Why Exercise Makes Long COVID Worse: Microclots, Vascular Injury and the Biology Behind Exercise Intolerance

Exercise can make Long COVID worse for more than one reason.

You are told that exercise will help your recovery. This is what everyone says. This is what medicine has said about almost every chronic condition for decades. Get moving. Your body will adapt. You will feel better.

So you try. A short walk, a gentle cycle, some light swimming. And then, somewhere between “this seems manageable” and “why am I so much worse,” you realise that the standard advice has spectacularly missed something about how your body is currently working.

You are not unfit. You are not deconditioned in the way that advice assumes. Something is happening in your bloodstream during exercise that is not supposed to happen. And as of 2025, researchers have measured exactly what it is.

What microclots are and why Long COVID patients have them

In a healthy circulatory system, blood flows through vessels from large arteries down to the tiniest capillaries, delivering oxygen and nutrients to every tissue, collecting waste, and circulating continuously. Clotting is a normal and essential process, but it is supposed to be tightly regulated, forming temporary plugs when needed and dissolving when they are no longer required.

In Long COVID, this regulation goes wrong. Microclots, tiny fibrin based deposits that are far smaller than the clots involved in deep vein thrombosis but far more numerous, have been found persistently elevated in Long COVID patients compared with healthy controls and with people who recovered from COVID without ongoing symptoms. A 2025 study in the Journal of Medical Virology found that these circulating microclots are structurally associated with neutrophil extracellular traps (NETs), inflammatory structures released by immune cells during infection that can further promote clotting and vascular injury.

These microclots are small enough to lodge in capillaries, the blood vessels at the end of the circulatory chain where oxygen actually transfers from blood to tissue. When capillaries are partially blocked, even intermittently, oxygen delivery to the tissue they supply is impaired. This is not a dramatic event in the way a stroke or heart attack is. It is a quiet, diffuse impairment happening in millions of tiny vessels simultaneously. The tissue is not receiving oxygen at the rate it needs. The body registers this as profound fatigue, breathlessness, brain fog and an inability to sustain physical activity.

What happens when you exercise

For years patients have said: “Exercise makes me worse.” Doctors often replied: “You need to build up slowly.”

In 2025 researchers decided to test what actually happens in the bloodstream after exercise.

A 2025 study from the University of Derby, the first of its kind, had 46 Long COVID patients complete two submaximal cardiopulmonary exercise tests separated by 24 hours. Submaximal means not pushing to maximum effort, just working within a moderate intensity range. The patients in this study were specifically selected for low risk of post exertional malaise, so this is not a study of crash prone patients.

What the researchers found was this. Exercise caused large microclots to fragment into smaller ones. That fragmentation correlated with increases in cytokines associated with both pro inflammatory and anti inflammatory responses, as well as markers of vascular injury. Performance on the second day was measurably worse: oxygen consumption at the first ventilatory threshold dropped, and so did oxygen pulse, the amount of oxygen delivered per heartbeat.

To put this plainly: exercise was not clearing the microclots. It was breaking them into smaller fragments that are harder to clear, triggering inflammatory signals, injuring the vascular lining, and leaving the cardiovascular system less able to deliver oxygen the following day.

The study authors described this as the first evidence of a biological basis that might explain exercise induced symptom exacerbation in people with Long COVID through microclot fragmentation, with important implications for Long COVID rehabilitation practices that may have the capacity to be harmful.

This is not a theoretical mechanism. It is a direct measurement of what is happening in the blood of Long COVID patients who exercise, even gently, even at submaximal intensity.

The oxygen delivery problem

The reason exercise intolerance in Long COVID feels different from ordinary unfitness is precisely this oxygen delivery impairment. In a deconditioned but otherwise healthy person, exercise capacity improves with training because the cardiovascular system adapts: the heart becomes more efficient, muscle cells develop more mitochondria, oxygen extraction improves. The system responds to the demand by getting better at meeting it.

In Long COVID with microclot driven vascular injury, exercise increases the demand for oxygen at precisely the moment when the capillary network is being further compromised by fragmented microclots and inflammation. The system is not adapting. It is being damaged further. The binding of SARS CoV 2 to ACE2 receptors has been shown to contribute to persistent microclot formation and impaired oxygenation, a hallmark symptom affecting the respiratory, central nervous and cardiovascular systems.

