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Long COVID Microclots are Wrapped In Sticky DNA Webs
Millions of people worldwide continue to struggle with Long COVID, a debilitating condition that leaves persistent symptoms long after the initial infection. Among the most common and disruptive are chronic fatigue and brain fog, which may stem in part from tiny blood clots, known as microclots, that obstruct blood flow in the body’s smallest vessels: the capillaries.
Recent studies have uncovered a striking detail: in patients with Long COVID, microclots are often wrapped in DNA released by neutrophils (a type of white blood cell). These sticky DNA webs, called neutrophil extracellular traps (NETs), appear to make the microclots unusually resistant to the body’s natural mechanisms for breaking them down.
As a result, these persistent microclots may fuel ongoing chronic inflammation, reduced oxygen delivery to tissues, and a range of symptoms, including profound fatigue, brain fog, and even organ damage. While this phenomenon has been most intensively studied in Long COVID, similar microclots have also been observed in other conditions, such as ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), rheumatoid arthritis, Alzheimer’s disease, and Parkinson’s disease.
If you’re eager to learn the latest microclot research and emerging treatment approaches, you’ve come to the right place. Let’s begin by understanding the difference between typical blood clots and microclots.
Brief Summary
A new discovery reveals that microclots in people with Long COVID are wrapped in DNA from neutrophil extracellular traps (NETs), webs of DNA and proteins released from neutrophils. These NETs appear to stabilize microclots, making them harder to break down and potentially worsening symptoms such as fatigue and brain fog by impairing blood flow. This blog post describes microclot triggers (e.g., the SARS-CoV-2 spike protein, LPS, and others), amyloid misfolding within microclots, and potential treatments, such as anticoagulants.
What Are Microclots and How Do They Differ from Typical Blood Clots?
Physiological (typical) clots form when a blood vessel is broken. Pathophysiological (harmful) clotting occurs when clots form inside vessels, blocking blood flow and thus oxygen (and nutrient) delivery to tissues. This can cause a stroke, heart attack, or a pulmonary embolism if the clot travels to the lungs.
The size of a typical clot that forms inside a blood vessel varies from pea-sized to grape-sized (millimeters to a centimeter in diameter). However, since the SARS-CoV-2 pandemic, work from Dr. Etheresia Pretorius’s Lab at Stellenbosch University in South Africa has revealed that microscopic (1-200 µm on their longest axis) clots, termed microclots, are found in individuals with COVID-19 and those who developed Long COVID.
Microclots in Human Health and Disease
As mentioned in the introduction, microclots are not exclusive to Long COVID or COVID-19; they have also been observed in patients diagnosed with ME/CFS, Alzheimer’s, Parkinson’s, and rheumatoid arthritis. These microclots are predicted to contribute to symptoms such as fatigue, cognitive impairment, or organ damage by restricting blood flow in the body’s smallest blood vessels, the capillaries. They can promote inflammation, though their exact role in different disease contexts remains to be investigated.
Interestingly, these microclots are also found at low levels in healthy individuals, but elevated numbers (and size) of the microclots correlate with disease severity in Long COVID. Specifically, recent work from Dr. Pretorius’s Lab found that patients with long COVID have 19 times as many microclots as healthy controls.
The composition of the microclots is surprisingly different from that of typical blood clots. One key difference lies in the structure of the most abundant protein in clots, fibrin.
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Microclots Are Reported To Contain Amyloid Structures
Blood clots are created when a free-floating protein called fibrinogen is cut by molecular scissors to make a smaller protein called fibrin. Fibrin sticks to itself, forming mesh-like webs known as clots. These clots can be easily dissolved by a process called fibrinolysis, a term describing the destruction of a fibrin clot.
However, the fibrin in microclots is structurally different, making the clots more difficult for the body to break down naturally. A 2022 paper from the Pretorius Lab describes microclots containing an amyloid form of fibrin, called amyloid-fibrin microclots, or fibrinaloids. This type of fibrin is folded differently due to inflammatory factors, such as the SARS-CoV-2 spike protein, which has been demonstrated to is physically interact with fibrinogen, creating amyloid-fibrin-like structures.
