Could Tiny Blood Vessel Problems Be Driving Long COVID?

by LCJ Team, posted in Symptoms and Complications

Understanding Endothelial Dysfunction, Microclots and Microvascular Injury

Research suggests that endothelial dysfunction, impaired microcirculation and persistent microclots may help explain many symptoms of Long COVID, including fatigue, brain fog, post-exertional malaise (PEM) and autonomic dysfunction. The endothelium is the thin lining inside your blood vessels that helps regulate blood flow, oxygen delivery and inflammation. When it doesn’t function normally, the body’s smallest blood vessels may struggle to respond to changing demands. Some researchers believe persistent microclots contribute to this process, while others see them as one consequence of broader vascular and immune dysfunction. Although these mechanisms are among the leading biological hypotheses in Long COVID research, they remain an active area of investigation and are unlikely to explain every person’s illness. 

Key Takeaways

  • Endothelial dysfunction affects the lining of blood vessels and may impair blood flow throughout the body.
  • Persistent microclots are one of the most studied findings in Long COVID, but their exact role is still being investigated.
  • Impaired microcirculation may reduce oxygen and nutrient delivery to tissues, particularly during physical or cognitive activity.
  • These mechanisms may contribute to fatigue, brain fog, post-exertional malaise (PEM), dysautonomia and muscle weakness, even when routine tests appear normal. 
  • Long COVID is a complex condition, and endothelial dysfunction and microclots are unlikely to be the only biological mechanisms involved.
  • Research continues to explore how vascular changes interact with immune dysregulation, autonomic dysfunction and other processes to produce Long COVID symptoms.

How can your scans, blood tests and heart tests all come back normal when simply climbing the stairs leaves you exhausted?

This is one of the biggest mysteries facing people with Long COVID. Increasingly, researchers believe part of the answer may lie in the body’s smallest blood vessels.

A growing body of research suggests that endothelial dysfunction, impaired microcirculation and persistent microclots may all contribute to Long COVID in some people. Exactly how these mechanisms interact—and whether they affect everyone in the same way remains an active area of research. 

At the centre of this framework lies the endothelium. Think of the endothelium as the intelligent inner lining of every blood vessel. It constantly tells blood vessels when to widen, narrow, repair themselves and regulate blood flow. When it isn’t working properly, oxygen and nutrients may not reach tissues as efficiently as they should.

Why Are Researchers Looking at the Endothelium?

Viruses such as SARS CoV 2 and Epstein Barr virus can affect endothelial cells both directly and indirectly. Viral particles inflammatory cytokines oxidative stress and immune activation all place strain on the endothelium. In some individuals endothelial cells do not recover fully but instead enter a senescent state.

Senescent endothelial cells are not dead. They remain metabolically active but dysfunctional. They secrete inflammatory mediators alter vascular tone impair nitric oxide signalling and disrupt coagulation balance. Under normal circumstances the immune system identifies and clears these cells. In post viral illness this clearance may fail. Reduced natural killer cell surveillance appears to play a role allowing dysfunctional endothelial cells to persist.

Depending on which organs are under the greatest physiological demand, endothelial dysfunction may contribute to different symptoms. For some people this may be brain fog and cognitive fatigue, while for others it may be muscle weakness, dizziness or digestive problems. This helps explain why Long COVID can look so different from one person to another.

What Does This Mean for Me?

Think of the endothelium as your body’s traffic control system. Every second it decides where blood needs to go, how much should arrive and how quickly it should get there. If that system isn’t working efficiently, the effects may only become obvious when demand suddenly increases—such as climbing stairs, concentrating during a meeting or standing in a queue.

Microclots and Impaired Microcirculation

One of the most striking findings in this research is the presence of persistent microclots within the circulation of people with Long Covid and ME CFS. These are not conventional clots detectable by routine coagulation tests. They are fibrin amyloid structures resistant to normal breakdown and capable of trapping inflammatory molecules. Although persistent microclots have become one of the most widely discussed findings in Long COVID research, scientists continue to debate exactly how important they are. Some researchers believe they directly impair blood flow through the smallest blood vessels, while others consider them one consequence of broader endothelial dysfunction, immune activation and inflammation rather than the primary driver of disease. These views are not necessarily contradictory, and different mechanisms may contribute to symptoms in different people.

These microclots may reduce capillary level blood flow. Oxygen delivery becomes uneven and inefficient particularly during exertion. Muscles may appear structurally normal yet function as if they are underperfused. The brain may receive sufficient blood at rest but struggle to adapt to cognitive demand.

This hypothesis may help explain why symptoms often worsen hours or days after activity rather than during it. It also offers one possible explanation for why rest alone does not always restore baseline function. However, researchers continue to investigate how microclots interact with endothelial dysfunction, immune dysregulation and other biological mechanisms in Long COVID.

