Derivatization of sialylated glycopeptides plus based sialoglycopeptides enrichment using cation exchange media.

Glycosylation is one of the most important post-translational modifications. However, the characterizations of glycopeptides, especially the negatively charged sialoglycopeptides that are associated with various diseases, remain challenging, due to the co-existence with high abundant peptides and the low ionization efficiency of sialoglycopeptides resulting from the carboxyl groups. Therefore, it is essential to develop an efficient enrichment method for sialoglycopeptides. Here, we present a novel derivatization-based enrichment method that can (i) identify linkage isomers of sialic acids by generating mass difference, (ii) unify the net charge of peptides into zero, and (iii) introduce positive charges to sialoglycopeptides by conjugating quaternary ammonium with sialic acid. The derivatization, termed derivatization of sialylated glycopeptides plus (DOSG+), enables efficient enrichment through electrostatic interaction using weak cation exchange (WCX) media. DOSG+ -based WCX enrichment was validated and optimized with samples derived from bovine fetuin. Peptides were removed efficiently (recovery rate <1%). The signal intensity of a selected model sialoglycopeptide was increased by ∼30% (suggesting recovery rate >100%). The method was employed on human alpha-1 acid glycoprotein (AGP), and recombinant human erythropoietin (EPO), demonstrating the application of DOSG+ -based WCX enrichment on complexed N-linked and O-linked sialoglycopeptides. The method is simple, efficient, and targets small-scale sialoglycopeptide enrichment.

Ameliorating effect of erythropoietin in a severe case of COVID-19: case report.

The COVID-19 pandemic is arguably one of the greatest public health crises since the 1918 influenza pandemic. Although several vaccines have been approved and rolled out, effective antiviral treatment options are very limited. Here, we present a case of severe COVID-19 that failed to respond to the standard interventions and continued to deteriorate. On day 22 of his illness, after informed consent, the patient was administered 4000IU of erythropoietin (EPO) subcutaneously, in the hope of improving his O2 saturation. Positive response was observed in the patient within 24 hours. This prompted us to continued EPO treatment for a total of 42 days until full recovery and discharge. Our findings warrant further studies to ascertain the use of EPO in severe cases COVID-19.

Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies.

INTRODUCTION: Postural orthostatic tachycardia syndrome (POTS) is an increasingly well-recognized condition encountered in clinical practice. Diagnosis and treatment remain extremely challenging. The limited success of currently available therapies has laid the foundation for a number of experimental therapies. AREAS COVERED: In this review, we will briefly outline the pathophysiology and clinical features of this syndrome, before moving on to its management, with a specific focus on experimental pharmacological therapies. Finally, we briefly discuss POTS related to the SARS CoV-2 (COVID-19) pandemic. EXPERT OPINION: Despite tremendous advances, the diagnosis and management of POTS remains extremely challenging. The multitude of contributory mechanisms, which predominate to varying degrees in different patients further complicates management. Improved characterization of pathophysiological phenotypes is essential to individualize management. Lifestyle measures form the first line of therapy, followed by beta-blockers, ivabradine, fludrocortisone, and midodrine. Supplemental therapies such as iron, vitamin D and α lipoic acid are quite safe and a trial of their use is reasonable. The use of erythropoietin, IVIG, desmopressin, etc., are more specialized and nuanced alternatives. In recent years, interest has grown in the use of cardiac neuromodulation. Though preliminary, some of these therapies are quite promising.

The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Desidustat: First Approval.

Desidustat (Oxemia™) is an orally bioavailable, small molecule, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor developed by Zydus Cadila for the treatment of anaemia associated with chronic kidney disease (CKD), COVID-2019 infections and chemotherapy induced anaemia. Desidustat inhibits prolyl hydroxylase domain enzymes, resulting in the stabilisation of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis. In March 2022, desidustat received its first approval in India for the treatment of anaemia in adults with CKD who are either on dialysis or not on dialysis. Desidustat is in clinical development in China for the treatment of anaemia in patients with CKD, in Mexico for the management of COVID-2019 infections and in the USA for the treatment of chemotherapy induced anaemia. This article summarizes the milestones in the development of desidustat leading to this first approval for anaemia associated with CKD.

