What Is Trapped Inside Long COVID Microclots?
Many people with long COVID get normal results on standard blood tests. So we stopped looking at the blood around the microclots and looked inside them instead.
Long COVID, also called post-acute sequelae of COVID-19 (PASC), leaves people with fatigue, brain fog and shortness of breath for months after the initial infection. One of the most frustrating parts for patients is that routine markers of inflammation and clotting, such as C-reactive protein and D-dimer, often come back normal.
Our group had already shown that people with long COVID carry microclots that resist being broken down, and that the spike protein alone can make clotting proteins resist breakdown. The next question was obvious: what exactly is caught inside these clots?
What We Did
The study was led by Arneaux Kruger in Prof Resia Pretorius’s group in the Department of Physiological Sciences at Stellenbosch University, with Prof Douglas Kell. We compared plasma from 99 people with long COVID and 29 healthy controls, and analysed 66 of the long COVID samples in depth.
Isolating the microclots relies on the fact that they resist digestion. A first digestion with the enzyme trypsin breaks down the normal, soluble blood proteins and leaves the tough microclots behind. A second digestion then opens up the clots, so the proteins trapped inside can be identified and measured by mass spectrometry.
My Part in the Study
I was responsible for the proteomics, carried out at Stellenbosch University’s Central Analytical Facility. That meant developing the methods, training the students on sample preparation, setting up the instruments, acquiring and processing the data, writing the data reports, and reviewing the manuscript before publication.
What We Found
Platelet proteins: platelet factor 4 and von Willebrand factor were raised in the long COVID microclots, consistent with overactive platelets.
Plasma kallikrein: this protein, which links clotting and inflammation, was lower than in controls.
α2-antiplasmin: a protein that blocks clot breakdown was slightly raised, echoing our earlier antiplasmin findings.
Antibodies: perhaps the most striking finding was the number of antibodies trapped inside the clots, molecules a routine blood test would never see.
What This Means
If inflammatory molecules and antibodies are locked inside clots that the body struggles to dissolve, that may help explain why standard tests look normal while patients feel anything but. The trapped molecules may also contribute to a fibrinolytic system that isn’t working properly, which could play a part in fatigue, breathlessness and cognitive problems.
The platelet findings matter too. People with long COVID who also have cardiovascular disease or type 2 diabetes may face extra risk, and this study adds weight to the case for looking at clotting more carefully in these patients.
For a plain-language overview of the wider field, see Unpacking Long COVID: How Proteomics Is Leading the Charge.