ACE2 Signalling and Vascular Imbalance

SARS-CoV-2 enters cells using the ACE2 receptor, an important regulator of blood vessel function and the body’s response to inflammation. Following infection, disruption of this system may contribute to blood vessel constriction, inflammation and impaired microcirculation. Although this mechanism is unlikely to explain Long COVID on its own, it provides another possible link between viral infection, endothelial dysfunction and reduced oxygen delivery to tissues. Like many aspects of Long COVID, it is likely to represent one piece of a much larger puzzle.

Muscle Microvascular Injury and Post Exertional Malaise

One of the biggest paradoxes in Long COVID is that muscles may appear normal on examination but struggle to cope with even modest activity. You manage to walk around the supermarket, but by the time you get home your legs feel heavy and your whole body seems to shut down. It doesn’t feel like ordinary tiredness. It feels as though your muscles simply couldn’t keep up with what you asked them to do.

One possible explanation is that oxygen delivery cannot increase quickly enough when demand suddenly rises. Researchers believe this may contribute to post-exertional malaise (PEM), where symptoms worsen hours or even days after activity rather than during it.

Why Can Long COVID Affect So Many Different Organs?

One of the puzzling features of Long COVID is that symptoms can affect almost any part of the body. This may be because different organs have different energy demands throughout the day. If blood flow cannot adapt efficiently when demand increases, the tissues working hardest at that moment may be the first to struggle.

The brain, for example, requires a constant supply of oxygen and nutrients. If microcirculation cannot respond normally during mental effort, this may contribute to brain fog, slowed thinking, word-finding difficulties and sensory overload. Likewise, the muscles may cope at rest but struggle during walking, climbing stairs or other physical activity.

Other organs, including the gut, may also be affected. Altered blood flow and endothelial dysfunction could contribute to digestive symptoms and changes in gut barrier function, although several other mechanisms, including immune dysregulation and changes in the gut microbiome, are also likely to play a role.

This may also help explain why symptoms seem to move around the body. One day brain fog may dominate, the next it could be muscle weakness, dizziness or digestive symptoms. That doesn’t necessarily mean the illness is changing. Instead, it may reflect which organs are under the greatest physiological demand at that particular time.

Why Can Routine Blood Tests and Scans Be Normal?

One of the most frustrating aspects of Long COVID is being told that everything looks normal despite feeling profoundly unwell. Understanding the difference between structural disease and functional dysfunction helps explain this apparent contradiction. We explore this concept further in Why Normal Results Do Not Equal Normal Function in Long COVID.

Most routine blood tests measure general inflammation, organ function or large-scale abnormalities. Standard MRI and CT scans are designed to identify structural damage, such as strokes, tumours or inflammation that can be seen with conventional imaging. They are not designed to measure how well the smallest blood vessels respond to changing demands throughout the day.

The microclot and endothelial dysfunction hypothesis suggests that the problem lies within the body’s microcirculation the tiny capillaries responsible for delivering oxygen and nutrients to tissues. At rest, blood flow may be sufficient for routine investigations to appear normal. During physical activity, standing, mental concentration or other forms of physiological stress, however, the microcirculation may struggle to increase blood flow quickly enough to meet demand.

How Endothelial Dysfunction May Contribute to Dysautonomia and POTS

Many people with Long COVID develop dysautonomia,, including conditions such as Postural Orthostatic Tachycardia Syndrome (POTS) and orthostatic intolerance. Although several biological mechanisms are likely to be involved, researchers believe endothelial dysfunction may be one of the factors contributing to these symptoms.

When you stand up, your blood vessels normally tighten slightly to help push blood back towards your heart and brain. If this response is impaired, blood may pool in the lower body instead. The result is reduced blood flow to the brain and a compensatory increase in heart rate, leading to symptoms such as dizziness, palpitations, blurred vision, brain fog and overwhelming fatigue.

If you’ve noticed that standing in a queue, cooking in the kitchen, taking a hot shower or being outside on a warm day makes you feel dramatically worse, these experiences fit with what researchers know about how the autonomic nervous system and the microcirculation work together.

Endothelial dysfunction is unlikely to explain every case of dysautonomia. Autoimmunity, small fibre neuropathy, persistent inflammation and other mechanisms are also being investigated. As with many aspects of Long COVID, the underlying biology is likely to differ from one person to another.

What Does This Mean for Exercise?

One of the most important messages from this research is that exercise intolerance in Long COVID may not simply be a matter of being “out of shape.”

If the body’s smallest blood vessels struggle to deliver enough oxygen and nutrients when demand increases, pushing beyond your physiological limits may place additional stress on an already compromised system. This may help explain why some people experience post-exertional malaise (PEM)a delayed worsening of symptoms hours or even days after physical, cognitive or emotional activity.