Morphofunctional Characteristics of Erythrocytes and Blood Erythropoietin Level in Patients as Predictors of Severe Course of COVID-19.

Morphological and functional characteristics of erythrocytes, hemoglobin, and erythropoietin level in the venous blood were evaluated by laser interference microscopy, Raman spectroscopy with a short-focus extreme aperture lens monochromator, and by ELISA, respectively, in 30 patients with verified moderate COVID-19 at the time of hospitalization and 30 healthy volunteers. The patients whose course of COVID-19 has worsened to critical by day 5 had already had lower (p<0.001) indicators at the time of hospitalization such as the area and thickness of erythrocytes, the hemoglobin distribution and packing density, hemoglobin conformation index (I1355/I1550)/(I1375/I1580) reflecting its oxygen affinity, and blood erythropoietin content. Our findings suggest that these characteristics of erythrocytes, hemoglobin, and erythropoietin can serve as potential predictors of COVID-19 aggravation in hospitalized patients.

Addressing the 'hypoxia paradox' in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues.

BACKGROUND: Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. SHORT CONCLUSION: Substitution of EPO may-among other beneficial EPO effects in severe COVID-19-circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.

Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector.

Despite the World Anti-Doping Agency (WADA) ban on gene doping in the context of advancements in gene therapy, the risk of EPO gene-based doping among athletes is still present. To address this and similar risks, gene-doping tests are being developed in doping control laboratories worldwide. In this regard, the present study was performed with two objectives: to develop a robust gene-doping mouse model with the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to identify gene doping by using this model. The rAdV including the hEPO gene was injected intravenously to transfer the gene to the liver. After injection, the mice showed significantly increased whole-blood red blood cell counts and increased expression of hematopoietic marker genes in the spleen, indicating successful development of the gene-doping model. Next, direct and potentially indirect proof of gene doping were evaluated in whole-blood DNA and RNA by using a quantitative PCR assay and RNA sequencing. Proof of doping could be detected in DNA and RNA samples from one drop of whole blood for approximately a month; furthermore, the overall RNA expression profiles showed significant changes, allowing advanced detection of hEPO gene doping.

