An exploration of the pathophysiological factors and abnormalities of coagulation of long-COVID

By Bhavana KunkalikarReviewed by Lily Ramsey, LLMApr 21 2023

In a recent study published in the Trends in Endocrinology & Metabolism Journal, researchers explored the pathophysiological variables and coagulation abnormalities associated with long coronavirus disease (COVID).

Study: Long COVID: pathophysiological factors and abnormalities of coagulation. Image Credit: JosieElias/Shutterstock.com

Background

COVID-19 is an infectious respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Post-acute sequelae of COVID-19 (PASC) or long COVID is a condition where approximately 10% of patients report continued or novel COVID-19 symptoms after the acute infection phase, even though COVID-19 symptoms usually last for up to two to three weeks.

In long COVID, acute COVID-19 symptoms may persist, or novel symptoms unrelated to the acute disease may appear. 

Pathophysiology of long COVID

Viral factors

Long COVID patients may have persistent SARS-CoV-2 in tissue reservoirs following acute infection. Hidden viral reservoirs can cause persistent symptoms by triggering repeated immune responses. SARS-CoV-2 messenger ribonucleic acid (mRNA) and spike protein have been found in the urinary tract and digestive system of long COVID patients several months after infection.

Spike proteins, homotrimers located on the surface of viruses, are class I viral fusion proteins that aid in the virus's entry into host cells. The host cell can release the spike protein through extracellular vesicles (EVs) and transport it to other parts of the body through the circulatory system.

EVs transport cargo to maintain homeostasis in neighboring or distant cells. Long COVID may occur when SARS-CoV-2 hides in EVs and attacks different organs and tissues via the circulatory system, resulting in long-term COVID symptoms.

SARS-CoV-2 was believed only to be able to survive and reproduce within eukaryotic cells of mammals. SARS-CoV-2 has been found to infect and replicate within gut bacteria, suggesting a possible bacteriophage-like behavior of the virus.

SARS-CoV-2's bacteriophagic action may lead to a potent viral persistence and contribute to gut dysbiosis in long COVID patients by promoting the replication of specific bacteria, leading to an imbalance within the gut microbiota.

Long COVID may be exacerbated by this, as it can lead to endothelial dysfunction, chronic inflammation, and hypercoagulation.

Host factors

The immune system responds to acute COVID-19 by triggering polyclonal T-cell activation and releasing various inflammatory molecules, including cytokines, chemokines, and interleukins. A cytokine storm, a unique immunopathological aspect of the disease, characterizes COVID-19.

Severe COVID-19 can lead to lymphopenia, which is a deficiency in B cell and T cell lymphocytes. Lymphocytes' absence in resolving inflammation after infection can lead to hyperinflammation. Persistent SARS-CoV-2 shedding is strongly linked to depleted B and T cell levels, which may exacerbate chronic immune activation observed in long COVID.

Autoimmunity may play a role in developing SARS-CoV-2 infection, both in acute and long COVID. COVID-19 patients have functional autoantibodies that target G-protein-coupled receptors (GPCR-AAbs) in their blood, which are linked to the severity of the disease.

Mast cell activation may contribute to the hyperinflammatory responses in acute COVID-19 infection and long COVID. Mast cell activation syndrome (MCAS) is a condition that can develop from mast cell activation and result in severe allergic symptoms that affect multiple body systems.

Long COVID patients report various symptoms, such as food allergies, gastrointestinal upset, urticaria, breathlessness, and wheezing, which are caused by unregulated chemical mediators release.

Coagulation abnormalities in individuals with long COVID

The S1 subunit of the SARS-CoV-2 spike protein has pro-inflammatory properties. SARS-CoV-2 can interact with fibrin, fibrinogen, and platelet, leading to fibrin(ogen) alterations and increased hypercoagulability.

Microclots have been observed in healthy PPP samples due to the SARS-CoV-2 S1 spike protein, as well as in long COVID or acute COVID-19 patients.

Untreated coagulopathy noted in the acute phase of COVID-19 can lead to prolonged impaired oxygen exchange and tissue hypoxia. This could explain the various bodily symptoms associated with long COVID.

Long COVID is strongly associated with endothelial dysfunction and damage. Patients recovering from SARS-CoV-2 infection exhibit significantly elevated levels of certain endothelial cell (ECs) biomarkers, including von Willebrand factor (VWF) and factor VIII.

Long COVID patients have shown dysregulation of endothelial markers, including ET-1 and angiopoietin-2, even eight months after experiencing mild-to-moderate COVID-19 infection.

Conclusion

The study findings showed that the factors involved in long-COVID have viral and host-related factors. The mechanisms cause persistent thrombotic endothelialitis and systemic hypercoagulability by interacting with the vascular endothelium.

Thus, the study suggests that generating fibrinaloid microclots, endothelial dysfunction, and platelet hyperactivation may result in clotting pathologies.

The researchers believe that randomized placebo-controlled trials are urgently required for therapeutics that target endothelialitis and dysregulated coagulation.