Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences

Abstract

Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 syndrome (PACS). Even nonhospitalized survivors have an elevated risk for the development of thromboinflammatory-associated events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis. Recent findings point to the persistence of many mechanisms of hypercoagulability identified to be associated with disease severity and mortality in the acute phase of the disease, such as sustained inflammation and endotheliopathy, accompanied by abnormal fibrin generation and impaired fibrinolysis. Platelets seem to be central to the sustained hypercoagulable state, displaying hyperreactivity to stimuli and increased adhesive capacity. Platelets also contribute to elevated levels of thromboinflammatory mediators and pro-coagulant extracellular vesicles in individuals with ongoing PACS. Despite new advances in the understanding of mechanisms sustaining thromboinflammation in PACS, little is known about what triggers this persistence. In this graphical review, we provide a schematic representation of the known mechanisms and consequences of persisting thromboinflammation in COVID-19 survivors and summarize the hypothesized triggers maintaining this prothrombotic state.

Keywords: Hypercoagulability; Platelet activation; Post-acute COVID-19 syndrome (PACS); Thromboinflammation.

Graphical abstract

Fig. 1

– Post-acute COVID-19 syndrome. Survivors of both severe and mild cases of COVID-19 can have persisting symptoms, affecting multiple systems for longer than 4 weeks after initial infection, a condition known as Post-acute COVID-19 syndrome (PACS). Survivors of COVID-19 have an increased risk of developing cardiovascular diseases and thromboembolic events for at least one year after infection.

Fig. 2

– Thromboinflammatory mechanisms in acute disease and post-acute COVID-19 syndrome. Severe acute COVID-19 is characterized by an exacerbated inflammatory response in the alveoli (usually the first site of infection), leading to a hypercoagulable state and the development of acute respiratory distress syndrome (ARDS). Many thromboinflammatory mechanisms known to be associated with severity and mortality in acute COVID-19 have been shown to persist in individuals with ongoing PACS, including inflammation, elevated platelet activation and reactivity, endothelial cell activation and exacerbated fibrin clot formation associated with impaired fibrinolysis. NET – Neutrophil extracellular trap; PLAs – Platelet-leukocyte aggregates; ARDS - acute respiratory distress syndrome; VWF – von Willebrand factor.

Fig. 3

– Possible stimuli and drivers of hypercoagulability. Some hypotheses have been proposed for the persistent hypercoagulable state found in COVID-19 survivors. These include unresolved inflammation, development of auto-antibodies, possible viral reservoirs or sources of viral RNA/proteins that could lead to activation of leukocytes and platelets, eliciting a continued inflammatory response. Regardless of the stimuli, individuals with PACS have persistent thromboinflammation, maintained by sustained endothelial cell and platelet activation and elevated fibrin clot formation. PF4 – Platelet Factor 4; CD62p – P-selectin; TF – Tissue Factor; VWF – von Willebrand Factor; PAR-1 – Protease activated receptor 1.