictive models of post-COVID cognitive deficits, they added.

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