Fig. 2: COVID-19 clinical spectrum.
The symptomatic outcomes of SARS-CoV-2 infection manifest in a tri-phasic manner as iron (Fe)-redox disruptive hematological syndromes27. Phase-I: Hypoxia/Hypoxemia. Viral binding to ACE2 alters RAAS, subsequently lowers blood pressure, lung function, and reduces O2 transport (hypoxia) in the infected host. This condition triggers a mitochondrial metabolic shift by alteration of OXPHOS/TCA cycle and activation of anaerobic glycolysis, the ‘Warburg Effect’. This metabolic shift is regulated by HIF-1α that causes impairment of host immune response, exacerbates inflammation, and elicits tissue damage88. This clinical phase of COVID-19 is considered a hypoxia-induced blood disease, associated with FeRD and HMRD27,93. Phase-II: Hyperferritinemia is characterized by a hyper-inflammatory state with elevated proinflammatory cytokines, which stimulates synthesis of both ferritin and hepcidin, the ultimate mediators of FeRD94. The altered iron homeostasis is reflected by high iron content in reticuloendothelial cells and elevated serum ferritin levels. Such uncontrolled and dysfunctional immune response associated with macrophage activation leads to hyperferritinemia, and ‘cytokine storm’ or cytokine release syndrome (CRS)97. Hyperferritinemia, cellular redox imbalance and FeRD play a critical role in the disease progression of COVID-19,27,98. Phase-III: Thrombocytopenia. SARS-CoV-2 could invade blood vessels, induce vascular damage, and activate systemic thrombotic events with severe to fatal coagulopathies in COVID-19 patients100. This clinical state along with hypoxia, could cast signs of hemolysis with release of heme proteins and accumulation of free heme. Heme from hemolysis could initiate oxidative and inflammatory stress that may cause microvascular thrombosis, organ ischemia and multi-organ failure in severe COVID-19 cases102,105.
