SARS-CoV-2 Spike Protein S1 and Its Role in Hypercoagulation: A Study on Fibrin(ogen) Resistance to Fibrinolysis

Published in Bioscience Reports in July 2021, the study titled "SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19" provides key insights into the mechanisms by which COVID-19 leads to blood clotting abnormalities.

Led by Lize Mireille Grobbelaar and co-authored by Chantelle Venter, Maré Vlok, Malebogo Ngoepe, Jaco Laubscher, Petrus Johannes Lourens, Janami Steenkamp, Douglas Kell, and Resia Pretorius, the research focuses on how the spike protein S1 of SARS-CoV-2 contributes to hypercoagulation and the formation of microclots, a dangerous pathology observed in COVID-19 patients.

Background

COVID-19, caused by the SARS-CoV-2 virus, is well-known for its severe respiratory symptoms. However, one of the less visible yet equally critical pathologies is hypercoagulation — the tendency of blood to form clots too easily. Microclots, especially in the lungs, have been a significant cause of the high morbidity and mortality rates seen in patients with severe cases of COVID-19. This study investigated whether the isolated spike protein S1 of SARS-CoV-2 plays a role in these coagulation abnormalities, particularly by influencing the behaviour of fibrinogen, a key protein in blood clotting.

Methods

The research team used a combination of advanced techniques, including scanning electron microscopy, fluorescence microscopy, and mass spectrometry, to study the interaction between the spike protein S1 and fibrin(ogen) in platelet-poor plasma (PPP) from healthy individuals. By adding the spike protein S1 to PPP, they could observe its direct effects on blood flow and clot formation.

Key Findings

Spike Protein S1 as an Inflammagen: The study suggests that the spike protein S1 acts as an inflammagen sui generis, meaning it is a unique inducer of inflammation. Its presence in circulation may be directly linked to blood clot formation, as it causes hypercoagulation when interacting with fibrin(ogen) and platelets.

Structural Changes in Clotting Proteins: When the spike protein S1 was added to healthy plasma samples, significant structural changes were observed in several proteins essential for normal blood clotting:

  • β and γ fibrinogen chains

  • Complement 3

  • Prothrombin

These proteins became resistant to breakdown through fibrinolysis — the body's natural process of dissolving blood clots. This resistance to trypsinisation (a digestion process used in the study) indicates that spike protein S1 contributes to creating persistent microclots that resist normal clot degradation.

Impaired Fibrinolysis and Microclot Formation: The inability of the body to break down these clots effectively is known as lytic impairment. The spike protein-induced impairment of fibrinolysis suggests that the persistent large microclots observed in COVID-19 patients may be partly due to the direct effect of the spike protein. This finding is consistent with earlier observations of microclots in the plasma of COVID-19 patients and could explain the prolonged hypercoagulability seen in both acute COVID-19 and long COVID.

Clinical Implications

This study has significant implications for treating COVID-19, particularly for managing patients who exhibit signs of hypercoagulation and are at risk of thrombotic events.

Understanding that the SARS-CoV-2 spike protein S1 contributes directly to the formation of microclots and impairs the body’s ability to break down these clots offers potential therapeutic targets. Treatments that enhance fibrinolysis or inhibit the spike protein’s interaction with fibrinogen could potentially mitigate the risk of severe blood clotting in COVID-19 patients.

In summary, this research provides crucial insights into the molecular mechanisms of COVID-19-associated hypercoagulation, emphasising the importance of fibrinolysis impairment in the disease's pathology. This new understanding may guide future therapies aimed at preventing or treating blood clot-related complications in COVID-19.