Evaluation of the efficacy and safety of recombinant erythropoietin on the improvement of hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: To evaluate the effect of recombinant erythropoietin on hospitalised COVID-19 patients. TRIAL DESIGN: Concealed, randomized, single-blinded, phase 2 controlled clinical trial with two arm parallel-group design of 20 patients allocated with 1:1 ratio and using the placebo in the control group. PARTICIPANTS: This study will be performed at Shahid Mohammadi Hospital in Bandar Abbas, Hormozgan in Iran. All positive (PCR confirmed) COVID-19 patients ≤65 years old who have Hb≤9 and at least one of the severe COVID-19 symptoms (tachypnea (breathing rate> 30 beats per minute), hypoxemia (O2 ≤93 saturation, the partial pressure ratio of arterial oxygen <300), Lung infiltration (> 50% of lung field within 24 to 48 hours), progressive lymphopenia, LDH>245 U/I, CRP>100) and are willing to cooperate in this project will be included in the study. Patients with a history of coronary heart disease, thrombosis, deep vein thrombosis, chronic lung disease, diabetes mellitus, weakened immune system, end-stage renal disease, liver disease, and patients with a history of taking oral contraceptive pills, systolic blood pressure more than 160 mm Hg, diastolic blood pressure more than 90 mm Hg and age over 65 and erythropoietin above 500 are excluded. INTERVENTION AND COMPARATOR: Patients will receive the standard of care (SOC) based on the treatment protocols of the Iranian National Committee of COVID-19 and recombinant erythropoietin (EPREX Manufactured by Johnson and Johnson Pharmaceutical Company) 300 units / Kg or 4000IU as subcutaneous (SQ) injection three times a day for 5 days and simultaneously Enoxaparin 1 mg/kg SQ daily is also taken to prevent thrombosis in the intervention group. Patients' blood pressure, along with other vital signs, are checked regularly and at regular intervals. In the control group, patients received SOC and the placebo (distilled water) is given as a subcutaneous injection three times a day for 5 days. We use sterile water for injection (EXIRpharmaceutical company) as the placebo. To the same appearance of the placebo and the recombinant erythropoietin, they are taken in a separate room in the same size syringes and cover with labels before injection. MAIN OUTCOMES: The main outcome for this study is a composite endpoint for Patient clinical symptoms (Respiratory rate, Oxygen saturation state and arterial oxygen partial pressure ratio, Lung infiltration status, blood pressure), Laboratory tests (LDH, CRP, Lymphocyte count, Endogenous erythropoietin, and Haemoglobin level). All of these will be assessed at the beginning of the study (before the intervention) and day 5 after the intervention. The study will also evaluate side effects and how to manage them. RANDOMISATION: Eligible participants (20) will be randomized in two arms in the ratio of 1: 1 (10 per arm) by permuted block randomization method using online web-based tools. BLINDING (MASKING): Patients participating in the study will not be aware of the assignment to the intervention or control group. The principal investigator, health care personnel, data collectors, and those evaluating the outcome are aware of patient grouping. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 20 patients will participate in this study, who are randomly allocated to the 2 arms with a 1:1 ratio; 10 patients in the intervention group will receive SOC and recombinant erythropoietin, and 10 patients in the control group will receive SOC and placebo. TRIAL STATUS: The protocol version is 3.0, approved by the Deputy of Research and Technology and the ethics committee of Hormozgan University of Medical Sciences on 6th June 2020, with the local grant number of 990108. The expected recruitment end date was on 21th December 2020 but since we had a wide and careful exclusion criteria because of the adverse reactions of the medication, the recruitment (for both cases and controls) was not so easy and did not finish on the expected date and we are still recruiting now. Recruitment began on 17th August 2020 and the updated expected recruitment end date is 1st August 2021. TRIAL REGISTRATION: The protocol was registered before starting subject recruitment under the title: Evaluation of the effect of recombinant erythropoietin on the improvement of COVID-19 patients, IRCT20200509047364N1, at Iranian Registry of clinical trials ( https://en.irct.ir/trial/49282 ) on 2020/08/09. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform.

L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤-0.7, p<0.001) and EPO (r≤-0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.

Use of face mask by blood donors during the COVID-19 pandemic: Impact on donor hemoglobin concentration: A bane or a boon.

BACKGROUND: COVID-19 virus has caused the world's deadliest pandemic. Early April 2020, the Delhi Government made it compulsory for people to wear face masks while going outdoors to curb disease spread. Prolonged use of surgical masks during the pandemic has been reported to cause many adverse effects. Intermittent hypoxia has been shown to activate erythropoietin (EPO leading to increased hemoglobin mass. AIM: To analyze whether face mask induced intermittent hypoxia has any effect on the hemoglobin levels of healthy blood donors. MATERIALS AND METHODS: We retrospectively analyzed donor data from 1st July 2019-31st December 2020 for hemoglobin distribution across hemoglobin ranges and donor deferral on basis of hemoglobin. Study population was divided into two cohorts Group 1- (1st July 2019-31 st March 2020): before implementation of mandatory face masks Group 2- (1st April 2020-31 st December 2020): after implementation of mandatory face masks RESULTS: Mean Hb of blood donors in Group 2 (15.01 ± 1.1 g/dl) was higher than Group1 (14.49 ± 1.15 g/dl), (p < 0.0001). 47.1 % group2 donors had Hb of 16.1-18 g/dl compared to group1 (38.4 %). 52.9 % group 2 donors had Hb between 12.5-15 g/dl compared to 61.6 % Group 1 (p < 0.05). Deferral due to anemia was lesser in group 2 compared to group 1 (p < 0.00001). Group 2 had significantly higher deferral due to high Hb (>18 gm/dl) was than Group 1 (p = 0.0039). CONCLUSION: This study including 19504 blood donors spanning over one and a half year shows that prolonged use of face mask by blood donors may lead to intermittent hypoxia and consequent increase in hemoglobin mass.

The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19.