This doesn’t mean people with Long COVID should avoid movement altogether. Gentle, appropriate activity remains important for overall health, but it needs to be adapted to each person’s individual capacity. For many people, strategies such as pacing, taking regular breaks and avoiding repeated crashes are currently supported by more evidence than trying to steadily increase activity regardless of symptoms.

As researchers continue to understand the biology behind Long COVID, more targeted rehabilitation approaches may become available. Until then, listening to your body’s signals and working within your current limits remains one of the most widely recommended approaches.

Not Everyone With Long COVID Appears to Have Microclots

One of the biggest questions researchers are still trying to answer is why persistent microclots appear to be more prominent in some people than others. Long COVID is increasingly recognised as a complex condition involving multiple overlapping biological mechanisms rather than a single disease process. Some people may have significant endothelial dysfunction or impaired microcirculation without obvious evidence of persistent microclots, while others appear to have more prominent clotting abnormalities. This is one reason why researchers believe there is unlikely to be a single explanation or a single treatment for everyone. This may also help explain why treatments that appear to help one person may have little effect in another. If the underlying biology differs between individuals, it is unlikely that a single treatment will work for everyone.

What Does This Mean for Me?

If you’ve been told that your blood tests, scans or heart investigations are normal but you still experience overwhelming fatigue, brain fog, dizziness or post-exertional malaise, this research may help explain why.

Rather than causing obvious structural damage, endothelial dysfunction and impaired microcirculation may affect how well the body’s smallest blood vessels respond when demand increases. This could help explain why symptoms fluctuate, why many people experience delayed crashes rather than immediate exhaustion, and why pushing through symptoms often makes recovery more difficult instead of improving fitness.

Although this remains an evolving area of research, it provides a biological framework that validates the experiences of many people living with Long COVID and ME/CFS. It also reinforces why pacing, protecting energy and avoiding repeated post-exertional crashes remain important management strategies while research continues.

What Does This Mean for Treatment?

If you’ve spent time in Long COVID communities online, you’ve probably come across discussions about treatments such as triple therapy (usually a combination of an anticoagulant and antiplatelet medications), apixaban, rivaroxaban, plasmapheresis, HELP apheresis, nattokinase, serrapeptase, lumbrokinase, or supplements claimed to improve blood flow, break down fibrin or support endothelial function.

It’s understandable to wonder whether these treatments could help, especially if you’ve read personal stories describing significant improvements.

The reality is more complex.

The growing research into endothelial dysfunction, impaired microcirculation and persistent microclots has opened up several promising areas for treatment. However, there is currently no universally accepted or proven treatment that specifically targets these mechanisms in Long COVID.

Some small studies, case reports and observational research have reported encouraging findings with treatments designed to improve blood flow or reduce abnormal clotting. At the same time, other researchers believe persistent microclots may be one consequence of a broader process involving endothelial dysfunction, immune dysregulation and persistent inflammation. If that is the case, targeting clotting alone may not be enough to improve symptoms. Anticoagulants mainly prevent new clot formation. They do not directly dissolve existing amyloid-like fibrin deposits.

This may also explain why experiences shared online vary so widely. Some people report meaningful improvements, while others notice little or no benefit. Personal experiences can be valuable, but they cannot tell us whether a treatment is safe or effective for the wider Long COVID population.

For now, most experts recommend focusing on treatments supported by the strongest available evidence, such as pacing, managing dysautonomia where appropriate, optimising sleep, nutrition and hydration, and treating any co-existing medical conditions. More targeted therapies are being actively studied, but larger, well-designed clinical trials are still needed before they can be recommended routinely.

If you’re considering treatments such as anticoagulants, antiplatelet medications or supplements marketed to dissolve fibrin or improve blood flow, it’s important to discuss them with your healthcare professional. Even supplements such as nattokinase, serrapeptase and lumbrokinase can have biological effects and may increase the risk of bleeding or interact with other medications. Decisions about using these treatments should always take into account your individual medical history and current medications.

What We Know So Far

✅ Endothelial dysfunction has been demonstrated in many people with Long COVID.

✅ Persistent microclots have been identified in several research studies and some patients.

✅ Impaired microcirculation may contribute to fatigue, brain fog, dysautonomia and PEM.

❓Researchers are still investigating how these mechanisms interact and whether they affect everyone in the same way.

Conclusion

Long Covid and blood clotting are complex and may look different from person to another.Although researchers are still piecing together the puzzle, one message is becoming increasingly clear: Long COVID is a biological illness, not simply a problem of motivation, fitness or stress. Endothelial dysfunction, impaired microcirculation and persistent microclots represent one possible frameworks for understanding why so many people experience fatigue, brain fog, post-exertional malaise and autonomic symptoms despite normal routine tests.

