The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa,  algae , and  plants  often have single-globin hemoglobins. Many  nematode  worms,  molluscs , and  crustaceans  contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in  fungi  and giant  annelids  may contain both globin and other types of proteins. [ 14 ]


One of the most striking occurrences and uses of hemoglobin in organisms is in the  giant tube worm  ( Riftia pachyptila , also called Vestimentifera), which can reach 2.4 meters length and populates ocean  volcanic vents . Instead of a  digestive tract , these worms contain a population of bacteria constituting half the organism's weight. The bacteria oxidize H 2 S from the vent with O 2  from the water to produce energy to make food from H 2 O and CO 2 . The worms' upper end is a deep-red fan-like structure ("plume"), which extends into the water and absorbs H 2 S and O 2  for the bacteria, and CO 2  for use as synthetic raw material similar to photosynthetic plants. The structures are bright red due to their content of several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are. [ 107 ] [ 108 ]


Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9  dopaminergic  neurons in the  substantia nigra ,  astrocytes  in the  cerebral cortex  and  hippocampus , and in all mature  oligodendrocytes . [ 12 ]  It has been suggested that brain hemoglobin in these cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production". [ 12 ]  It has been noted further that "A9  dopaminergic  neurons may be at particular risk of anoxic degeneration since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals". [ 12 ]  This may explain the risk of degeneration of these cells in  Parkinson's disease . [ 12 ]  The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia  nigra ), but rather is due to  neuromelanin .


Outside the brain, hemoglobin has non-oxygen-carrying functions as an  antioxidant  and a regulator of  iron metabolism  in  macrophages , [ 109 ]   alveolar cells , [ 110 ]  and  mesangial cells  in the kidney. [ 111 ]


Historically, an association between the color of blood and rust occurs in the association of the planet  Mars , with the Roman god of war, since the planet is an orange-red, which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the  porphyrin   moiety  of hemoglobin to which the iron is bound, not the iron itself, [ 112 ]  although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.


Artist  Julian Voss-Andreae  created a  sculpture  called  Heart of Steel (Hemoglobin)  in 2005, based on the protein's backbone. The sculpture was made from glass and  weathering steel . The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron. [ 113 ] [ 114 ]


Montreal artist Nicolas Baier created  Lustre (Hémoglobine) , a sculpture in stainless steel that shows the structure of the hemoglobin molecule. It is displayed in the atrium of  McGill University Health Centre 's research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres. [ 115 ] [ 116 ]


Hemoglobin A  (HbA), also known as  adult hemoglobin, hemoglobin A1  or  α 2 β 2 , is the most common human  hemoglobin  tetramer, accounting for over 97% of the total  red blood cell  hemoglobin. [ 1 ]   Hemoglobin  is an oxygen-binding protein, found in  erythrocytes , which transports oxygen from the lungs to the tissues. [ 2 ]   Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). [ 3 ]   Hemoglobin A2  (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults. [ 4 ]


Hemoglobin A (HbA) is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). [ 3 ]   Each subunit contains a  heme  group that diatomic oxygen (O 2 ) molecules can bind to. [ 5 ]   In addition to oxygen, subunit assembly and quaternary structure are known to play important roles in Hb affinity. When hemoglobin binds to O2 ( oxyhemoglobin ), it will attach to the Iron II (Fe2+) of heme and it is this iron ion that can bind and unbind oxygen to transport oxygen throughout the body. [ 2 ]   All subunits must be present for hemoglobin to pick up and release oxygen under normal conditions. [ 6 ]


Heme  synthesis involves a series of  enzymatic  steps that take place within the  mitochondrion  and  cytosol  of the cell. First, in the mitochondrion, the condensation of  succinyl CoA  and  glycine  by ALA synthase takes place to produce  5-aminolevulinic acid  (ALA). ALA then moves to the cytosol and after a series of reactions creates  coproporphyringen III . This molecule moves back into the mitochondrion where it reacts with protoporphyrin-III oxidase to produce  protoporphyrin IX . Iron is then enzymatically inserted into protoporphyrin via  ferrochelatase  to produce heme. [ 7 ]


Globin synthesis takes place in the  ribosomes  which are located within the cytosol. Two globin chains that have heme groups combine to form hemoglobin. One of the chains is an alpha chain and the other is a non-alpha chain. Non-alpha chain nature in hemoglobin molecules varies due to different variables. Fetuses have a non-alpha chain called gamma and after birth it is then called beta. The beta chain will pair with the alpha chain. It is the combining of two alpha and non-alpha chains which create a hemoglobin molecule. Two alpha and two gamma chains form fetal hemoglobin or  hemoglobin F  (HbF). After the first five to six months after birth, the combining of two alpha chains and two beta chains form adult hemoglobin (HbA). The genes that encode for the alpha chains are located on  chromosome 16 , while the genes that encode for non-alpha chains are located on  chromosome 11 . [ 7 ]


Due to the numerous steps and processes during hemoglobin synthesis, there are many places in which errors can occur. Heme synthesis involves multiple  enzymes  and when these enzymes are deficient or do not function properly consequences such as  mutations  or deletions in genes coding for the globin chain can occur. [ 2 ]  This results in globin gene disorders ( hemoglobinopathies ) which can be either abnormal globin chain variants ( sickle cell anemia ) or reduced chain synthesis in erythroid cells ( thalassemia ) during the cellular process of  hematopoiesis . [ 8 ]  These hemoglobinopathies are often inherited as  autosomal recessive  traits. [ 9 ]


Alpha-thalassemia  (α-thalassemia) is defined by a lack of α-globin chain production in hemoglobin, and those who carry a mutation impacting the α-globin chain on only one  chromosome  are considered to have a “silent” α-thalassemia whereas, if the mutation is on both then it is considered an α-thalassemia trait. [ 9 ]   α-thalassemia is mostly found in sub-tropical and tropical areas, where individuals who carry the gene is 80-90% of the population. [ 10 ]   Like other hemoglobin related disorders (sickle cell and β-thalassemia), it is hypothesized that α-thalassemia is selected for within populations due to carriers being better protected against  malaria falciparum . [ 9 ]   Most carriers of α-thalassemia are  asymptomatic  and are diagnosed if it is found after routine hematological analyses or before birth screenings. [ 11 ]   Single α-globin gene carriers usually have no profound fatigue or  anemia  because they have a compensating increase in the number of  microcytic  red blood cells. [ 9 ] [ 11 ]  In contrast, mild α-thalassemia carriers could have symptoms of anemia due to other factors not related specifically to the disorder: poor diet, drop in hemoglobin levels due to blood loss, or other diseases. [ 9 ]


The most severe form of α -thalassemia is a condition that begins at infancy in which there is no expression of α-genes and results in a large production of hemoglobin Bart's  (Hb Bart's) . [ 11 ]   The most common cause of Hb Bart’s is the inheritance of a deletion  allele  in that lacks functional α-globin genes from both parents. [ 9 ]   Hb Bart’s is a tetramer of four gamma-globulin subunits and is ineffective at transporting oxygen to the tissues due to its very high oxygen affinity. [ 12 ]  This usually results in fatal hydrops fetalis and associated symptoms include intra-uterine anemia, slowing of brain growth,  oedema ,  deformities  of the skeleton, and cardiovascular deformities that could lead to  cardiac failure . [ 13 ]


