Persistent thromboinflammation in post-acute COVID-19 syndrome

An extensive review article by Brazilian investigators discusses the known underlying mechanisms, possible trigger factors and consequences of persistent thromboinflammation in post-acute COVID-19 syndrome (PACS).

More than two years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long-COVID-19 or post-acute COVID-19 syndrome. Although this disease is more common in hospitalization survivors, even those who have experienced mild acute COVID-19 have a wide range of organ dysfunction and clinical symptoms, including fatigue, muscle weakness, dyspnea, cough, headache, hypoxia, cardiac arrhythmias, palpitations, memory impairment, loss of taste and smell, anxiety and depression.

One of the biggest causes of concern associated with PACS is the increased risk of cardiovascular disorders. Even nonhospitalized survivors have an increased risk for thromboinflammatory events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis.

About the study

The authors emphasized that many mechanisms of hypercoagulability persist in post-acute COVID-19 syndrome, including persistent inflammation and endotheliopathy, accompanied by abnormal fibrin formation and impaired fibrinolysis. Previous studies demonstrated a significant load of fibrin amyloid microclots that are resistant to fibrinolysis in the circulation of long COVID patients. In addition, it has been shown that recombinant SARS-CoV-2 spike protein can induce these microclots in normal plasma. 

Following vascular injury, a series of simultaneous events involving cellular and molecular components are necessary for plugging of the vascular leak. These include the release of adenosine triphosphate and Von Willebrand factor, exposure of adhesion molecules by the damaged endothelium, adhesion of platelets and leukocytes, activation of the coagulation cascade and formation of a fibrin mesh that stabilizes the clot.

Patients with long COVID have in the soluble part of the blood a significantly higher concentration of inflammatory molecules known to be the main drivers of endothelial and coagulation pathology, such as Von Willebrand factor (VWF), platelet factor 4 (PF4), serum amyloid A (SAA), alpha 2-antiplasmin (α2AP). Addition of endothelial-leukocyte adhesion molecule 1 (E-selectin), and platelet endothelial cell adhesion molecule 1 (PECAM-1), to samples from healthy controls results in the significant microclot formation and platelet hyperactivation. 

However, the authors emphasized that platelets appear to be a central factor in the persistent hypercoagulable state in post-acute COVID-19 syndrome. The same research group previously reported that platelets from PACS patients show increased surface expression of degranulation markers and increased spontaneous release of granule products and thromboxane A2 up to six months after symptom onset.

Image from the original article by Martins-Gonçalves et al.

Platelets also contribute to increased levels of thromboinflammatory mediators. After their activation, platelets express tissue factor (TF, coagulation factor III) on their surface. Once in the outer membrane, TF can be released bound to extracellular vesicles (EVs). An increased level of total and TF-bearing EVs in the circulation of COVID-19 survivors has been found. According to the authors, these data suggest that persistent EV-bound TF activity via continuous platelet activation is a possible mechanism for the persistent hypercoagulability in PACS.

In their previous publication, based on pharmacological approach, the same research group investigated the pathways leading to excessive platelet activation, and showed that plasma from individuals with PACS activates platelets through mechanisms dependent on purinergic receptors and integrin αIIbβ3 engagement. (Martins-Gonçalves et al., 2022. Circ Res 131, 944947.

Despite recent advances, little is known about the triggers of persistent thromboinflammation in post-acute COVID-19 syndrome. The authors of this review suggested that the potential triggers of persistent thromboinflammation in PACS and long COVID can be narrowed down to persistent inflammation, cross-reactive autoantibody formation, and viral persistence. Persistent inflammation contributes to the elevated levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF) in PACS. The formation of cross-reactive autoantibodies and their role in PACS are not fully understood. Viral persistence in specific tissue reservoirs may contribute to systemic inflammation and immunothrombosis, and viral RNA has been detected in stool and serum samples up to 4 months after initial infection.

This article was published in Current Research in Immunology.

Journal Reference

Martins-Gonçalves et al. Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences Current Research in Immunology 4 (2023) 100058.

Other studies have also investigated the binding of the SARS-CoV-2 spike protein to the platelet integrin receptors αIIbβ3, αvβ3, and α5β1. This study visualized for the first time directly binding of the S protein to the platelet plasma membrane. The results showed weak, but direct binding of integrin α5β1 and αvβ3 to the S protein, whereas integrin αIIbβ3 did not interact with it. In addition, it was shown that the S protein triggers the dynamic deformation of platelets morphologies. Cryo-electron tomography showed the formation of actin-rich filopodia at the end of the elongated platelets.