High levels of 2 blood-clotting proteins may portend post-COVID brain fog

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High levels of two blood biomarkers during infection could predict cognitive dysfunction, or "brain fog," among COVID-19 survivors 6 and 12 months after hospitalization, according to a UK study published yesterday in Nature Medicine.

The findings, the authors said, provide further insights into the diverse biologic factors involved in post-COVID cognitive deficits.

University of Oxford researchers identified two profiles related to elevated levels of the biomarkers fibrinogen and D-dimer relative to C-reactive protein (CRP) in 1,837 hospitalized adults who tested positive for COVID-19 in the United Kingdom from January 2020 to November 2021.

The team collected blood samples from patients at hospital admission and gathered clinician- and patient-acquired measurements of cognition 6 and 12 months later. Average patient age was 57.9 years, and 36.6% were women.

"One in eight patients receives their first ever neurological or psychiatric diagnosis within 6 months following COVID-19," the researchers wrote. "Among these symptoms, cognitive deficits (including 'brain fog') are particularly worrisome; they are common, persistent and they affect the ability to work."

Brain fog, occupational problems

Two blood-clotting protein profiles were highly correlated with persistent cognitive impairment. High levels of fibrinogen were correlated with both objective and subjective cognitive impairment, and high levels of D-dimer were correlated with subjective cognitive deficits such as brain fog and occupational impairment mediated by fatigue, as well as shortness of breath.

Elevated levels of both biomarkers occurred in patients with lower-than-expected levels of CRP, when levels of both are typically correlated at the cohort level. High D-dimer levels were linked with occupational impairment at 6 and 12 months, while fibrinogen was not.

The associations were specific to biomarkers measured during the acute (rather than post-acute) phase and they cannot be accounted for simply by more severe illness (as there was no mediation by severity of the acute illness) nor by pre-existing cognitive deficits.

When subjective pre- and post-COVID cognition were compared, cognitive function had deteriorated from before infection to 6 and 12 months. Preexisting cognitive problems weren't tied to either biomarker profile, providing evidence that high fibrinogen or D-dimer levels relative to CRP aren't seen in people with pre-existing deficits.

Patients with high fibrinogen levels were at greater risk of post-acute cognitive deficits, regardless of whether they had COVID-19 or a different disease. In contrast, high D-dimer levels were linked to post-acute cognitive deficits in COVID-19 patients, who differed from other patients with high D-dimer levels in their risk of peripheral (venous blood clots) rather than central (ischemic stroke) thrombosis.

The results were largely replicated in a separate study using the health records of 17,911 US patients that compared pandemic and prepandemic groups, which the researchers said suggests the specificity of D-dimer for SARS-CoV-2.

Illness severity alone can't explain deficits

"The associations were specific to biomarkers measured during the acute (rather than post-acute) phase and they cannot be accounted for simply by more severe illness (as there was no mediation by severity of the acute illness) nor by pre-existing cognitive deficits," the study authors wrote.

"These biomarker profiles, based on routine blood tests, might help in the development of predictive models of post-COVID cognitive deficits, which could facilitate prognosis and accelerate research into management strategies," they added.

In expert reaction published by the Science Media Centre, Aravinthan Varatharaj, BMBCh, PhD, a clinical lecturer in neurology at the University of Southampton who wasn't involved in the study, said that although brain fog is common and disabling, it doesn't have an accepted medical definition and likely describes more than one set of related symptoms.

"It is interesting that raised fibrinogen, which might have a direct effect on the brain, was associated with both objective and subjective thinking problems, suggesting a common mechanism," he said. "Whereas raised D-dimer, which is linked to lung problems, was only associated with subjective thinking problems, suggesting perhaps effects of low oxygen levels and fatigue."

Varatharaj said future research should examine whether blood thinners could help patients with persistent post-COVID cognitive deficits.

"However, several large studies have shown that stronger blood thinning treatment during acute covid has little or no benefit and is potentially harmful due to increased risk of bleeding," he said. "Further studies should look at whether certain people might benefit from targeted blood thinning treatment during and after covid."


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