Neutrophil Extracellular Traps in Long COVID: The Microclot-NET Study

Long COVID research often talks about two things separately: microclots and NETs (neutrophil extracellular traps). A 2025 paper argues they may be part of the same process. This walkthrough defines the terms first, then explains what the study did, what it found, and how much weight it can bear.

What did the 2025 microclot-NET study find?

The paper is Thierry, Usher, Sanchez and colleagues, Circulating Microclots Are Structurally Associated With Neutrophil Extracellular Traps and Their Amounts Are Elevated in Long COVID Patients, published in the Journal of Medical Virology in 2025. The team included Etheresia Pretorius and Douglas Kell, whose group first described fibrin amyloid microclots.

Its core claims, for this cohort:

• people with Long COVID had more circulating microclots
• they also had higher NET markers in plasma
• those two signals tracked together
• microscopy suggested NET material is physically part of some microclots

That doesn't explain all of Long COVID. It does strengthen the case that abnormal clotting and innate immune activation are working in the same process.

Start with the vocabulary

What is a microclot?

In this research, a microclot is a small clot-like particle in plasma that resists normal breakdown. Pretorius, Kell and colleagues describe many of them as fibrin amyloid microclots (also called fibrinaloid microclots), meaning the fibrin has folded into a tougher, amyloid-like form (Kell et al., 2022).

That doesn't mean every microclot is the same as the amyloid in Alzheimer's plaques. It does mean structural biology is a useful comparison: proteins that adopt ordered fibrillar shapes become unusually stable and hard to clear. We cover that background in amyloid-beta as immune defense, which looks at amyloid as a host-defense tool. For the clinical picture, see our pillar on amyloid microclots and Long COVID.

What are NETs?

Neutrophils are immune cells. One of their emergency moves is to throw out web-like nets made of their own DNA plus enzymes, which trap microbes. That's useful in infection, but it can turn harmful if it's excessive, poorly controlled or not cleared.

What is cirDNA?

Circulating cell-free DNA (cirDNA) is DNA floating in plasma. When NETs form and break down, DNA fragments end up in the blood, so cirDNA is a rough signal of NET activity.

What is fibrinolysis?

Think of clotting as "build the patch" and fibrinolysis as "take the patch down when it's no longer needed." Microclots matter because they seem to resist that cleanup.

The short version

• microclots = tiny, stubborn clot-like bits
• NETs = immune webs
• cirDNA = scraps from those webs
• fibrinolysis = the body's clot cleanup crew

What did the researchers do?

The study compared:

• 50 people with Long COVID
• 38 healthy controls: 14 from South Africa and 24 French blood donors

They measured:

• the number and size of microclots, using Thioflavin T (ThT) fluorescence microscopy
• three NET-related markers in plasma: myeloperoxidase (MPO), neutrophil elastase (NE) and cirDNA

They also stained samples for DNA alongside ThT to ask a harder question: are NET components just raised in the same patients, or are they part of the microclots themselves? That's what makes this more than a "marker A is up and marker B is up" study.

ThT is the same amyloid dye used in other microclot research. If you want to know how ThT detection of fibrin amyloid works, our amyloid fibrin test guide explains it.

Clinical next step

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What were the main findings?

1. Long COVID patients had more microclots

The Long COVID group had far more circulating microclots than healthy controls: a 19.7-fold median difference, with higher counts in every size range measured. That's consistent with earlier microclot work, now tied more directly to immune-trap biology. The fibrin amyloid microclots research summarizes those earlier studies.

2. NET markers were higher too

The Long COVID group had higher MPO, NE and cirDNA. These aren't generic inflammation markers: they point specifically to neutrophil activation and NET activity.

Neutrophil elastase is interesting for another reason. It's the same enzyme that can cut spike protein into amyloid-forming fragments in the lab, as covered in how neutrophil elastase turns spike protein into amyloid.

3. Microclots and NET markers moved together

The number and size of microclots correlated with the NET markers. In plain English, when NET signals were higher, microclot burden tended to be higher too. That doesn't prove cause, but it makes "these are unrelated" harder to defend.

4. Microscopy suggests NETs sit inside microclots

This is the strongest claim and deserves the most careful reading. DNA stains overlapped ThT-stained microclots, which the authors interpret as NET material embedded in the clots.

If that holds up, a microclot isn't just a clotting artifact. It's a mixed immune-and-clotting object, and that's a meaningful shift.

5. The markers separated patients from controls

Microclot counts discriminated Long COVID from healthy controls well, with an area under the ROC curve of about 0.90 for total microclot count. The NET markers also separated the groups, with AUCs of 0.85 to 0.94 alone and 0.95 combined.

That doesn't mean there's now a validated Long COVID test panel. The authors note they didn't include disease-matched controls, such as people with other inflammatory conditions, so specificity is unknown.

What is immunothrombosis?

• immuno = immune system
• thrombosis = clotting

Immunothrombosis means the immune and clotting systems acting together. During infection that can be protective, a way to wall off a threat. The concern in Long COVID is a combined response that lasts longer than it should or doesn't fully resolve. The same authors have proposed feedback loops in which inflammation, clotting and autoimmunity keep neutrophils switched on (Thierry & Salmon, 2024).

Why does this paper matter?

One line of Long COVID research focuses on abnormal fibrin, poor blood flow, small-vessel problems and clot material that resists cleanup. Another focuses on persistent innate immune activation, neutrophil dysregulation and NETs. This paper suggests they may be two views of the same event.

It also sharpens the next question: if NETs are inside microclots, why doesn't the body clear them? Part of the answer may be enzymes called DNases, which digest NET DNA. Hospital studies found reduced DNase activity in COVID-19, which we explain in DNase and NET clearance in Long COVID.

What the paper does not prove

It doesn't prove:

• that every Long COVID patient has this biology
• that microclots are the single cause of all Long COVID symptoms
• that NETs are the original trigger rather than one part of a larger loop
• that current assays are standardized enough for routine clinical use
• that changing these markers will improve how patients feel

It also leaves open questions:

• will independent labs get the same results?
• how sensitive are the findings to sample handling and assay methods?
• do different symptom clusters show different patterns?
• do the markers rise and fall with symptom severity over time?
• which treatments, if any, change both the biology and the symptoms?

That's not a flaw. It's the difference between a meaningful study and a settled body of evidence.

How should you read this study?

Read it as a careful observational study with a plausible mechanism, one that ties immune webs and clot biology together more directly than earlier work. It still needs replication, standardization and follow-up.

Practical questions to keep asking: can it be replicated, how reliable are the assays, which part of the patient population does it describe, and what changes when a patient improves? That's how to avoid both overstatement and dismissal.

What can you do with this today?

Standard clotting tests, such as D-dimer, weren't designed to find fibrinolysis-resistant microclots; our comparison of D-dimer vs microclot testing explains why. Microclot research uses ThT fluorescence microscopy instead.

Our amyloid fibrin test applies that ThT method to a finger-prick dried blood sample and returns a videographic microscopy report you can share with your doctor. It doesn't measure NET markers like cirDNA, MPO or neutrophil elastase, and it isn't a diagnosis. For clinicians and centers that work with microclot findings, see our list of microclot testing labs and treatment centers, and for day-to-day steps, the Long COVID survival guide.

The bottom line

In at least some people with Long COVID, abnormal clot material and immune-web material may be part of the same physical process. The Thierry study supports a model where innate immune activation and abnormal clotting are linked, while still needing replication, standardization and clinical follow-up.

This article is educational and doesn't diagnose illness or recommend treatment.