Could iron-chelation with EDTA and bloodletting/transfusion be a therapeutic option in COVID-19 worst scenario? Proposal for a protocol

Abstract

COVID-19 is a complex, multi-organ disease where lungs are primarily affected, resulting in a form of ARDS in the later stages. In fact, a relevant role has been attributed to iron dysmetabolism and series of literature data highlight a clear-cut alteration in a few related parameters; significantly high figures of ferritin, hepcidin, red blood cell width distribution, lactate dehydrogenase and lactate, in combination with low levels of serum iron and transferrin, have been repeatedly reported in patients affected by Sars-Cov-2 infection at later stages. Overall, these alterations have a negative prognostic value, indicating a pattern of ferroptosis and of a possible dysfunctional hemoglobin, with pro-coagulant and pro-inflammatory repercussions. Different pathomechanisms have been proposed, from erythrocyte attack and an hepcidin-mimetic action of the viral spike proteins, to a more general iron and calcium deregulated intracellular accumulation. Iron chelation has been advocated as one of the possible treatments of COVID-19 and CaNa2ethylendiaminetetraacetic acid (EDTA) is known as a safe and effective mineral-chelator. In this review the authors propose an EDTA-based therapeutic protocol for those patients in most critical stages and admitted to intensive care unit, with the aim to reduce intracellular and blood ferritin overload. Bloodletting and blood transfusion have proved to be beneficial in patients with viral disease-associated iron accumulation. The inclusion of these two procedures in the proposed protocol aims at improving oxygenation by new normo-functioning hemoglobin, while decreasing toxic hyperferritinemia and interleukins. Lastly, a few specific compounds are also taken into consideration to synergistically complement EDTA infusion. A series of technical details are provided for the possible use of the protocol in clinical practice.

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

“…[185][186][187][188] With reference to the possible therapeutic proposals targeting the basic pathophysiology steps elucidated above, literature highlights a number of options to address this cation dysregulation, based on chelation for example. 15,187,352 Equally, a large series of drugs and natural compounds have been tested, or advocated, to target the sialylated receptors, hepcidin/ ferroportin axis and the cation channels deregulation. More robust data are needed before drawing definitive conclusions about the role of intracellular cation accumulation in the onset and perpetuation of the inflammatory and immune-mediated processes of this infection.…”

“…In fact, based on the evidence above, the SARS-CoV-2-induced intracellular cation overconcentration may easily lead to a progressive deregulation of mitophagy, with a documented consequent ferroptosis-based cell degeneration in later stages and in worst scenarios. 1,2,15,18,183,184 Viruses were shown to generally alter iron metabolism, inducing somehow a form of iron deposition in the host cells; COVID-19 features a similar cell condition, which may be considered a sort of evolutionary and protective mechanism for viruses to survive and proliferate. [185][186][187][188][189][190] The high levels of intracellular calcium and iron in these patients, especially in later stages, significantly contribute to a number of dysfunctional metabolic pathways, both at mitochondrial level and at greater cell level.…”

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

“…[183][184][185][186] With reference to the possible therapeutic proposals targeting the basic pathophysiology steps elucidated above, literature highlights a number of options to address this cation dysregulation, based on chelation for example. 15,185,347 Equally, a large series of drugs and natural compounds have been tested, or advocated, to target the sialylated receptors, hepcidin/ ferroportin axis and the cation channels deregulation.…”

“…1,[7][8][9][10][11][12][13][14] Similarly, a series of possible treatments aimed at controlling iron dysmetabolism have been proposed. [15][16][17][18][19] Together with these biochemical changes, a number of RBC alterations have been described, both in terms of hemoglobin decrease/denaturation, and in terms of RBC altered morphology/functionality. 1,[20][21][22][23] Another well-documented cation dysmetabolism, especially in later stages is represented by lower serum calcium levels, which is equally a proven negative prognostic factor in COVID-19 patients [24][25][26][27][28][29][30][31][32] ; additionally, early autopsies also highlighted a higher representation of calcium deposits in many tissues.…”

“…In fact, based on the evidence above, the SARS-CoV-2-induced intracellular cation overconcentration may easily lead to a progressive deregulation of mitophagy, with a documented consequent ferroptosis-based cell degeneration in later stages and in worst scenarios. 1,2,15,18,181,182 Viruses were shown to generally alter iron metabolism, inducing somehow a form of iron deposition in the host cells; COVID-19 features a similar cell condition, which may be considered a sort of evolutionary and protective mechanism for viruses to survive and proliferate. [183][184][185][186][187][188] The high levels of intracellular calcium and iron in these patients, especially in later stages, significantly contribute to a number of dysfunctional metabolic pathways, both at mitochondrial level and at greater cell level.…”