key: cord-0936934-693dqoqb authors: Aydemir, Duygu; Ulusu, Nuriye Nuray title: People with blood disorders can be more vulnerable during COVID-19 pandemic: A Hypothesis Paper date: 2021-02-10 journal: Transfus Apher Sci DOI: 10.1016/j.transci.2021.103080 sha: 3e99407fa1e019cfcf6ad937339d14dd1efb4313 doc_id: 936934 cord_uid: 693dqoqb The world has been encountered with COVID-19 pandemic since at the beginning of 2020 and the number of infected people by COVID-19 is increasing every day. Despite various studies conducted by researchers and doctors, no treatment has been developed until now, therefore self-protection and isolation are strongly recommended to stop the spread of the virus. The elderly population and people with chronic diseases such as hypertension, cardiovascular diseases, diabetes, and cancer are categorized as risk groups, however, we suggest that people with hemoglobinopathies or porphyria can be described as risk groups as well. Current in silico studies have revealed that the COVID-19 virus can attack heme and hemoglobin metabolisms which are responsible for the oxygen transport to the tissues, iron metabolism, elevated levels of oxidative stress, and tissue damage. Data of the in silico study have been supported with the biochemistry and hemogram results of the COVID-19 patients, for instance hemoglobin levels decreased and serum ferritin and C-reactive protein levels increased. Indicated biochemistry biomarkers are tightly associated with inflammation, iron overload, and oxidative stress. In conclusion, since people with hemoglobinopathies or porphyria have already impaired heme and hemoglobin metabolism, COVID-19 infection can enhance the adverse effects of impaired hemoglobin metabolism and accelerate the progression of severe symptoms in patients with hemoglobinopathies or porphyria compared to the normal individuals. Thus those people can be considered as a risk group and extra precautions should be applied for them to protect them. individual to another by respiratory droplets via infected person's cough, sneeze, or direct contact with infected individuals and objects like other influenza viruses' transmission ways. Since no effective drugs, treatments or vaccines against COVID-19 have been developed until now and virus spreads very quickly, self-isolation and protection are strongly suggested for all people especially the ones who are at the risk groups [1] [2] [3] . People over 65 years old and population with chronic diseases including hypertension, cardiovascular diseases, diabetes, cancer, immune system disorders and metabolic disorder are categorized as major risk groups [3] . Another risk groups can be stated patients with porphyria and hemoglobinopathies since COVID-19 impairs human heme metabolism via attacking it and impairs hemoglobin function in the erythrocytes and affects oxygen transport according to a recent in silico study [2] . Heme is porphyrin containing iron and found in the hemoglobin structure. Data obtained by in silico study have been supported with the serum biochemical and hemogram analysis of patients infected by COVID-19. For instance, hemoglobin levels of the infected people significantly decreased, on the other hand serum ferritin, erythrocyte sedimentation rate and C-reactive protein (CRP) levels increased which indicate impaired hemoglobin metabolism. Thus people with hemoglobinopathies and porphyria can be considered as risk groups as a result of enhanced impairment in the heme and hemoglobin metabolisms compared to the their general situation. Therefore, extra precautions should be considered for those people suffering from impaired heme and hemoglobin metabolisms [1, 2, 4 ]. J o u r n a l P r e -p r o o f Hemoglobinopathies such as alpha (α), beta (β) thalassemia and sickle-cell anemia, are most common monogenic disorders in the clinic and affect millions of people worldwide [5, 6] . Thalassemia is a genetic disorder caused by defects in either α or β globin chain of hemoglobin which is a heterotetramer consisting of two α and two β globin chains. 280 millions of people are affected by thalassemias all over the world [7] . On the other hand, sickle cell anemia is inherited blood disorder caused by a point mutation in the 11. Chromosome of the β-globulin subunit of the hemoglobin. Approximately, 250 millions of people are affected of sickle cell anemia worldwide and the number of the newborn having sickle cell anemia is increasing every day [8] . Porphyrins are the major precursors of heme involving in the hemoglobin structure. Dysfunction of the porphyrin metabolism results in the accumulation of intermediates of the heme biosynthesis as a result of decreased heme synthesis and this condition is called as porphyria. Porphyrias can be categorized as liver or erythropoietic based depending on the sire where heme precursors accumulate such as liver, erythrocytes or bone marrow [9, 10] . Function of heme, hemoglobin and RBC have been impaired in both hemoglobinopathies and porphyria's that leads to impairment in the RBCs homeostasis leading to the oxygen transport to the tissues and elevated levels of oxidative stress. Iron overload, impairment in the heme metabolism and elevated levels of the oxidative stress have been occurred as a result of these diseases. In silico data have revealed that COVID-19 virus can attack β-globulin chain of hemoglobin and impairs oxygen transport in the patients that can make people with impaired hemoglobin metabolism more vulnerable against COVID-19 compared to the normal individuals [2] . Additionally, we have previously suggested that people with glucose 6phosphate dehydrogenase (G6PD) enzyme