COVID-19: Hemoglobin, Iron, and Hypoxia beyond Inflammation. A Narrative Review

Abstract

Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV- 2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicinebased narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

“…The low oxygen saturation observed in COVID-19 patients 14 , suggested SARS-CoV-2 infection may have an effect on erythropoiesis. In this study, we observed that COVID-19 infection results in the expansion of CECs in the peripheral blood of patients compared to healthy controls (HCs).…”

“…Preliminary modeling reports have suggested that SARS-CoV-2 may inhibit heme metabolism and induce hemoglobin denaturation 14 . As such, hemoglobin alteration may compromise oxygencarrying capacity of red blood cells (RBCs) in COVID-19 patients resulting in hypoxia.…”

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression

“…This mechanism occurs because SARS-CoV-2 attacks hemoglobin (Hb) groups in the red blood cells, thereby producing the release of free Fe(III) ions from the heme groups to the bloodstream [ 30 ], which in turn produces an increase in ferritin levels [ 31 ]. Hemoglobinopathy and iron dysmetabolism, mediated by the virus, may contribute to clinical syndromes highlighted during COVID-19 including oxidative stress, ferroptosis, lipid peroxidation, and mitochondrial damage, among others [ 32 ].…”

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

“…An oxygen saturation above 90% is associated with better outcomes 6 . Over 80% of COVID-19 patients in the intensive care unit have severe hypoxemia 7 . A kind of "silent hypoxia" in which COVID-19 patients deteriorate rapidly without warning and develop respiratory failure has been described 8 .…”