Beta-thalassemia  (β-thalassemia) is an inherited mutation of the β-globulin gene which causes the reduced synthesis of the β-globin chain of hemoglobin. [ 14 ]   The majority of the mutations are point mutations that affect  translation , transcriptional control, and  splicing  of the hemoglobin β gene and gene product. [ 15 ]   Individuals with one gene mutation ( heterozygocity ) are considered to have β-thalassemia minor (carrier or trait β-thalassemia), while those who have two gene mutations ( homozygosity  or compound heterozygosity) are diagnosed with β-thalassemia or intermedia. [ 14 ] [ 2 ]   Due to the lack of  beta-globin , accumulation of alpha-globin subunits and alpha tetramers begin to accumulate leading to damage of erythrocytes. [ 2 ]  People of Asian, Middle Eastern, and Mediterranean descent have a much higher incidences of β-thalassemia. [ 14 ]   It has been determined that there is a wide variation in  phenotypes  and  genotypes  of the disease due to more than 200 different thalassemia-associated mutations have being found in the beta-globin gene. [ 15 ]   Individuals with β-thalassemia major usually require medical attention within the first 2 years of life and require regular  blood transfusions  to survive. Patients who present the disorder later usually do not require  transfusions  and are diagnosed with thalassemia intermedia. [ 16 ]


health/health-topics/topics/sca/


Sickle hemoglobin (HbS) is the most common variant of hemoglobin and arises due to an  amino acid  substitution in the beta-globin subunit at the sixth residue from  glutamic acid  to  valine . There are different forms of  sickle cell disease . HB SS which is the most common and severe form of sickle cell. Hb SC is due to inheriting Hb S from one parent and Hb C ( hemoglobin C ) from the other parent. Hb S beta thalassemia is the least common and is experienced in patients who have inherited beta thalassemia hemoglobin from one parent and HbS from the other. [ 17 ]   In addition, there is sickle cell trait (HbAS) which is defined by having HbA and HbS. This makes the individual heterozygous for sickle cell. Of the world population, it is estimated that there are about 300 million individuals with the sickle cell trait and about 100 million of those are in sub-Saharan Africa. [ 18 ]   There is also a higher prevalence of sickle cell trait in areas that malaria is commonly found, with the prevalence in some parts of Africa and Saudi Arabia being as high as 25% and 60%, respectively. [ 19 ]  Individuals who have HbAS have about 40%HbS, 56% HBA, and are usually asymptomatic unless there is a severe lack of oxygen to the body (hypoxia) which can lead to symptoms of sickle cell disease. [ 12 ]   However, HbAS does not cause vaso-occlusive crisis, which is known to be associated with sickle cell disease. [ 17 ]


Patients that are homozygous for HbS have multi-stranded fibers that induce a change in shape of  red blood cells  from  biconcave disks  to elongated crescents. The sickling reaction is reversible after re-oxygenating the hemoglobin, therefore, red blood cells can go through cycles of sickling and unsickling depending on the concentration of oxygen present in the bloodstream. [ 12 ]  Red blood cells that are sickle-shaped lack flexibility and stick to the walls of blood vessels decreasing or stopping the flow of oxygen to nearby tissues. This decrease in oxygen to the tissues cause  vaso-occlusive crisis  which presents itself in muscle pain and injury to tissues. Some symptoms of sickle cell anemia include fever, fatigue from  anemia , swelling of the hands and feet,  stroke , and organ failure. [ 20 ]  Current treatments include  blood transfusions  which aid with increasing the number of normal red blood cells,  bone marrow transplants  to help the patients body produce healthy red blood cells, and medications to help alleviate the symptoms listed previously. [ 21 ]


Hemoglobin


Hemoglobin variants:


Hemoglobin protein subunits (genes):


Hemoglobin A2  ( HbA 2 ) is a normal variant of  hemoglobin A  that consists of two alpha and two  delta chains  (α 2 δ 2 ) and is found at low levels in normal human  blood .  Hemoglobin A2 may be increased in  beta thalassemia  or in people who are  heterozygous  for the beta thalassemia gene.


HbA2 exists in small amounts in all adult humans (1.5–3.1% of all hemoglobin molecules) and is approximately normal in people with  sickle-cell disease . [ 1 ]  Its biological importance is not yet known.


HbA2 may seem physiologically minor, but it plays a very crucial role in identifying the beta-thalassemia traits, also known as BTT, and identifying other hemoglobin disorders. [ 2 ]  Human hemoglobin is made up of two different chains, this includes alpha-globin and beta-globin. In the blood, there are two different variants, HbA and HbA2, and these variants only differ by 10 amino acids. These two variants have distinctions with the alpha and beta-globin chains. HbA2 is a vital component for screening programs targeting beta-thalassemia and hemoglobin pathogens. Typically the normal HbA2 levels range from 2.1% to 3.2%, but these values may change based on individual factors and different hemoglobin or hematological patterns. [ 3 ]  Testing HbA2 levels can be challenging because different disorders can cause it to have higher or lower values. Testing for the beta-thalassemia trait is usually identified when the value of HbA2 is higher than 3.5%. [ 3 ]  HbA2 is also important for diagnosing sickle cell disease, which is one of the most prevalent genetic conditions. Sickle cell disease exhibits characteristics of either homozygous hemoglobin S, also known as Hb S, or Hb S paired with another hemoglobin variant. In diagnosing patients with sickle cell, HbA2 is taken into account alongside a complete blood count, family history, and clinical data. [ 4 ]


Elevated HbA2 levels that surpass 3.5%, indicate a potential mutation in the beta-globin genes. This potential mutation typically occurs in the -87 and -88 promoter region, which affects the proximal CACCC box. Another factor leading to increased HbA2 levels involves the deletion of bases that are placed adjacent to the beta-globin genes. This deletion results in a heightened HbA2 levels due to removing the locus control regions in the beta promoter. This specific promoter is crucial for gene interactions with both gamma and beta globin genes, which also enables both genes to be expressed. [ 3 ]


Low values of HbA2, defined as 2.1% and below, can stem from various factors. The different reasons for reduced HbA2 levels depend on the factors such as hematological indices, hemoglobin patterns, red blood cells, and iron status. Reports suggest that individuals with low iron levels often exhibit low levels of HbA2. Additionally, low levels of HbA2 may be caused from decreased transcription or translation of the globin chains, which would affect how they bind. [ 3 ]


Hemoglobin pathogens are disorders caused by inherited autosomal recessive genes or hemoglobin structures that have been altered and changed. Autosomal recessive inheritance means acquiring two changed genes from each parent. If both parents are carriers for the autosomal recessive gene, there is a 75% chance the child will be normal and a 25% chance of having and expressing the disorder. There are various autosomal recessive disorders and hemoglobin pathogens, among these, beta-thalassemia is associated with changes in HbA2 levels in our blood. Thalassemia is a disorder involving both alpha and beta globin chains, is characterized by a deficiency in the globin chains within the hemoglobin, not characterized by the structural change to these chains. This deficiency leads to two disorders: beta-thalassemia and alpha-thalassemia. Beta-thalassemia has beta globin chains that are reduced and alpha-thalassemia has alpha globin chains that are also reduced. [ 5 ]  This disorder is the most common autosomal recessive disorder in some countries. [ 6 ]  Hemoglobin A2 is employed to diagnose thalassemia disorders, encompassing both beta and alpha types. In beta-thalassemia, affected individuals express elevated HbA2 levels, which can be a potential indicator of the heterozygous gene marker for the disorder. Normal levels range from 2.1-3.2%, but in the beta-thalassemia disorder, the levels increase to 3.5-6.0%. Additionally, individuals with beta-thalassemia exhibit a high red cell count and low hemoglobin levels. [ 3 ]  Individuals that express lower levels of hemoglobin A2, have the a 0 -thalassemia trait or homozygous gene for a + -thalassemia. [ 2 ]