What is an Amyloid?
When you hear the word amyloid, you might think of amyloid plaques in Alzheimer’s disease. The word amyloid, however, is not unique to Alzheimer’s. It is a term used to describe a protein that misfolds, forming a rod-like structure (fibril) that is difficult for the body to break down naturally. This characteristic of proteins causes them to clump together, forming aggregates that can trigger inflammation, tissue damage, and even cell death. The amyloid-fibrin microclot structures in the blood, however, are considerably larger (50-150 nm) compared to classical amyloid structures (5-25 nm).
Amyloids Formed From Misfolded Proteins
To understand what an amyloid is, we must understand that proteins are linear chains of amino acids strung together like beads on a string. These linear chains spontaneously fold to form secondary structures consisting of α-helices and β-sheets, which are more complex protein structures, as in the cartoon Pac-Man typically used to represent an enzyme (a type of protein).
Image: Protein Folding
The image illustrates how a linear chain of amino acids (1) can spontaneously fold into one of two secondary structures (2): α-helices or β-sheets. These secondary protein structures will fold again, forming a more complex tertiary structure composed of α-helices and β-sheets (3).
Under specific circumstances, proteins can misfold, reducing their susceptibility to proteolytic cleavage by molecular scissors called proteases. This can lead to protein aggregates, where a large number of misfolded proteins clump together
How Does Amyloid-Fibrin(ogen) Form in Long COVID?
Amyloid fibrin(ogen) is thought to form when the circulating precursor to blood clots (fibrinogen) interacts with the SARS-CoV-2 spike protein. This interaction is proposed to alter the shape of fibrinogen, not only allowing it to form a clot (without being converted to fibrin) but also delaying the normal process of clot destruction.
Image: The Spike Protein Creates Amyloid Fibrin(ogen)
The image above shows the spike protein binding to α-helices in fibrinogen (1), which has been reported to induce protein misfolding (2), in which α-helices misfold into β-sheets. This misfolded form of fibrinogen is an amyloid structure that has been reported to aggregate to form microclots (3).
Factors Reported to Trigger Amyloid Fibrin Formation
The formation of amyloid fibrin (also known as fibrinaloids) is triggered by a variety of biological, chemical, and physical factors that cause soluble fibrinogen to undergo a conformational change into a β-sheet-rich, insoluble state. The reported triggers include (but might not be limited to) the following. For specific references, please see this review paper.
| Category | Trigger | Key Details/Mechanism |
|---|---|---|
|
Viral and Bacterial Pathogens |
SARS-CoV-2 Spike Protein |
The S1 subunit binds directly to the Bβ and γ chains of fibrinogen, catalyzing misfolding into amyloid form; sufficient to induce anomalous amyloid microclots. |
|
|
Bacterial Lipopolysaccharide (LPS) |
Potent trigger from gram-negative bacteria; induces amyloid clotting even in highly substoichiometric amounts (as low as 1 molecule per 100 million fibrinogen molecules). |
|
|
Lipoteichoic Acid |
Cell wall component from gram-positive bacteria; might promote an amyloid state similarly to LPS. |
|
|
Herpesviridae |
Viruses from this family are noted for seeding or inducing amyloid production in inflammatory contexts. |
|
Biochemical and Hormonal Factors |
Oestrogens |
Female sex hormones, specifically 17beta-estradiol, has been reported to induce ultrastructural changes in fibrin networks. |
|
|
Serum Amyloid A |
An inflammatory protein that binds to fibrinogen and promotes aggregation into amyloid forms. |
Microclots Are Wrapped In DNA
The microclots from Long COVID patients not only contain amyloid fibrinogen, but they are also wrapped in DNA, making them even more challenging for the body to naturally break down.