deficiency can be considered as risk groups because of the impairment in red blood cell (RBC) metabolism leading to the elevated levels of oxidative stress levels [1] . Since people having either hemoglobinopathies or porphyrias Heme is iron (Fe) containing porphyrin found in the RBCs and synthesized in the both cytosol and mitochondria. Senescent RBC are degraded by macrophages leading to the releasing heme and iron from hemoglobin structure. Heme groups participate in the protein structures called as hemoproteins involving in the various cellular processes including oxygen transport, redox metabolism, drug metabolism, oxygen storage, mRNA processing and steroid metabolism. Thus impairment in the heme metabolism causes elevated levels of oxidative stress as a result of dysfunction hemeproteins and free heme toxicity [11] . Elevated levels of free heme in the extracellular space is resulted from impairment in the heme and hemeprotein metabolisms and tightly associated with increased levels of oxidative stress [13] . Hemoproteins enable to balance free heme via protecting organisms from cytotoxic effects of free heme. Increased levels of free heme result in the overproduction of reactive oxygen species (ROS) which attack lipid, protein and DNA [14] . Increased levels of oxidative stress J o u r n a l P r e -p r o o f can damage tissue leading to the organ damage and associated with several diseases including diabetes, cardiovascular diseases, cancer and metabolic syndrome [15] [16] [17] [18] . Besides free heme, hemoglobin (Hb) can be another oxidative stress source in the organisms. Hb is a hemeprotein found in the red blood cells (RBCs) and responsible for the oxygen transport. Oxygen bounds to the hemoglobin molecules in the lungs as a region with high pressure of oxygen and hemoglobin releases oxygen at the tissues as regions with low oxygen pressures. ROS molecules including hydrogen peroxide (H2O2) and superoxide (O -2 ) are produced during this process called as hemoglobin autoxidation [19, 20] . This oxidant molecules are neutralized by powerful anti-oxidant metabolism of RBCs, however there is limited anti-oxidant capacity in the RBCs. Extracellular Hg originating by hemolysis of RBCs is the another potential source of oxidative stress and molecules including haptoglobin and hemopexin bind to both extracellular Hg and free heme to neutralize ROS. Impairment of the heme and Hg metabolisms causes adverse health effects as a result of elevated levels of oxidative stress leading to the tissue damage [21] . Hemoglobin is the hemeprotein found in the RBCs responsible for the oxygen transport in the mammalians and hemoglobin synthesis accounts for 85% of heme synthesis daily [28] . Following the same logic people with hemoglobinopathies and porphyrias may be more vulnerable against COVID-19 infection, since both diseases result in the impaired oxygen transportation and oxidative stress metabolism as a result of dysfunction in the both heme and hemoglobin metabolisms [32] . For instance, in the thalassemia pathogenesis, unstable hemoglobin molecules are formed and degraded that leads to the elevated levels of free heme and iron which both contribute to formation of the oxidative stress [11, 13, 33] . On the other hand, sickle cell disease (SCD) is another hemoglobinopathy described by increased autoxidation of hemoglobin, impaired oxygen transportation, iron accumulation and impaired function of RBCs contributing elevated levels of oxidative stress. Additionally, heme degradation significantly increases in the hemoglobinopathies including thalassemias and sickle cell disease [34] . On the other hand, porphyrias arise from the accumulation of the J o u r n a l P r e -p r o o f porphyrins and their precursors such as 5-Aminolevulinic acid (ALA), which are known by their contribution to the formation of ROS [35] . Overall, hemoglobinopathies and porphyrias cause impaired oxygen transport, elevated levels of oxidative stress, inflammation and damaged RBC metabolism because of dysfunction in the both heme and hemoglobin metabolism [32] [33] [34] [35] . A current in silico study has revealed that COVID-19 attacks heme and hemoglobin causing impairment in the oxygen transport and RBCs metabolisms same as pathology of hemoglobinopathies and porphyrias [2] . Data of the in silico study have been validated via serum biochemistry and hemogram data, for instance hemoglobin levels significantly decreased in the COVID-19 patients [2] . Since hemoglobin is responsible for the oxygen transport to the tissues, decreased levels of hemoglobin results in the impaired oxygen transport and increased levels of oxidative stress in the tissues [36] . On the other hand serum ferritin, erythrocyte sedimentation and CRP levels significantly increased in the COVID-19 patients [2] . Ferritin is a cytosolic protein and responsible for the intracellular iron homeostasis. Elevated levels of serum ferritin can be associated with the iron overload which can be resulted from impaired hemoglobin and heme metabolism. Elevated levels of iron is also contributed to the oxidative stress [37] [38] [39] . CRP is produced by liver and indicator of the both chronic and acute inflammation in the body [40] . There is no funding used for this paper Ethical approval was not needed, since this article was a commentary article. J o u r n a l P r e -p r o o f Is glucose-6-phosphate dehydrogenase enzyme deficiency a factor in Coronavirus-19 (COVID-19) infections and deaths? Pathogens and Global Health COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism World Health Organization. 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