The experience of this is distinctive once you know what to look for. Breathlessness that appears at a much lower exercise intensity than it should for your level of fitness. A heart rate that feels disproportionate to the effort. A sense of oxygen not quite reaching where it needs to go, that slightly hollow, heavy quality to exertion. Fatigue that feels different from muscular tiredness, more systemic, less local.

The distinction from post exertional malaise

At this point it is worth being precise about something, because the language around exercise and Long COVID can blur together in ways that are not helpful.

The vascular mechanism described here, microclot fragmentation, oxygen delivery impairment, inflammatory cascade triggered by exertion, is one biological pathway explaining why exercise makes Long COVID worse. It is not the same as post exertional malaise, though both can be present in the same person.

Post exertional malaise, covered in depth in our PEM article, is a separate mechanism involving mitochondrial dysfunction, immune disruption and a delayed crash pattern 12 to 48 hours after exertion. The Thomas et al. study specifically excluded people at high risk of PEM, which means it was measuring the vascular pathway in patients who do not have the full PEM picture.

In practice: if you crash the day after exercise regardless of intensity, that is more likely PEM. If you run out of breath and capacity during exercise at an intensity that should not cause this, and feel systemically worse immediately or within hours, that may be the vascular and microcirculatory mechanism being described here. Many people have both. The biology is layered.

What this means for rehabilitation

The practical implication is uncomfortable for rehabilitation medicine as it is currently structured. Standard cardiac and pulmonary rehabilitation protocols are based on progressive overload: increase intensity over time, the body adapts, function improves. This model is directly contraindicated by what the microclot fragmentation study found.

Persistent inflammation, endothelial dysfunction and microvascular injury contribute to prolonged symptoms such as dyspnoea, chest pain and exercise intolerance in Long COVID, as confirmed by a 2025 BMC Cardiovascular Disorders systematic review. These are not features that improve by challenging the damaged system with greater demands. They require the damaged system to be supported while healing occurs.

The honest clinical position as of mid 2025 is that standard exercise rehabilitation protocols for Long COVID with significant exercise intolerance require careful individualisation, monitoring of response, and a willingness to reduce or pause when biomarkers or symptoms suggest the vascular system is being further stressed rather than adapted. The tools for routine microclot monitoring are not yet in standard clinical use, but symptom response, breathlessness disproportionate to effort, worsening over repeated sessions, systemic deterioration after sessions, provide clinical signals that should not be overridden.

What actually helps

The honest position on treatment is that this is an active research area and nothing has yet been proven to resolve microclot driven exercise intolerance in Long COVID. Several directions are supported by mechanism.

Pacing movement rather than progressing it. Working consistently within the boundary at which symptoms do not worsen, rather than incrementally pushing beyond it, avoids the repeated microclot fragmentation events that the research suggests are causing compounding vascular injury.

Supporting vascular function. The endothelial lining of blood vessels is both a victim and a mediator of the microclot problem. Adequate hydration, avoidance of prolonged standing or sitting, and compression garments for those with venous pooling all support vascular function without adding the stressor of exercise.

Anticoagulation and antiplatelet approaches are being investigated, with some clinicians using low dose aspirin or other agents in selected patients with evidence of significant microclot burden. This is not yet a standard protocol and involves clinical risk assessment. It is worth discussing with a haematologist or a Long COVID specialist if vascular symptoms are prominent.

Avoiding exercise in heat or immediately after eating, since both of these reduce the vascular reserve available before symptoms emerge.

The research is pointing toward treatments that address the upstream driver, the persistent microclots themselves, rather than trying to train the body to work around them. Whether that involves targeted fibrinolytic approaches, immune modulation to reduce platelet hyperactivation, or other mechanisms is something active research programmes are working toward.

For now, the most useful thing this research offers is validation and a mechanism. Exercise does not make Long COVID worse because you are weak or giving up. It makes things worse because it fragments microclots in your bloodstream, triggers inflammation, damages vascular endothelium, and impairs oxygen delivery to your tissues. That is biology. It is measurable. And it completely overturns the “just keep moving” advice that has been given to far too many Long COVID patients for far too long.

Why Doesn’t This Happen To Everyone?

Not everyone with Long COVID experiences the same degree of exercise intolerance.

Some people recover their exercise capacity relatively quickly. Others mainly experience post-exertional malaise. Some appear to have predominantly vascular problems, while others have more significant autonomic dysfunction or mitochondrial impairment.

