The One Where We Discovered that Increased Antiplasmin in Long Covid Contributes to Microclots:

Persistent Clotting Protein Pathology in Long COVID/PASC Linked to Increased Antiplasmin Levels

A significant study published in Cardiovascular Diabetology in August 2021, led by Resia Pretorius along with co-authors Maré Vlok, Chantelle Venter, Jandré Bezuidenhout, Jaco Laubscher, Janami Steenkamp, and Douglas Kell, shed light on the persistent clotting abnormalities seen in patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC).

The study highlighted a key finding: increased levels of antiplasmin, a protein that prevents the breakdown of clots, may contribute to the ongoing symptoms of Long COVID/PASC.

Background: Clotting Abnormalities in COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has been linked to a wide range of long-term clinical complications, particularly involving coagulopathies. These include hypercoagulation and platelet hyperactivation, which can lead to the formation of blood clots that block small blood vessels, or microclots.

As more patients recovered from the acute phase of COVID-19, a new syndrome emerged, termed Long COVID/PASC, in which lingering symptoms persist for six months or longer. These symptoms include fatigue, muscle weakness, shortness of breath, sleep disturbances, and anxiety. Given that blood clots can obstruct microcapillaries, limiting oxygen exchange, the researchers sought to determine if persistent microclots resistant to normal clot breakdown processes (fibrinolysis) might be responsible for these symptoms.

Study Methodology

Using advanced techniques like proteomics and fluorescence microscopy, the research team analyzed plasma samples from various groups, including:

Healthy individuals,
People with Type 2 Diabetes Mellitus (T2DM),
Individuals with acute COVID-19,
Those suffering from Long COVID/PASC.

Their goal was to identify any differences in clotting patterns between these groups, particularly focusing on the presence and resistance of plasma microclots to fibrinolysis.

Key Findings: Persistent Microclots and Antiplasmin

Prof Resia Pretorius conducted fluorescence microscopy and found that plasma from both acute COVID-19 and Long COVID/PASC patients contained large, anomalous microclots, primarily composed of amyloid deposits. Dr Maré Vlok then developed a new method to isolate microclots, prior to conducting proteomics analysis using LC-MS/MS. Importantly, these microclots were resistant to hydrolysis using the enzyme trypsin, under non-denaturing (natural) conditions. Maré discovered that the other blood proteins not associated with the microclots, however, did break down when digested with trypsin.

Further analysis revealed a significant increase in α(2)-antiplasmin (α2AP) in the Long COVID/PASC patients compared to healthy controls. α2-antiplasmin is a key inhibitor of plasmin, the enzyme responsible for breaking down fibrin clots. Elevated levels of α2-antiplasmin, along with increased amounts of fibrinogen chains and Serum Amyloid A (SAA) in the microclots, suggested that these clots remain resistant to the body’s natural clot-dissolving processes, potentially explaining the ongoing symptoms in Long COVID/PASC patients.

Clinical Implications and Conclusion

The study’s findings had phenomenal implications for the treatment of Long COVID/PASC. The persistence of these fibrinolysis-resistant microclots may contribute to the lingering symptoms experienced by many COVID-19 survivors. The authors suggest that patients with Long COVID/PASC could potentially benefit from continued anticoagulant therapy to help support the body’s fibrinolytic system and reduce the burden of persistent clotting abnormalities.

From the findings in this study, the triple-anticoagulant protocol was born, and is now used by many medical professionals in practice, when treating patients with Long Covid/PASC.

This research marks a crucial step in understanding the underlying biological mechanisms of Long COVID and offers hope for the development of targeted treatments to alleviate the suffering of those affected by this long-term condition.

To read the full article in Cardiovascular Diabetology, click here.