Potential Biomarkers of Long COVID


A new study offers some clues into the pathophysiology and biomarkers of post-acute Sequelae of SARS-CoV-2 (PASC).

It remains a mystery in why acute COVID-19 infections can evolve into PASC or Long COVID. Medical science has been investigating some potential clues with pathophysiology and biomarkers that offer some indications. Still, until an understanding of the condition has been developed, definitive tests to identify and diagnose Long COVID remains impossible.

One area that might offer a key to diagnosing Long COVID is blood serum proteins. Carlo Cervia-Hasler et al, showed that patients experiencing Long COVID, “exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury.” This was a multicenter study, which consisted of 39 healthy control patients and 113 COVID-19 patients who were followed-up to 1 year after initial confirmation of infection through PCR test. After confirmation of acute infection, patients were seen for follow-up appointments at 6 months and 12 months to identify biomarkers associated with Long COVID. At the 6-month follow-up, 40 patients had Long COVID symptoms.1

More research shared at this week’s ongoing Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, CO, looks to shed some more light into characteristics of Long COVID through blood-related biomarkers.

In previous research performed by Zhu, et al, COVID-19 pathophysiology was seen to be profoundly altered by infection of lung megakaryocytes (MKs) and platelets by SARS‐CoV‐2. For the CROI study, He et al, collected blood samples from 3 different groups: participants with Long COVID with symptoms duration > 3 months with 30 in this group; patients who were previously infected with COVID-19 but without persistent symptoms (10 people); and healthy donors (20 people).2

Flow cytometry was utilized to quantify MK frequency. The investigators analyzed platelets and blood MKs for microclots, and the presence of spike protein and SARS-CoV-2 RNA. Spike and serotonin were quantified in plasma.2

“The frequency of CD41+ MKs in peripheral blood mononucleated cells (PBMCs) was significantly higher than healthy donors (0.28± 0.05 versus 0.03± 0.02) as a sign of MK infection, as we previously shown in acutely infected individuals with SARS-CoV-2 in platelets. Accordingly, in all samples analyzed, circulating MK in Long COVID sheltered both Spike and SARS-CoV-2 ssRNA, but also dsRNA suggestive of viral replication,” the investigators wrote.2

Potential Takeaway

“In patients developing Long COVID, SARS-CoV-2 persists and replicates in MKs producing virus-containing platelets,” the investigators wrote. The presence of spike in plasma might be an additional sign of viral persistence that could be used as a Long COVID biomarker,” the investigators wrote. 2

They postulate that the presence of SARS-CoV-2 could “lead to abnormal platelet activation and the formation of microclots, which would contribute to the various symptoms and to deregulation of serotonin uptake, contributing to the neurocognitive symptoms observed in long-onset COVID.”2


1.Parkinson J. Changes to Blood Proteins May Offer Further Insights Into Diagnosing Long COVID. ContagionLive. Janauary 23, 2024. Accessed March 4, 2024. https://www.contagionlive.com/view/changes-to-blood-proteins-may-offer-further-insights-into-diagnosing-long-covid

2. He F, Huang B, Cottignies-Calamarte A, et al. Persistence of SARS-CoV-2 in Platelets and Megakaryocytes in Long COVID. Poster #347 presented at CROI 2024. March 3-6, 2023. Denver, CO.

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