In 2023, Dr. Alain Thierry‘s team was among the first to identify elevated levels of neutrophil extracellular traps (NETs) in patients with COVID-19 and Long COVID. These NETs are webs of DNA (green) and proteins from white blood cells called neutrophils (yellow). The DNA is cast from the neutrophil like a net used to trap pathogens, like an angler casts a net to trap fish.
A neutrophil (yellow) releases a DNA NET (green) to capture bacteria (purple) attacking a red blood cell (orange). Source: Wikimedia Commons, CHDENK
The research teams of Dr. Thierry and Dr. Pretorius combined their expertise to examine the composition of Long COVID microclots in greater detail.
Below is an image from their recent paper showing the DNA (red) surrounding the amyloid fibrin (labeled using ThT dye, green). The data suggest that the DNA was from a neutrophil, as indicated by the presence of a neutrophil-specific enzyme, myeloperoxidase (MPO, blue), and other neutrophil markers.
What Triggers NET Formation (NETosis) In Long COVID?
Data suggest that NETosis in Long COVID is triggered by persistent SARS-CoV-2 components (like viral RNA/proteins), ongoing inflammation, activated platelets, immune complexes, and complement proteins. This can cause chronic neutrophil activation and NET release, damaging tissues and perpetuating symptoms. Start here for an excellent review on the triggers of NETosis in Long COVID and COVID-19.
Essentially, the virus kickstarts a self-perpetuating cycle of inflammation and NET production that is slow to resolve, contributing to long-term pathology. Now, these DNA NETs are proposed to play a new role: structurally associating with and stabilizing microclots.
Is The DNA Stabilizing Microclots?
There is no evidence that NETs initiate the clotting process. Instead, the authors suggest the DNA NETs act as structural reinforcement for the clot.
The NETs were found to wrap around or weave into the misfolded fibrin, stabilizing the microclots and making them much harder for the body to break down and clear. These dense clots can also trap various inflammatory substances, including potentially the spike protein itself or immune markers, which turn them into masses that may contribute to ongoing symptoms such as fatigue and brain fog.
Additionally, the SARS-CoV-2 spike protein binds to fibrin and directly delays plasmin action, rendering the clots resistant to fibrinolysis. These microclots also trap protective inhibitors such as alpha-2-antiplasmin, a potent blocker of clot breakdown.
While the body has a slow background clearance rate for these microclots, this process is significantly slower than fibrinolysis, which dissolves typical clots. The microclots are not permanent, but they can persist for months or longer without intervention.
Can Microclots Be Therapeutically Removed?
Although no widely approved standard treatments currently exist for targeting these microclots in Long COVID, and large-scale clinical trials remain lacking, preliminary research suggests several promising approaches that may help reduce them and improve symptoms.
A small, preliminary study involving 91 patients used a closely monitored combination of dual antiplatelet therapy plus a direct oral anticoagulant for 3–4 weeks to dissolve microclots. This reduced microclot severity, addressed platelet issues, and resolved symptoms in most participants, with no serious bleeding reported. However, this approach should be considered high-risk for bleeding and must be monitored by a health professional. Health professionals must also protect patients from ischemia-reperfusion injury, which can paradoxically worsen tissue health by triggering a burst of oxidative stress upon reperfusion.
Other interventions, such as plasmapheresis (blood filtration), have been explored anecdotally but lack strong evidence for microclot removal and for preventing the amplification loop of clotting in this context.
Study Caveats To Consider
The Thioflavin T (ThT) dye binds amyloid proteins, hinting that an amyloid-like protein is buried in the interior of microclots. However, it’s unknown if it’s exclusively amyloid-fibrin(ogen) aggregates or if other amyloid-like structures are present.
It’s unclear whether the NETs wrap around the microclots after they form or whether they cause their formation.
Other chronic inflammatory conditions were not compared, so it’s unknown if microclots from other conditions also contain NET-derived DNA.