Long COVID is increasingly understood as a collection of overlapping biological mechanisms rather than a single disease following the same pathway in every patient.

This is one reason rehabilitation needs to be individualised rather than following a one-size-fits-all approach.

Frequently asked questions

This article is for general information and education. It does not replace personalised medical advice. If exercise consistently worsens your symptoms, please discuss this specifically with your GP or a clinician familiar with Long COVID, and ask about referral to a Long COVID clinic with cardiopulmonary expertise.

Sources and further reading

The key study Exercise induced changes in microclotting and cytokine levels, vascular injury and inflammation in Long COVID, Thomas et al. Research Square 2025: https://www.researchsquare.com/article/rs-6717727/v1 Science for ME thread with discussion and full results: https://s4me.info/threads/exercise-induced-changes-in-microclotting-and-cytokine-levels-point-to-vascular-injury-and-inflammation-in-people-with-lc-2025-callum-thomas-et-al.44338/

Microclot biology Circulating microclots and neutrophil extracellular traps in Long COVID, Journal of Medical Virology 2025: https://pmc.ncbi.nlm.nih.gov/articles/PMC12489976/ ACE2, microclots and impaired oxygenation in Long COVID, PMC 2024: https://pmc.ncbi.nlm.nih.gov/articles/PMC11270324/

Vascular context Vascular complications of Long COVID, endothelial dysfunction and coagulopathy, systematic review IJMS 2025: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12786942/ Cardiopulmonary crosstalk in Long COVID, BMC Cardiovascular Disorders 2025: https://link.springer.com/article/10.1186/s12872-025-05185-7 ENDOFFILE

Understanding Long COVID and Exercise Intolerance

Long COVID, the persistent condition following COVID-19 infection, affects millions worldwide. One puzzling symptom is exercise intolerance where physical activity worsens symptoms instead of improving health. Recent research sheds light on why this happens, offering crucial insights for both patients and healthcare professionals managing Long COVID.

The Study at a Glance: Microclots, Cytokines, and Vascular Injury

A recent study titled “Exercise-induced Changes in Microclotting and Cytokine Levels Point to Vascular Injury and Inflammation in People with Long COVID” investigated how exercise affects Long COVID patients. Researchers found that even mild physical exertion can cause large microclots in the blood to fragment into smaller ones. This fragmentation correlates with increased inflammation and markers of vascular injury.

Microclots and Inflammation: The Hidden Drivers of Symptom Worsening

Microclots are tiny blood clots that block capillaries, reducing oxygen supply to body tissues. In Long COVID patients, these microclots persist abnormally and are believed to contribute to ongoing symptoms such as fatigue, breathlessness, and brain fog.

The study observed that exercise causes these microclots to break into smaller fragments, potentially worsening blood flow blockages and triggering an inflammatory response. This mechanism helps explain why physical activity might exacerbate symptoms in Long COVID.

Exercise in Long COVID: Why a Personalized Approach Matters

Exercise is generally a cornerstone of health and rehabilitation. However, this study suggests that in Long COVID, physical activity can sometimes aggravate symptoms due to microclot fragmentation and inflammation. This highlights the need for personalized exercise plans rather than a one-size-fits-all recommendation.

Patients should be cautious and work closely with healthcare providers to tailor physical activity to their condition, avoiding overexertion that may worsen symptoms.

Implications for Treatment: Targeting Microclots and Inflammation

Understanding the role of microclots and inflammation opens new pathways for potential treatments in Long COVID. Therapeutic strategies may focus on:

• Improving blood flow
• Reducing clot formation
• Controlling inflammation

While promising, these approaches require further research to develop safe and effective interventions.

Key Takeaways for Patients and Healthcare Providers

• Exercise can worsen symptoms in some Long COVID patients due to microclot fragmentation and inflammation.
• Personalized, cautious exercise regimens are essential.
• Patients should always consult healthcare professionals before starting or modifying exercise plans.
• Ongoing research is vital to discover targeted treatments addressing vascular injury and inflammation in Long COVID.

Learn More

For the full research details, visit the Research Square article.

Disclaimer:
This article is for informational purposes only and does not constitute medical advice. The research discussed is ongoing, and Long COVID symptoms vary widely among individuals. Patients should always consult their healthcare providers before making any changes to their exercise routines or treatment plans. This content is not intended to diagnose, treat, cure, or prevent any medical condition.