Hemoglobin A2 is a crucial role for screening and measuring for the beta-thalassemia trait. Various laboratory methods exist, each providing different outcomes of accuracy. The different quantification methods of HbA2 relies on how effective it can be separated from other hemoglobin variants. [ 3 ]  Various laboratory methods are employed, such as cation exchange high-performance liquid chromatography (HPLC), microcolumn chromatography, and cellulose acetate electrophoresis with elution. At first, cellulose acetate electrophoresis was utilized to measure HbA2, but this process proved to be too time-consuming and labor-intensive, making it impractical for large examinations or samples. Similar efficiency issues were encountered with other methods like IEF and scanning densitometry. These two methods separate proteins based on their isoelectric point. Chromatography, another commonly used method, demonstrated reliability in diagnosing individuals with the beta carrier gene. However, this method was also time-consuming and inefficient when dealing with large sample numbers. [ 3 ]  Out of the various methods, the one that accurately measures HbA2 is HPLC. [ 2 ]  It is a reliable technique because it's able to accurately determine HbA2, HbF, and Hb variants. The various different Hb variants include: HbS, HbE, Hb Lepore, HbC,  HbD  and HbO-Arab. [ 3 ]  There are several different factors that can contribute to the quantification of HbA2 to be inaccurately measured. These factors include column defects, batch variations, sample concentrations, dilution, calibration discrepancies, and the overall conditions of the samples. [ 3 ]


Hemoglobin A3  is a predominantly historic term for a fraction of normal hemoglobin molecules that is seen when hemoglobin is separated out using starch block electrophoresis. These Hemoglobin molecules are non-enzymatic modifications of the hemoglobin molecules and they encompass  hemoglobin A1c , Hb 1a  (both the subtypes Hb 1a1  and Hb 1a2 ) and Hb 1b . [ 1 ]


As these Hemoglobin subtypes are formed over time, they are found more prevalent in older red cells.


This  cell biology  article is a  stub . You can help Wikipedia by  expanding it .


Hemoglobin Barts , abbreviated  Hb Barts , is an abnormal type of  hemoglobin  that consists of four  gamma globins . It is moderately insoluble, and therefore accumulates in the  red blood cells . Hb Barts has an extremely  high affinity for oxygen , so it cannot release oxygen to the tissue. Therefore, this makes it an inefficient oxygen carrier. As an  embryo  develops, it begins to produce alpha-globins at  weeks 5–6 of development . When both of the  HBA1  and  HBA2  genes which code for alpha globins becomes dysfunctional, the affected fetuses will have difficulty in synthesizing a functional hemoglobin. As a result, gamma chains will accumulate and form four gamma globins. These gamma globins bind to form hemoglobin Barts. [ 1 ]  It is produced in the disease  alpha-thalassemia  and in the most severe of cases, it is the only form of hemoglobin in circulation. In this situation, a fetus will develop  hydrops fetalis  and normally die before or shortly after birth, unless intrauterine  blood transfusion  is performed. [ 2 ]


Since hemoglobin Barts is elevated in alpha thalassemia, it can be measured, providing a useful screening test for this disease in some populations. [ 3 ]


The ability to measure hemoglobin Barts makes it useful in newborn screening tests.  If hemoglobin Barts is detected on a newborn screen, the patient is usually referred for further evaluation since detection of hemoglobin Barts can indicate either one alpha globin gene deletion, making the baby a silent alpha thalassemia carrier, two alpha globin gene deletions (alpha thalassemia), or  hemoglobin H disease  (three alpha globin gene deletions).  Deletion of four alpha globin genes was previously felt to be  incompatible with life , but there are currently 69 patients who have survived past infancy. [ 4 ] [ 5 ]


Table 1: α represents the presence of α-globin gene and- represents the deletion of α-globin gene. [ 6 ]


The chance of a fetus developing Hemoglobin Bart's hydrops fetalis is dependent upon if one or both parent carries the alpha-thalassemia trait. Due to this disease being incompatible with life, diagnosis for it is done prenatally. [ 7 ]  Early detection of Hemoglobin (Hb) Bart's disease before the development of hydrops fetalis is crucial because fetuses that develop hydrops fetalis will either be stillborn or may die shortly after birth. There can be early pregnancy termination to prevent serious complications for the baby or mother. Studies shows that in 11 to 14 weeks of gestation, sonographic markers can associate affected from unaffected pregnancies. It was found that the most sensitive marker was CT ratio and MCA‐PSV. [ 8 ]


Parents at risk of having a child with Fetal Hydrops can continue their pregnancy with regular ultrasounds and intrauterine blood transfusion. Babies of such parents are born with no edema or major neurological defects, and eventually, this disease can be cured with  Haematopoietic Stem Cell Transplantation . A newly developed diagnostic test, called Immunochromatography (IC) Strip Tests, uses monoclonal antibodies to detect Hemoglobin Barts in red blood cells' lysate. This diagnostic test is validated for positive and negative predictive values. It is also cheap and easy, making regular screening for alpha-thalassemia a plausible possibility. [ 9 ] [ 10 ]


Anemia is a factor in fetuses with Hemoglobin Bart's disease as there is an "increased cardiac output" and hypovolemia as the tissues of the fetus require oxygen because of the gamma globulin's high affinity for oxygen. This deprives the tissues of receiving oxygen to function well. The symptoms of anemia occur within the first trimester. [ 11 ]


This variant of hemoglobin is so called as it was discovered at  St Bartholomew's Hospital  in London, often abbreviated to Barts. [ 12 ]


Hemoglobin Constant Spring  is a  variant  of  hemoglobin  in which a  mutation  in the  alpha globin   gene  produces an alpha globin chain that is abnormally long. It is the most common nondeletional  alpha-thalassemia  mutation associated with  hemoglobin H  disease. [ 1 ]  The quantity of hemoglobin in the cells is low because the  messenger RNA  is unstable and some is degraded prior to protein synthesis. Another reason is that the Constant Spring alpha chain protein is itself unstable. The result is a thalassemic phenotype. [ 2 ] [ 3 ]


Hemoglobin Constant Spring is renamed after  Constant Spring district  in  Jamaica . [ 4 ]


Within the medical specialty of  hematology ,  Hemoglobin D-Punjab , also known as  hemoglobin D-Los Angeles , [ 1 ]   D-North Carolina ,  D-Portugal ,  D-Oak Ridge , and  D-Chicago , [ 2 ]  is a  hemoglobin variant . It originates from a  point mutation  in the  human β-globin locus  and is one of the most common hemoglobin variants worldwide. [ 1 ]  It is so named because of its higher prevalence in the  Punjab region  of  India  and  Pakistan , along with northern China, and North America. It is also the most frequent hemoglobin variant in  Xinjiang Uyghur Autonomous Region  of  China , with a 1997 study indicating that Hemoglobin D-Punjab accounts for 55.6% of the total hemoglobin variants. [ 2 ]


Hemoglobin D is a result of a mutation in the one or both of the Beta-chains that make up hemoglobin molecules.  Having one gene effected is referred to as trait; having two is referred to as homozygous "disease" although the symptoms of this disease are mild.