NETs Found In Other Chronic Inflammatory Diseases
Let’s zoom in on NETosis in the context of other medical conditions caused by or associated with neuroinflammation. The following table summarizes conditions with strong, well-established evidence in the scientific literature linking dysregulated neutrophil extracellular trap formation to disease pathology.
In these diseases, excessive NETs or impaired NET clearance have repeatedly been shown to contribute directly to inflammation, autoimmunity, tissue damage, thrombosis, and other key disease mechanisms. However, the absence of a strong NETosis association in a given condition from this list does not rule out the possibility that NETs may still play a contributing role in its pathology, especially in emerging research, overlapping autoimmune/inflammatory processes, or individual patient subsets. Ongoing studies continue to explore NETs across a broader range of chronic and neuroinflammatory illnesses.
| Disease Group | Role of NETs | Triggers/Causes of NET Formation |
|---|---|---|
|
Elevated NETs promote joint inflammation, citrullination of proteins (leading to autoantigens like ACPA), autoantibody production, and perpetuate chronic synovitis. |
Proinflammatory cytokines (e.g., TNF-α, IL-17), autoantibodies (e.g., ACPA, RF), ROS production, receptor engagement (e.g., FcγR, TLRs), and genetic factors (e.g., PAD4 polymorphisms). |
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Increased NET propensity correlates with neuroinflammation and elevated cytokines (e.g., IL-6, TNF-α) and contributes to immune dysregulation in the CNS. |
Infection/inflammatory triggers, autoantibodies, and immune activation leading to neutrophil hyper-responsiveness. |
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|
NETs are increased in tissue/serum; sustain mucosal inflammation, barrier damage, cytokine release, and promote chronic gut inflammation. |
Dysbiosis of the gut microbiota, proinflammatory cytokines, epithelial damage, and pathogen-associated molecular patterns activate neutrophils. |
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|
Strongly linked to thromboinflammation; NETs embed in/ stabilize microclots, resist fibrinolysis, reduce blood flow, and drive persistent symptoms (e.g., fatigue, brain fog). |
Persistent viral/inflammatory signals (post-SARS-CoV-2), cycles of inflammation and clotting, endothelial dysfunction, and hyperactivated neutrophils/platelets. |
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|
Classic association; excessive NETs and impaired clearance expose autoantigens (e.g., DNA/histones), drive type I interferon production, autoantibody formation, and organ damage (e.g., nephritis). |
Impaired DNase activity/clearance, low opsonins, autoantibodies (e.g., anti-dsDNA), complement activation, and inflammatory cytokines create a vicious cycle. |
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|
Inflammatory cytokines, ROS, and CNS damage signals activating neutrophils may involve genetic/immune dysregulation. |
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NETs contribute to skin inflammation, amplify cytokine loops (e.g., IL-17, IL-36), keratinocyte activation, and chronicity of lesions. |
Skin trauma/injury, microbial triggers, proinflammatory cytokines (e.g., IL-17, TNF-α), and TLR activation in keratinocytes/neutrophils. |
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|
NETs are part of systemic autoimmune pathology; they contribute to glandular inflammation, type I interferon-driven responses, and extra-glandular manifestations. |
Type I interferon activation, epithelial cell damage/apoptosis, and innate immune dysregulation leading to neutrophil activation. |
Future Outlook
Unraveling the role of these resilient microclots offers a promising path toward explaining the persistent inflammation and symptoms of Long COVID and related conditions like ME/CFS, Alzheimer’s, and Parkinson’s. While challenges remain in fully understanding their formation and clearance, emerging insights point to targeted therapies that might disrupt this cycle.
At the Brain Inflammation Collaborative, we’re committed to advancing this research and translating it into effective treatments. For more science updates like these, check out our free newsletter sent directly to your inbox once per month.
Written By
Matthew Menendez, Ph.D.
Director of Science Communication, Brain Inflammation Collaborative
Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care, access timely treatments, and reclaim their quality of life.
