Same Symptoms, Different Chemistry: Telling POTS and Long COVID Apart

By Dr Maré Vlok, Founder of Trace Labs

POTS and long COVID can look remarkably similar from the outside. In this study, the difference showed up not in how much of each protein was there, but in what had happened to those proteins.

Three Conditions That Overlap

Postural orthostatic tachycardia syndrome (POTS) is a condition in which the heart rate climbs abnormally when a person stands up, bringing dizziness, fatigue and brain fog. POTS existed long before COVID-19, but it is also common in people with long COVID, and some develop both. Because the symptoms overlap so much, it has been hard to tell whether these are the same illness or different ones.

What We Did

The study was led by Renata Booyens in Prof Resia Pretorius’s group at Stellenbosch University, with collaborators including Prof Satish Raj, a leading POTS researcher, and Prof Douglas Kell. We compared four groups: healthy controls, people diagnosed with POTS before the pandemic, people with long COVID, and people with long COVID who also have POTS.

From each person’s plasma, we isolated the insoluble fraction, which contains the microclots our group has been studying in long COVID, and analysed it by mass spectrometry. This time we looked beyond which proteins were present to their post-translational modifications.

What Is a Post-Translational Modification?

Once a protein has been made, it can be chemically altered. Some of these changes are deliberate switches the body uses to control proteins. Others are damage. Oxidation is a little like rust, and glycation, where sugars stick to a protein, is a little like caramelising. These changes can alter how a protein folds and behaves, even when the amount of the protein stays the same.

My Part in the Study

My role covered the proteomics, from the methodology and the laboratory work through to the data analysis and visualisation. I also helped administer the project and reviewed and edited the manuscript.

What We Found

The amounts of most proteins barely differed between the groups. The modifications told a different story:

Long COVID: fibrinogen, a key clotting protein, carried sugar-related damage (advanced glycation end products) and oxidation, a pattern consistent with clots that form easily and resist breakdown.
POTS diagnosed before the pandemic: oxidised and otherwise modified apolipoproteins, the proteins that carry fats in the blood, along with changes in immune proteins, pointing to metabolic and immune involvement.
Long COVID with POTS: oxidation changes in clotting proteins, together with immune features shared with pre-pandemic POTS.

What This Means

If what has happened to proteins matters more than how much of them there is, that may help explain why routine blood tests, which mostly measure amounts, so often come back normal in these patients. Modification patterns could one day support better biomarkers, and treatments aimed at glycation, oxidative stress or the immune system.

This is a preliminary study with small groups, and the findings need to be confirmed in larger cohorts. But it is a good example of what modern proteomics can see that standard tests cannot.

Read more about our earlier work on what is trapped inside long COVID microclots.