Until the early 1950s,  hemoglobin A  and some of its variants had been identified, such as  hemoglobin S  and  hemoglobin C . Hemoglobin D was discovered in 1951 with one source stating it was the third variant discovered, [ 2 ]  and another source claiming it was the fourth. [ 1 ]  Later in 1962, it was found that five other regional variants of hemoglobin D all had the same chemical structure termed hemoglobin D-Punjab. [ 1 ]


Hemoglobin is the main ingredient in red blood cells. Hemoglobin helps red blood cells carry oxygen from the lungs to other parts of the body. Normal red blood cells have hemoglobin A. People with hemoglobin D trait have red blood cells that have normal hemoglobin A (made up of normal alpha and beta chains) and abnormal hemoglobin D (made up of normal alpha chains and variant beta chains). People with hemoglobin D trait have slightly more hemoglobin A than hemoglobin D. The abnormal hemoglobin is called hemoglobin D. [ 3 ]


People with Hemoglobin D trait do not have health problems related to having the trait. People with hemoglobin D trait do not have Hemoglobin D  disease  or  sickle cell disease . They cannot develop these diseases later in life. While Hemoglobin D can be detected without a DNA test, one is needed to ascertain that a person who carries Hemoglobin D carries hemoglobin D-Punjab. [ citation needed ]


There is no clinical disease detected, however children of affected individuals have increased risk of having Hemoglobin D Disease, Hemoglobin SD disease or  Beta-thalassemia  Disease. [ citation needed ]  Among the seven known types of Hemoglobin D, only Hemoglobin D Punjab can cause a serious hemoglobin disorder.


usually present with mild hemolytic anemia and mild to moderate splenomegaly.


Even homozygous Hemoglobin D disease does not typically cause clinically significant symptoms. It is usually present with mild haemolytic  anaemia  and moderate  splenomegaly . [ 4 ]  The anemia usually occurs in the first few months of life, as fetal hemoglobin decreases and hemoglobin D increases. [ citation needed ]


Hb D-Punjab becomes significant when it is co-inherited with Hb S or B thalassemia.


1. Tyagi S, Marwaha N, Parmar V, Basu S. Sickle cell hemoglobin-D Punjab disease (Compound Heterozygous state). Ind J Hematol Blood Transf 2000;18:31-2.
2.  Zeng YT, Huang SZ, Ren ZR, Li HJ (1989).  "Identification of Hb D-Punjab gene: application of DNA amplification in the study of abnormal hemoglobins" .  Am. J. Hum. Genet .  44  (6):  886– 9.  PMC   1715661 .  PMID   2729278 .
3.  http://www.idph.state.il.us/HealthWellness/fs/hemoglobin_d.htm
4.  http://health.utah.gov/newbornscreening/Disorders/HB/Hb_D_Disease_DD/FactSheet_Provider_HbDD_En.pdf
5. www.chime.ucl.ac.uk/APoGI/data/rtf/hb/carriers/b/dp/carbook.rtf


Hemoglobin E  ( HbE ) is an abnormal  hemoglobin  with a single point  mutation  in the β chain. At position 26 there is a change in the  amino acid , from  glutamic acid  to  lysine  (E26K). Hemoglobin E is very common among people of  Southeast Asian ,  Northeast Indian ,  Sri Lankan  and  Bangladeshi  descent. [ 1 ] [ 2 ]


The βE mutation affects β-gene expression creating an alternate splicing site in the mRNA at codons 25-27 of the β-globin gene. Through this mechanism, there is a mild deficiency in normal β mRNA and production of small amounts of anomalous β mRNA. The reduced synthesis of β chain may cause  β-thalassemia . Also, this hemoglobin variant has a weak union between α- and β-globin, causing instability when there is a high amount of oxidant. [ 3 ]  HbE can be detected on  electrophoresis .


Hemoglobin E disease results when the offspring inherits the gene for HbE from both parents. At birth, babies  homozygous  for the hemoglobin E allele do not present symptoms because they still have HbF ( fetal hemoglobin ). In the first months of life, fetal hemoglobin disappears and the amount of hemoglobin E increases, so the subjects start to have a mild β-thalassemia.
Subjects homozygous for the hemoglobin E allele (two abnormal alleles) have a mild hemolytic anemia and mild  enlargement of the spleen .


Heterozygous  AE occurs when the gene for hemoglobin E is inherited from one parent and the gene for hemoglobin A from the other. This is called hemoglobin E trait, and it is not a disease. People who have hemoglobin E trait (heterozygous) are asymptomatic and their state does not usually result in health problems. They may have a low  mean corpuscular volume  (MCV) and very abnormal red blood cells ( target cells ), but clinical relevance is mainly due to the potential for transmitting E or β-thalassemia. [ 4 ]


Compound heterozygotes with sickle-hemoglobin E disease result when the gene of hemoglobin E is inherited from one parent and the gene for hemoglobin S from the other. As the amount of fetal hemoglobin decreases and hemoglobin S increases, a mild hemolytic anemia appears in the early stage of development. Patients with this disease experience some of the symptoms of  sickle cell anemia , including mild-moderate anemia, increased risk of infection, and painful sickling crises. [ 5 ]


People who have hemoglobin E/β-thalassemia have inherited one gene for hemoglobin E from one parent and one gene for β-thalassemia from the other parent. Hemoglobin E/β-thalassemia is a severe disease, and it still has no universal cure. However, the mutation is amenable to genome editing at high efficiency in preclinical studies. [ 6 ]  It affects more than a million people in the world. [ 7 ]  Symptoms of hemoglobin E/β-thalassemia vary but can include growth retardation, enlargement of the spleen ( splenomegaly ) and liver ( hepatomegaly ),  jaundice , bone abnormalities, and cardiovascular problems. [ 8 ]  Recommended course of treatment depends on the nature and severity of the symptoms and may involve close monitoring of hemoglobin levels, folic acid supplements, and potentially regular blood transfusions. [ 8 ]


There is a variety of phenotypes depending on the interaction of HbE and α-thalassemia. The presence of the α-thalassemia reduces the amount of HbE usually found in HbE heterozygotes. In other cases, in combination with certain thalassemia mutations, it provides an increased resistance to  malaria  ( P. falciparum ). [ 4 ]  This disease was first described by  Virginia Minnich  in 1954, who discovered a high prevalence of it in Thailand and initially referred to it as "Mediterranean Anaemia." [ 8 ]


Hemoglobin E is most prevalent in  mainland Southeast Asia  (Thailand, Myanmar, Cambodia, Laos, Vietnam [ 9 ] ),  Sri Lanka ,  Northeast India  and  Bangladesh . In mainland Southeast Asia, its prevalence can reach 30 or 40%, and  Northeast India , in certain areas it has carrier rates that reach 60% of the population. In Thailand the mutation can reach 50 or 70%, and it is higher in the northeast of the country. In Sri Lanka, it can reach up to 40% and affects those of  Sinhalese  and  Vedda  descent. [ 10 ] [ 11 ]  It is also found at high frequencies in Bangladesh and Indonesia. [ 12 ] [ 13 ]  The trait can also appear in people of Turkish, Chinese and Filipino descent. [ 1 ]  The mutation is estimated to have arisen within the last 5,000 years. [ 14 ]  In Europe, there have been found cases of families with hemoglobin E, but in these cases, the mutation differs from the one found in South-East Asia. This means that there may be different origins of the βE mutation. [ 15 ] [ 16 ]


Hemoglobin Hopkins-2  (Hb Hop-2) is a mutation of the protein  hemoglobin , which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates.  The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains (human hemoglobin consist of 2 α and 2 β polypeptides usually termed chains). [ 1 ]   The mutation is the result of  histidine  112 being replaced with  aspartic acid  in the protein's polypeptide sequence. [ 1 ]  Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. [ 2 ]  This mutation can cause  sickle cell anemia . [ 3 ]


