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.