A new investigation into Long COVID has identified a physical connection between circulating microclots and neutrophil extracellular traps (NETs). This link points to underlying biological interactions between the two, which may contribute to illness when these processes fall out of balance.
Microclots are small, unusual clusters of blood clotting proteins that circulate in the bloodstream. The term became widely used in 2021 after Prof Resia Pretorius of Stellenbosch University's Department of Physiological Sciences reported finding these abnormal protein clumps in blood samples from COVID-19 patients. Their potential involvement in COVID-related clotting problems drew significant attention as the pandemic unfolded.
Dr. Alain Thierry and his group at the Montpellier Cancer Institute (IRCM) at INSERM in Montpellier were among the first to highlight the importance of NETs in COVID-19. NETs form when neutrophils release their DNA through a process called NETosis, creating thread-like structures filled with harmful enzymes that can quickly trap and neutralize invading microbes.
Although NETs help defend against infection, producing too many of them can be harmful. Excess NET formation has been linked to serious inflammatory and clotting conditions, including severe infections, autoimmune diseases, cancer, diabetes, and arthritis. Dr. Thierry notes that ongoing overproduction of NETs, driven by cycles of inflammation and clot formation, may worsen disease severity.
In light of this, the teams led by Prof Pretorius and Dr. Thierry worked together to examine whether microclots and NETs interact in patients with Long COVID.
Using imaging flow cytometry and fluorescence microscopy, the researchers conducted detailed measurements of microclots and NETs in the plasma of individuals with Long COVID and compared the results to healthy controls. They also quantified NETs by assessing proteic markers and circulating DNA.
They reported several major observations:
"This finding suggests the existence of underlying physiological interactions between microclots and NETs that, when dysregulated, may become pathogenic," explains Dr. Thierry.
The researchers also incorporated Artificial Intelligence tools, including machine learning, to analyze biomarker patterns. These methods allowed them to accurately differentiate Long COVID patients from healthy individuals and to pinpoint the most informative biomarker combinations. Such insights could support more precise diagnostics and future personalized treatments.
Prof Pretorius emphasizes that the study reveals a buildup of microclots in the plasma of Long COVID patients, likely supported by excessive NET activity: "This interaction could render microclots more resistant to fibrinolysis, promoting their persistence in circulation and contributing to chronic microvascular complications," she explains.
By clarifying how NETs may stabilize microclots, the study contributes valuable information about the biological processes involved in Long COVID. The findings also highlight potential therapeutic approaches aimed at reducing harmful clotting and inflammation.
In addition, the work advances the search for new biomarkers that could help diagnose and manage Long COVID. As the authors note, "The combination of advanced imaging techniques and machine learning confers methodological robustness and contributes significantly to the ongoing scientific discourse on post-viral syndromes."
In patients with Long COVID, a new study has revealed structural association between circulating microclots and neutrophil extracellular traps (NETs).
This finding suggests the existence of underlying physiological interactions between microclots and NETS that, when dysregulated, may become pathogenic.
The term microclots, recently adopted in the scientific literature, refers to abnormal clumps of blood clotting proteins circulating in a patient's blood stream. The concept was introduced in 2021 by Prof. Resia Pretorius from Stellenbosch University's Department of Physiological Sciences, when they found the abnormal presence of such microclots in the blood samples of COVID-19 patients. This discovery generated widespread attention during the pandemic due to its potential role in COVID-related coagulopathies.
What are neutrophil extracellular traps (NETs)?
Dr. Alain Thierry's team at the Montpellier Cancer Institute (IRCM) at INSERM in Montpellier, was among the first to identify the critical role of NETs in the pathogenesis of COVID-19. NETs are produced through a specialised form of innate immune response known as NETosis, whereby neutrophils expel their DNA to form filamentous structures embedded with cytotoxic enzymes capable of rapidly trapping and neutralizing pathogens.
However, excessive NETs formation can become detrimental, contributing to a wide range of inflammatory and thrombotic diseases, including severe infections, autoimmune disorders, cancer, diabetes, and arthritis.
According to Dr. Thierry, it may be that persistent overproduction of NETs, fueled by self-perpetuating inflammatory and thrombotic loops, exacerbates disease severity.
In a collaborative effort, the teams of Prof. Pretorius and Dr. Thierry investigated the potential interaction between microclots and NETs in the context of Long COVID.
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