Following the initial discovery of hemoglobin, two researchers working at  Johns Hopkins Hospital  in the mid-twentieth century, Ernest W. Smith and J.V. Torbert, discovered the Hopkins-2 mutation of hemoglobin. [ 4 ]   Work by  Harvey A. Itano  and Elizabeth A. Robinson in 1960 confirmed Smith's and Torbert's finding and emphasized the importance of the alpha loci in the mutation. [ 5 ]   Later in the twentieth century, Samuel Charache, another Hopkins affiliated scientist and doctor, studied the physiological impacts of the variant on health. [ 6 ]   His findings suggest that the variant plays no effect clinically. [ 7 ]


In the mid-1900s, many factors prompted hemoglobin research in  Baltimore, Maryland  and ultimately led to the discovery of Hemoglobin Hopkins-2.  First, the development of new technology, including  x-ray crystallography  and protein chemistry, that could be utilized in molecular biology studies catalyzed research. [ 8 ]   Furthermore, the large presence of  thalassemia  (Hb H), a disorder in which the alpha gene is dysfunctional, in Southeast Asia and southern China further concerned researchers as, if left untreated, the mutation could result in bone deformities,  swelling of the spleen , slowed growth rate, or  cardiac dysfunction . [ 9 ] [ 10 ]   Additionally,  Max Perutz 's, a Cambridge researcher, discovery of hemoglobin's basic  tertiary structure  in 1962 catalyzed research in hematology. [ 11 ]   Vernon Ingram's  research surrounding  sickle cell anemia  in 1956 revealed that variants, or mutations, in hemoglobin's RNA resulted in the  sickle cell disease . [ 8 ] [ 3 ]


Ernest W. Smith and J.V. Norbert examined Ingram's discovery and, in 1958, they discovered the hemoglobin Hopkins-2 mutation.  Smith and Torbert, research fellows working in Lockard Conley's  Hematology  Research Department at Johns Hopkins University, proved that recombination of  non-allelic genes  resulted in two variants of the gene that produced hemoglobin.  Variants of the "normal" hemoglobin gene result in mutation in the hemoglobins produced. [ 4 ]    In other words, the researchers discovered two versions of  hemoglobin :  the [Hb-Hop2] and  S variants . [ 8 ]


Smith's and Torbert's findings were confirmed and built upon by  Harvey A. Itano  and Elizabeth A. Robinson in 1960.   In their paper,  Genetic Control of the a- and B-Chains of Hemoglobin ,  Itano  and Robinson explained that both the alpha and beta  loci  are involved in the regulation of hemoglobin.  The recombination of the alpha loci on the gene coding for hemoglobin results in a mutation of the hemoglobin protein.  Researchers refer to this mutated protein as a Hopkins-2 variation of hemoglobin. [ 5 ]


Further research surrounding the Hopkins-2 genetic mutation was conducted by Johns Hopkins doctors, who remained engaged in research in the hematologic field despite a general change in focus away from hematology in the medical community.  Prominent Hopkins researcher Samuel Charache was one of many scientists at Hopkins who investigated  blood  and its components during the late twentieth century. [ 8 ]  Specifically, Charache is well known for his work with George Dover, another Hopkins researcher; together, they discovered a treatment option for  sickle cell anemia .  However, Charache was also engaged in hemoglobin Hopkins-2 research.  In his  Nature  article, titled  Clinical Studies and Physiological Properties of Hopkins Hemoglobin-2,  Charache announced his discoveries surrounding the hemoglobin variant.  Charache focused on physical implications of the variant, rather than on genetics themselves. Ultimately, Charache asserts in his paper that the variant is not prominent  phenotypically  and plays an unnoticeable or no effect on human health. [ citation needed ]


Hematologic studies were prominent at Johns Hopkins Hospital prior to the discovery of the hemoglobin Hopkins-2 variant. After observing the cells under a  microscope , Sir William Osler connected the concept of dysfunctional platelets to the development of ulcerative endocarditis and  thrombosis .  Osler's initial observations of platelets catalyzed the study of blood and hematology at Hopkins and in other research environments. [ 12 ]  Platelets were discovered independently by Max Schultze in 1865 [ 13 ]  and G. Bizzozero in 1882. [ 14 ]


Beginning in 1920, doctors at Johns Hopkins Hospital conducted research on  sickle cell anemia , or sickle cell disease.  Although their conclusions surrounding the disease are outdated, Doctors Taliaferro and Huck discovered a  latent  form of sickle cell anemia.  Their study on sickle cell anemia was the first of many to occur at Hopkins.  In 1940, Irving Sherman, a medical student at Johns Hopkins, correctly identified the  deoxygenation  of hemoglobin in sickle cell patients after he noted  refraction  patterns characteristic of deoxygenation when light was passed through the protein. [ 15 ]   The deoxygenation of hemoglobin in sickle cell patients has severe implications on those who carry the mutation.  The hemoglobin proteins, present in those with sickle cell disease, cannot carry oxygen to the organs and other tissues of the human body.  This results in  pain crises  and the disease results in an abbreviated  life expectancy  of 40–60 years. [ 16 ]


Ernest W. Smith and Torbert were integral in the discovery of Hopkins Hemoglobin-2, in addition to many other hematologic mutations and conditions. [ 4 ]   The two scientists worked together at Hopkins to identify the N-Baltimore mutation of Hemoglobin in 1958. [ 17 ]   Also referred to as the Hopkins-I, Jenkins, N-Memphis, or Kenwood mutation, the N-Baltimore mutation is a point mutation in which a  glycine  codon is replaced with an  adenosine  codon.  The N-Baltimore mutation is associated with the C and S mutations of hemoglobin. [ 18 ]


Smith conducted extensive research in conjunction with Locklard Conley, one of Smith's bosses at the time of the Hopkins Hemoglobin-2 variant discovery.  Lockard Conley, commonly referred to as "Lock," was a  Johns Hopkins  undergraduate and  Columbia  trained doctor.  In 1947, Conley became the first director of the Hematology Department at Hopkins and remained in the position for 33 years.  While there, he studied blood-related diseases, such as  blood coagulation  and  sickle cell anemia , and invented machinery to analyze molecular species. [ 19 ]   Specifically, he and Smith created a device that allowed for the separation of hemoglobin variants from standard hemoglobin molecules.  Conley's impact on hematology, therefore, was not only scientific discovery; but, also, technological discovery that allowed the hematologic field to expand. [ 20 ]   Conley remained a doctor and professor at  Johns Hopkins Hospital  until his death in 2010. [ 19 ]


Although a significant amount of hematologic research was completed during the 1950s and 1960s, scientists questioned whether more research could be completed without the development of more advanced technology. Ultimately, this doubt resulted in fewer scientists pursuing research in hematology in the mid twentieth century. [ 8 ]   Despite the scarcity of researchers, new discoveries surrounding genetics and hemoglobin were made.  However, research continued in major medical laboratories, like Hopkins. [ 21 ]


In the mid and late twentieth century, both doctors George J. Dover and Samuel Charache studied sickle cell anemia's pathology at Johns Hopkins Hospital. [ 7 ]   Together, they implemented treatment of the disease through the use of a cancer drug,  hydroxyurea ; the drug was successful in alleviating some of the painful spurts associated with  sickle cell anemia , in addition to  pulmonary  symptoms associated with the disease.  Dover, a pediatric hematologist and expert on  fetal hemoglobin , initiated the use of the protein as a way to treat sickle cell anemia in adults. [ citation needed ]


The Hopkins-2 variant of hemoglobin has an oxygen affinity within the body, meaning that there is an increase of oxygen spreading through the body due to the fact that Ho-2 carries a higher amount of oxygen. [ 22 ]  There is no red cell effect with Ho-2 compared to  Hemoglobin S , which changes the shape of the cell to become sickled. The Hopkins-2 variant of hemoglobin is not involved in forming  sickle cells . There is a lack of phenotypic expression of Ho-2 in terms of sickle cell, so a person with sickle cell and hemoglobin Hopkins-2 would be asymptomatic. [ citation needed ]