Much remains to be discovered, but this research is helping shift the conversation from “nothing is wrong” to a better understanding of the biological changes that may underlie Long COVID. For many people, that change in understanding is an important step in itself

FAQ

Do Microclots Cause Long COVID?

Scientists don’t yet know for certain. Persistent microclots are one of the most widely studied findings in Long COVID research and may contribute to symptoms by impairing blood flow through the smallest blood vessels. However, many researchers believe they are only one part of a much more complex illness that also involves endothelial dysfunction, immune dysregulation, autonomic dysfunction and other overlapping mechanisms. At present, no single cause explains every case of Long COVID.

Why Are Researchers Interested in Endothelial Dysfunction?

The endothelium is the thin lining inside every blood vessel. It helps regulate blood flow, inflammation and oxygen delivery. Growing evidence suggests that endothelial dysfunction may contribute to many Long COVID symptoms by making it harder for the body’s smallest blood vessels to respond to changing demands.

If My Blood Tests and Scans Are Normal, Could This Still Be Happening?

Yes. Routine blood tests, CT scans and MRI scans are designed to detect structural damage or major abnormalities. Endothelial dysfunction and impaired microcirculation are functional changes that often require specialised research techniques to detect. This may help explain why many people experience significant symptoms despite reassuring routine investigations.

Could This Explain My Fatigue and Brain Fog?

Possibly. If blood flow through the smallest blood vessels cannot increase efficiently during physical or cognitive activity, tissues may receive less oxygen and fewer nutrients when demand rises. Researchers believe this could contribute to symptoms such as fatigue, brain fog, dizziness and post-exertional malaise in some people.

Does This Mean My Symptoms Are Caused by Poor Circulation?

Not in the usual sense. The research focuses on the microcirculation—the tiny blood vessels responsible for delivering oxygen and nutrients to tissues—rather than blocked arteries or traditional circulatory disease. The problem appears to involve how blood flow is regulated rather than simply how much blood is present.

Can Doctors Test for Microclots or Endothelial Dysfunction?

At present, specialised microclot testing is not part of routine clinical care in most countries, and there is no single standard test for endothelial dysfunction in Long COVID. Most of these techniques are still used mainly in research. Your healthcare professional is more likely to assess your symptoms, functional limitations and other possible causes than rely on one specific laboratory test.

Does This Change How Long COVID Is Treated?

Research into endothelial dysfunction and microclots is helping scientists develop potential new treatments, but there is currently no universally accepted therapy targeting these mechanisms. Management still focuses on symptom control, pacing, treating associated conditions such as dysautonomia where appropriate, and supporting recovery while research continues.

Will We Know More in the Future?

Almost certainly. Endothelial dysfunction and microclots remain among the most active areas of Long COVID research. Scientists are working to understand how these mechanisms interact with immune dysfunction, viral persistence, autonomic dysfunction and other biological processes. Future discoveries may improve both diagnosis and treatment.n a specific test that may not be available or validated.

Disclaimer

This article is for educational purposes only. It does not replace medical advice. People with persistent or worsening symptoms should seek assessment from qualified healthcare professionals.

About Long Covid Journey

Long Covid Journey is an independent educational resource dedicated to helping people understand Long COVID through evidence-informed articles, peer-reviewed research and lived experience. Our aim is to explain complex medical topics in clear, balanced language while recognising that Long COVID is a rapidly evolving field of research.

Every article is carefully researched using current scientific literature and reputable clinical sources wherever possible. Because knowledge continues to evolve, our content is regularly reviewed and updated to reflect new evidence while acknowledging areas of ongoing uncertainty.

This article explores one of the leading biological hypotheses in Long COVID research: endothelial dysfunction, microvascular injury and persistent microclots. While these mechanisms are supported by a growing body of research, they continue to be actively investigated and should be interpreted within the context of the wider scientific evidence. Our goal is to present balanced, evidence-informed information that supports informed conversations between patients and their healthcare professionals.

References

Pretorius et al. (Cardiovascular Diabetology, 2021) – landmark microclot paper.Grobbelaar et al. (Biochemical Journal, 2021) – spike protein and abnormal fibrin.Venter, Kell & Pretorius (Cardiovascular Diabetology, 2024) – endothelial dysfunction + platelet hyperactivation + fibrinaloid microclots.Wüst et al. (Nature Communications, 2023) – links impaired muscle oxygen use to exercise intolerance.Scherlinger et al. (Journal of Clinical Medicine, 2023) – balanced review of endothelial dysfunction with discussion of biomarkers and therapeutic perspectives.

Suggested Further Reading