1.2 Clinical manifestations and thrombo-inflammation
Since the discovery of SARS-Cov-2 infection, a number of clinical manifestations such as: fever, dry cough, malaise, sore throat, chest pain, dyspnoea, nausea, diarrhoea and vomiting.(Tian et al. 2020) The spectrum of symptomatic infection ranges from mild to critical, although there remains uncertainty around the proportion of asymptomatic infections. Among hospitalised patients, the proportion of critical or fatal disease is higher, with many progressing to acute respiratory distress syndrome (ARDS), respiratory failure and eventually death.(Bost et al. 2021) Interestingly, the ARDS associated with COVID-19 patients differs from that caused by other infective or traumatic insults, with the “cytokine storm” (i.e. increased cytokines released from the blood, which is associated with disease severity) being only partially involved in COVID-19 patients.(Maier et al. 2020) Furthermore, interleukin (IL)-6 levels are 60-90-fold higher in ARDS patients compared to COVID-19 patients, although the reasons for these differences are unknown. It is conceivable that SARS-CoV-2 takes over the host immune system, impairing antiviral immunity and triggering chronic inflammation by involving inflammatory cytokines.(Sinha, Matthay, and Calfee 2020; Bost et al. 2021) Certainly a hallmark of SARS-CoV-2 is the release of not only IL-6, but other cytokines and chemokines including IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, TNF-α, chemokine ligand-2 (CCL2), CCL3, interferon gamma-inducible protein, C-X-C motif chemokine ligand-10, and monocyte chemoattractant protein-1, all of which correlate with adverse clinical outcomes. The inflammatory effects of cytokines also activate vascular endothelial cells, disrupting endothelial function and integrity, which leads to increased platelet and leukocyte recruitment, resulting in a pro-inflammatory and pro-thrombotic state.(Connors and Levy 2020)
Autopsy reports from SARS-CoV-2 patients show multi-organ dysfunction, with highest viral titres in the lungs and immune cells, and the presence of endothelial inflammation and cell death.(Gu et al. 2005; Mazzulli et al. 2004) It is likely that hypoxia, also promotes a pro-thrombotic endothelial phenotype in SARS-CoV-2 via hypoxia-inducible transcription factor activation and endothelial tissue factor (TF) upregulation.
The scale of COVID-19 severity also increases with comorbidities such as hypertension, chronic kidney disease, obstructive sleep apnoea, asthma diabetes and obesity.(Tian et al. 2020) Patients with underlying cardiovascular disease are prone to increased severity of COVID-19 and a 5-fold increase in mortality.(Yang et al. 2020) Therefore, managing and controlling cardiovascular risk factors is a high priority.
COVID-19 is associated with a prothrombotic state, which can manifest as microvascular thrombosis, venous thromboembolism (VTE) or arterial thrombosis.(McFadyen, Stevens, and Peter 2020) The cause of this pro-thrombotic state may relate to the appreciated link between thrombosis and inflammation (termed ‘thromboinflammation’) in which thrombosis can amplify inflammation and systemic inflammation can beget thrombosis. Whilst efforts to understand the complex immunological landscape in COVID-19 are evolving, both platelet activation and platelet–neutrophil interactions play a crucial role in thromboinflammation.