The Hopkins 2 variant of  hemoglobin  is the result of a mutation.  Specifically, the mutated protein is composed of two alpha chains.  The mutation for the Hopkins-2 variant of hemoglobin is located on the surface of the molecule.  Within the Ho-2 variant,  aspartic acid  replaces  histidine  at position 112 on the alpha chain. [ 2 ]  Dr.  Max Perutz  examined the aspartic acid in alpha 112 claiming that the carboxyl group of the amino acid forms a hydrogen bond with phenolix hydroxyl, which in turn stabilizes the structure of the molecule and increases oxygen affinity.  Ho-2 hemoglobin has high levels of oxygen, which replaces the lack of oxygen within red blood cells.  Ho-2 is similar to  Hemoglobin A , which is normal hemoglobin and also contains two α-chains.  This provides an explanation as to how the Hopkins-2 variant of hemoglobin is related to the symptoms of  sickle cell . [ citation needed ]


Hopkins-2 can also interact specifically with Hemoglobin S.   Hemoglobin S  is the most common abnormal hemoglobin variant.  Hemoglobin S is the variant that causes  sickle cell , which is a disorder in which red blood cells break down and become abnormally shaped.  Hemoglobin S has two beta chains, whereas hemoglobin Hopkins-2 has two alpha chains.  Hopkins-2 makes up 22% of hemolysates in single heterozygotes; therefore, there is the normal version of the gene in these patients.  Hemolysates are the products of the destruction of red blood cells.  Ho-2 also comprises 11% of hemolysates in ‘double’ heterozygotes, which are when the gene contains both Hopkins-2 and Hemoglobin S. [ 23 ]


There are currently multiple possible explanations as to how the Hemoglobin variant Hopkins-2 works. One explanation that scientists have come up with is that Ho-2 is created due to a point mutation causing the substitution of histidine by aspartic acid. [ 23 ]  The other explanation is that there is an unequal crossing over between two α genes which explains the replacement of histidine by aspartic acid. [ 23 ]  This then led a deletion occurring within the chromosome housing Ho-2. This deletion removes the region where the N-terminus is located in the major α-chain and where the c-terminus is located on the minor α-chain. [ 23 ]  Deletion of the N-terminus inactivates enzymes and halting their ability to cut chains at certain areas, which inevitably damages the chain. [ citation needed ]


Case studies were completed on some patients who carried the Hemoglobin Hopkins-2 genetic mutation by Samuel Charache and others. Researchers concluded after completing the studies that many of carriers of the mutation were asymptomatic to sickle cell and were overall quite healthy.  Any medical issues that occurred had no correlation to sickle cell.  These studies occurred in the 1970s. [ 8 ]


There were five carriers of Hemoglobin Hopkins 2 in the Fuller-Carr family and ten double heterozygotes of Ho-2 and Hemoglobin S. [ 24 ]  All the carriers were in good health and had normal hematology test results. Out of those carrying  hemoglobin S  and Ho-2, none were  anemic ; but, a few of those studied displayed elevated reticulocyte counts. [ 24 ]  This is measured through a blood test that analyzes the speed of production of red blood cells by bone marrow and its release into the blood. There was no suggestion of symptomatic sickle cell anemia in the family. [ citation needed ]


There was a study on a three-year-old that was a carrier of the hemoglobin variant of Hopkins-2. The child had mild anemia and reticulocytosis, which is commonly seen in anemia. [ 25 ]  There were, however, no sickled cells found in the blood and they had no symptoms relating to sickle cell. There was also a reduced mean corpuscular volume (MCV), which is the average volume of  red blood cell  count. [ 25 ]


Hemoglobin Lepore syndrome   is typically an  asymptomatic   hemoglobinopathy , which is caused by an  autosomal recessive   genetic mutation . The Hb Lepore variant, consisting of two normal  alpha globin  chains (HBA) and two delta-beta globin fusion chains which occurs due to a "crossover" between the  delta  (HBD) and  beta globin  (HBB) gene  loci  during  meiosis  and was first identified in the Lepore family, an Italian-American family, in 1958. [ 1 ]  There are three varieties of Hb Lepore, Washington (Hb Lepore Washington, AKA Hb Lepore Boston or Hb Lepore Washington-Boston), Baltimore (Hb Lepore Baltimore) and  Hollandia  (Hb Hollandia). All three varieties show similar  electrophoretic  and  chromatographic  properties and hematological findings bear close resemblance to those of the  beta-thalassemia   trait ; a blood disorder that reduces the production of the iron-containing  protein   hemoglobin  which carries oxygen to cells and which may cause  anemia .


The  homozygous  state for Hb Lepore is rare. Patients of  Balkan  descent tend to have the most severe presentation of symptoms including severe  anemia  during the first five years of life. They also presented with significant  splenomegaly ,  hepatomegaly , and skeletal abnormalities identical to those of homozygous  beta-thalassemia . The amount of Hb Lepore in the patients  blood  ranged from 8 to 30%, the remainder being  fetal hemoglobin  (Hb F) which is present in minute quantities (typically<1 percent) in the  red blood cells  of adults. Known as F- cells they are present in a small proportion of overall RBCs. [ 2 ]


Homozygous  Hb Lepore is similar to beta-thalassemia major; however, the clinical course is variable. Patients with this condition typically present with severe anemia during the first two years of life. The heterozygote form is mildly anemic (Hb 11–13 g/dl) but presents with a significant  hypochromia  (deficiency of hemoglobin in the  red blood cells ) and  microcytosis . [ 3 ] [ 4 ]


A potential complication that may occur in children that suffer acute anemia with a hemoglobin count below 5.5 g/dl is  silent stroke [ 5 ] [ unreliable medical source? ]  A silent stroke is a type of  stroke  that does not have any outward symptoms ( asymptomatic ), and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms a silent stroke still causes damage to the brain, and places the patient at increased risk for both  transient ischemic attack  and major stroke in the future. [ 6 ]


Sickle cell-Hb Lepore Boston syndrome is a type of sickle cell disease (HbS) that differs from homozygous sickle cell disease where both parents carry sickle hemoglobin. In this variant one parent has the sickle cell hemoglobin the second parent has Hb Lepore Boston, the only one of the three variants described in association with HbS. [ 7 ]


The diagnosis of Hb Lepore syndrome may be performed antenatally or postnatally via the use of a variety of tests


Those homozygous (Hb LeporeLepore; a very rare situation) or compound heterozygous (Hb Lepore-Β-thalassaemia) might suffer from a severe anaemia. They should be managed in a comprehensive multi-disciplinary program of care. [ 10 ]  Management includes a regular course of  blood transfusions , although the clinical severity in compound (double) heterozygotes can range from minor to major, depending on the combination of genes that have caused the condition. [ 11 ]


Individuals heterozygous for the Hb Lepore require no particular treatment. There is no anemia or, if there is, it is very mild. [ 10 ]


The Hb Lepore trait has a worldwide distribution and may affect individuals of various ethnicities however the three main varieties which been defined tend to be more prevalent among specific ethnic groups, typically  Caucasians  of the Southern regions  Central  and  Eastern Europe . The three main varieties are named for the geographical areas they were first identified in with various subtypes, the three main varieties are: [ citation needed ]


Hemoglobin O-Arab  (American English) or Haemoglobin O-Arab (British English) is a rare alternation of Hemoglobin (American English) or Haemoglobin (British English), characterised with the presence of β^121Glu → Lys (Hb O-Arab). Mutations of  heterozygotes  for Hb O-Arab have been reported in Saudi Arabia, North Africa, Sudan, the Mediterranean and the United States. Diagnosis of Hb O-Arab requires  liquid chromatography  on both  cellulose acetate  and  citrate agar , due to  co-migrating  with Hb C at alkaline pH. When combined with Hemoglobin S (β^6Glu → Val) it causes a severe form of  Sickle cell disease  known as Hemoglobin S/O-Arab. Detection of Hb O-Arab can be carried out with a blood test, identifying the carries of hemoglobinopathies, so as to inform patients their chances of producing an affected child and ensure appropriate guidance is given.