INTRODUCTION: Studies have shown that iron metabolism is affected by coronavirus disease 19 (COVID-19), which has spread worldwide and has become a global health problem. Our study aimed to evaluate the relationship between COVID-19 and serum erythropoietin (EPO), hepcidin, and haptoglobin (Hpt) levels with disease severity, and other biochemical values. METHODS: Fifty nine COVID-19 patients hospitalized in the intensive care unit (ICU) and wards in our hospital between March and June 2020 and 19 healthy volunteers were included in the study. Participants were divided into mild, severe, and critical disease severity groups. Group mean values were analyzed with SPSS according to disease severity, mortality, and intubation status. RESULTS: Hemoglobin (Hb) levels were significantly lower in the critical patient group (P < .0001) and deceased group (P < .0001). The red blood cell distribution width-coefficient of variation (RDW-CV) and ferritin values were significantly higher in the intubated (P = .001, P = .005) and deceased (P = .014, P = .003) groups. Ferritin values were positively correlated with disease severity (P < .0001). Serum iron levels were lower in the patient group compared with the reference range. (P < .0001). It was found that the transferrin saturation (TfSat) was lower in the patient group compared with the control group (P < .0001). It was found that the mean EPO of the deceased was lower than the control group and the survived patient group (P = .035). Hepcidin levels were found to be significantly lower in the patient group (P < .0001). Hpt values were found to be significantly lower in the intubated group (P = .004) and the deceased group (P = .042). CONCLUSION: In our study, while serum iron and hepcidin levels decreased in patients diagnosed with COVID-19, we found that EPO and Hpt levels were significantly lower in critical and deceased patient groups. Our study is the first study examining EPO and Hpt levels in patients diagnosed with COVID-19.

A Perspective on Erythropoietin as a Potential Adjuvant Therapy for Acute Lung Injury/Acute Respiratory Distress Syndrome in Patients with COVID-19.

The novel coronavirus 2019-nCoV (SARS-CoV-2) infection that emerged in China in December 2019 has rapidly spread to become a global pandemic. This article summarizes the potential benefits of erythropoietin (EPO) in alleviating SARS-CoV-2 pathogenesis which is now called COVID-19. As with other coronavirus infection, the lethality of COVID-19 is associated with respiratory dysfunction due to overexpression of proinflammatory cytokines induced by the host immune responses. The resulting cytokine storm leads to the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Erythropoietin, well known for its role in the regulation of erythropoiesis, may have protective effects against ALI/ARDS induced by viral and other pathogens. EPO exerts antiapoptotic and cytoprotective properties under various pathological conditions. With a high safety profile, EPO promotes the production of endothelial progenitor cells and reduce inflammatory processes through inhibition of the nuclear factor-κB (NF-κB) and JAK-STAT3 signaling pathways. Thus, it may be considered as a safe drug candidate for COVID-19 patients if given at the early stage of the disease. The potential effects of erythropoietin on different aspects of ALI/ARDS associated with SARS-CoV-2 infection are reviewed.

No Relevant Analogy Between COVID-19 and Acute Mountain Sickness.

Berger, Marc Moritz, Peter H. Hackett, and Peter Bärtsch. No relevant analogy between COVID-19 and acute mountain sickness. High Alt Med Biol. 21:315-318, 2020.-Clinicians and scientists have suggested therapies for coronavirus disease-19 (COVID-19) that are known to be effective for other medical conditions. A recent publication suggests that pathophysiological mechanisms underlying acute mountain sickness (a syndrome of nonspecific neurological symptoms typically experienced by nonacclimatized individuals at altitudes >2500 m) may overlap with the mechanisms causing COVID-19. In this short review, we briefly evaluate this mistaken analogy and demonstrate that this concept is not supported by scientific evidence.

Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.

Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin [weighted mean difference (WMD), - 4.08 g/L (95% CI - 5.12; - 3.05)] and red blood cell count [WMD, - 0.16 × 1012 /L (95% CI - 0.31; - 0.014)], and higher ferritin [WMD, - 473.25 ng/mL (95% CI 382.52; 563.98)] and red cell distribution width [WMD, 1.82% (95% CI 0.10; 3.55)]. A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.