Although the molecular structure of hemoglobin itself has been determined by molecular biologist,  Max Perutz , by X-Ray Crystallography, earning his work with partner, John Kendrew the 1962 Nobel Prize in Chemistry, the molecular structure of hemoglobin O-Arab has not been obtained yet. The first sighted case of Hb O-Arab in combination with sickle hemoglobin was described in 1960 in an Arabic boy with severe hemolytic anaemia and recurrent painful episodes. Following cases of patients inheriting hetereozygotes for Hb O-Arab have been evident in the Middle Eastern descent, having clinical and laboratory manifestations characteristic of a sickling disease with hemolytic anaemia.


The most commonly used method for Hemoglobin analysis used is alkaline cellulose acetate electrophoresis at pH 8.6, due to its ability to split hemoglobin into its common variants, however a review of the College of American Pathologists (CAP) Hemoglobinopahty Survey Reports has provided the number of laboratories that utilise high-performance liquid chromatography (HPLC) technology for identification of hemoglobin variants, increasing approximately 12.5 fold in over the past decade. It is of clinical significance to be able to differentiate accurately between hemoglobin variants because of their reactions with Hemoglobin S to clinically different diseases, allowing data to be displayed through chromatograms to represent a visual insight of elution of Hb O-Arab using retention time.  to By using HPLC, it can accurately and reliable differentiate between Hemoglobin C and Hemoglobin O-Arab without any requirements for further confirmatory tests as stated by current CAP standards.


When Hemoglobin O-Arab co-inherits with Hemoglobin S, it produces a syndrome with similarities in severity to sickle cell anaemia, [ 1 ]  having severe haemolytic anaemia and red cells denser than normal with occurrences of some cells as dense as if contract with sickle cell anaemia. A description with the presence of two variations of β-globin chains, β^6Glu → Val (HbS) and β^121Glu → Lys (Hb O-Arab), patients heterozygous for Hemoglobin O-Arab had denser red cells, having similar traits to sickle cell disease, with few outliers of cells of normal density. From a study formulated at Harvard Medical School, the authors have concluded that "The erythrocytic pathogenesis of Hemoglobin O-Arab involves the dehydration of red cells due to the K:Cl cotransport system." The abnormality thus explains the severe pathology of the double heterozygote for Hemoglobin S and Hemoglobin O-Arab, leading to the conclusion of a correlation of these hemoglobins present to additional haemolytic risk factor.


Case reports analysed by Doctor Sayar Dror, [ 2 ]  PhD, at the Paediatric Hemato-Oncology Unit, “Dana” Children Hospital in Israel, feature three patients; a 12 month-old female of consanguineous parents, a 35 month-old female born to parents known to have the Hemoglobin O-Arab trait, and a 9 month-old male who was asymptomatic and was referred because of contracting mild anaemia. The origins of all three offspring were from South Sudan, with all three suffering from microcytic anaemia, with an average of 67.2-79% of their Hemoglobin, being Hemoglobin-O Arab. The peripheral blood smears of the tested patients displayed target cells, microcytosis, polychromasia and nucleated red blood cells. The basis drawn from these case reports is that Hemoglobin O-Arab is a rare, alternation of Hemoglobin, demonstrating effects similar to those diagnosed with mild to moderate microcytic anemia.


Another case study with data collection apparent for over 1,000 adults and paediatric patients followed by the Duke University Comprehensive Sickle Cell Center was used to identify patients, reviewing age. Gender and race to record similarities in complications in each patient such as painful vaso-occlusive events, acute chest syndrome and leg ulcers. Out of the cohort tested, with Hemoglobin O-Arab present, all patients shown a median Hemoglobin concentration of 8.7gm/dL, which is higher than the average concentration in a healthy being.


Treatment and counselling offered, depending on different ages of contraction of Hb O-Arab and severity of inheritance of the alternation.
Generalised, evolution of Hb O-Arab has long survival with no visual symptoms, but act as carriers of haemoglobin disorder. Thus, treatment can include screening and blood tests before coitus can detect any affected offspring, with provided genetic counselling and chances of producing affect offspring. [ 3 ]


[ 4 ]
 [ 5 ]
 [ 6 ]
 [ 7 ]
 [ 8 ]


6HBW ,  1A00 ,  1A01 ,  1A0U ,  1A0Z ,  1A3N ,  1A3O ,  1ABW ,  1ABY ,  1AJ9 ,  1B86 ,  1BAB ,  1BBB ,  1BIJ ,  1BUW ,  1BZ0 ,  1BZ1 ,  1BZZ ,  1C7B ,  1C7C ,  1C7D ,  1CBL ,  1CBM ,  1CH4 ,  1CLS ,  1CMY ,  1COH ,  1DKE ,  1DXT ,  1DXU ,  1DXV ,  1FN3 ,  1G9V ,  1GBU ,  1GBV ,  1GLI ,  1GZX ,  1HAB ,  1HAC ,  1HBA ,  1HBB ,  1HBS ,  1HCO ,  1HDB ,  1HGA ,  1HGB ,  1HGC ,  1HHO ,  1IRD ,  1J3Y ,  1J3Z ,  1J40 ,  1J41 ,  1J7S ,  1J7W ,  1J7Y ,  1JY7 ,  1K0Y ,  1K1K ,  1KD2 ,  1LFL ,  1LFQ ,  1LFT ,  1LFV ,  1LFY ,  1LFZ ,  1LJW ,  1M9P ,  1MKO ,  1NEJ ,  1NIH ,  1NQP ,  1O1I ,  1O1J ,  1O1K ,  1O1L ,  1O1M ,  1O1N ,  1O1O ,  1O1P ,  1QI8 ,  1QSH ,  1QSI ,  1QXD ,  1QXE ,  1R1X ,  1R1Y ,  1RPS ,  1RQ3 ,  1RQ4 ,  1RQA ,  1RVW ,  1SDK ,  1SDL ,  1THB ,  1UIW ,  1VWT ,  1XXT ,  1XY0 ,  1XYE ,  1XZ2 ,  1XZ4 ,  1XZ5 ,  1XZ7 ,  1XZU ,  1XZV ,  1Y09 ,  1Y0A ,  1Y0C ,  1Y0D ,  1Y0T ,  1Y0W ,  1Y22 ,  1Y2Z ,  1Y31 ,  1Y35 ,  1Y45 ,  1Y46 ,  1Y4B ,  1Y4F ,  1Y4G ,  1Y4P ,  1Y4Q ,  1Y4R ,  1Y4V ,  1Y5F ,  1Y5J ,  1Y5K ,  1Y7C ,  1Y7D ,  1Y7G ,  1Y7Z ,  1Y83 ,  1Y85 ,  1Y8W ,  1YDZ ,  1YE0 ,  1YE1 ,  1YE2 ,  1YEN ,  1YEO ,  1YEQ ,  1YEU ,  1YEV ,  1YFF ,  1YG5 ,  1YGD ,  1YGF ,  1YH9 ,  1YHE ,  1YHR ,  1YIE ,  1YIH ,  1YVQ ,  1YVT ,  1YZI ,  2D5Z ,  2D60 ,  2DN1 ,  2DN2 ,  2DN3 ,  2DXM ,  2H35 ,  2HBC ,  2HBD ,  2HBE ,  2HBF ,  2HBS ,  2HCO ,  2HHD ,  2HHE ,  2M6Z ,  2W6V ,  2W72 ,  2YRS ,  3B75 ,  3D17 ,  3D7O ,  3DUT ,  3HXN ,  3IC0 ,  3IC2 ,  3KMF ,  3NL7 ,  3NMM ,  3ODQ ,  3ONZ ,  3OO4 ,  3OO5 ,  3P5Q ,  3QJB ,  3QJC ,  3QJD ,  3QJE ,  3R5I ,  3S65 ,  3S66 ,  3SZK ,  3W4U ,  3WCP ,  3WHM ,  4FC3 ,  4HHB ,  4IJ2 ,  4L7Y ,  4M4A ,  4M4B ,  4MQC ,  4MQG ,  4MQH ,  4MQI ,  4N7N ,  4N7O ,  4N7P ,  4N8T ,  4NI0 ,  4NI1 ,  4ROL ,  4ROM ,  4WJG ,  4X0L ,  4XS0 ,  5E29 ,  5E6E ,  5EE4 ,  5HU6 ,  5JDO ,  5KDQ ,  5E83


NP_032246 NP_001188320 NP_001265090


Hemoglobin subunit beta  ( beta globin ,  β-globin ,  haemoglobin beta ,  hemoglobin beta ) is a  globin   protein , coded for by the  HBB  gene, which along with alpha globin ( HBA ), makes up the most common form of  haemoglobin  in adult humans,  hemoglobin A  (HbA). [ 5 ]  It is 147 amino acids long and has a molecular weight of 15,867  Da . Normal adult human HbA is a  heterotetramer  consisting of two alpha chains and two beta chains.


β-globin is encoded by the  HBB  gene on  human chromosome 11 . Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as  sickle-cell disease  and  beta thalassemia , as well as beneficial traits such as  genetic resistance to malaria . [ 6 ] [ 7 ]  At least 50 disease-causing mutations in this gene have been discovered. [ 8 ]


HBB protein is produced by the gene  HBB  which is located in the multigene locus of  β-globin locus  on  chromosome 11 , specifically on the short arm position 15.4.  Expression  of beta globin and the neighbouring globins in the β-globin locus is controlled by single  locus control region  (LCR), the most important regulatory element in the locus located upstream of the globin genes. [ 9 ]  The normal allelic variant is 1600  base pairs  (bp) long and contains three  exons . The order of the genes in the beta-globin cluster is 5' -  epsilon  –  gamma-G  –  gamma-A  –  delta  – beta - 3'. [ 5 ]


HBB  interacts  with  Haemoglobin, alpha 1  (HBA1) to form haemoglobin A, the major haemoglobin in adult humans. [ 10 ] [ 11 ]  The interaction is two-fold. First, one HBB and one HBA1 combine, non-covalently, to form a dimer. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemoglobin. [ 12 ]


Beta thalassemia  is an inherited genetic mutation in one (Beta thalassemia minor) or both (Beta thalassemia major) of the Beta globin alleles on chromosome 11. The mutant alleles are subdivided into two groups: β0, in which no functional β-globin is made, and β+, in which a small amount of normal β-globin protein is produced. Beta thalassemia minor occurs when an individual inherits one normal Beta allele and one abnormal Beta allele (either β0, or β+). Beta thalassemia minor results in a mild microcytic anemia that is often asymptomatic or may cause fatigue and or pale skin. Beta thalassemia major occurs when a person inherits two abnormal alleles. This can be either two β+ alleles, two β0 alleles, or one of each. Beta thalassemia major is a severe medical condition. A severe anemia is seen starting at 6 months of age. Without medical treatment death often occurs before age 12.  [ 13 ]  Beta thalassemia major can be treated by lifelong  blood transfusions  or  bone marrow transplantation . [ 14 ] [ 15 ]


According to a recent study, the stop gain mutation  Gln40stop  in  HBB  gene is a common cause of  autosomal recessive   Beta- thalassemia  in  Sardinian people  (almost exclusive in Sardinia). Carriers of this mutation show an enhanced red blood cell count. As a curiosity, the same mutation was also associated to a decrease in serum  LDL  levels in carriers, so the authors suggest that is due to the need of  cholesterol  to regenerate cell membranes. [ 16 ]


More than a thousand naturally occurring  HBB  variants have been discovered. The most common is HbS, which causes  sickle cell disease . HbS is produced by a  point mutation  in  HBB  in which the  codon  GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid  glutamic acid  with the hydrophobic amino acid  valine  at the seventh position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent hemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire  red blood cells  in the  homozygous  ( HbS/HbS ) condition. [ 17 ]  The homozygous allele has become one of the deadliest genetic factors, [ 18 ]  whereas people heterozygous for the mutant allele ( HbS/HbA ) are resistant to  malaria  and develop minimal effects of the anaemia. [ 19 ]


Sickle cell disease is closely related to another mutant haemoglobin called  haemoglobin C  (HbC), because they can be inherited together. [ 20 ]  HbC mutation is at the same position in HbS, but glutamic acid is replaced by  lysine  (β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against  Plasmodium falciparum   in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals. [ 21 ]  This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions. [ 22 ]


Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of  haemoglobin E  (HbE). [ 23 ]  HbE has a very unstable α- and β-globin association. Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria. [ 24 ]


Malaria due to  Plasmodium falciparum  is a major selective factor in  human evolution . [ 7 ] [ 25 ]  It has influenced mutations in  HBB  in various degrees resulting in the existence of numerous HBB variants. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic. [ 26 ]  People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival. [ 6 ] [ 27 ]  Such selection markers are important for tracing human ancestry and  diversification from Africa . [ 28 ]


1JEB ,  3W4U


Hemoglobin subunit zeta  is a  protein  that in humans is encoded by the  HBZ   gene . [ 5 ] [ 6 ]


Zeta-globin is an alpha-like hemoglobin. The zeta-globin polypeptide is synthesized in the yolk sac of the early embryo, while alpha-globin is produced throughout fetal and adult life. The zeta-globin gene is a member of the human alpha-globin gene cluster that includes five functional genes and two pseudogenes. The order of genes is: 5' -  zeta  - pseudozeta -  mu  - pseudoalpha-1 -  alpha-2  -  alpha-1  -  theta1  - 3'. [ 6 ]


Hemoglobin  is a protein that transports oxygen in the blood. Genetic differences lead to structural variants in the hemoglobin protein structure. Some variants can cause disease while others have little to no effect.


The normal hemoglobin types are Hemoglobin A (HbA), which makes up 95–98% of total hemoglobin in adults, Hemoglobin A2 (HbA2), which constitutes 2–3% of total hemoglobin in adults, and Hemoglobin F (HbF), which is the predominant hemoglobin in the fetus during pregnancy, and may persist in small amounts in adults. [ 1 ]


Hemoglobin variants occur when there are mutations in specific genes that code for the protein chains, known as globins, which make up the hemoglobin molecule. This leads to  amino acid   substitutions  in the hemoglobin molecule that could affect the structure, properties, and/or the stability of the hemoglobin molecule. There are over 1,000 naturally occurring structural variants of  hemoglobin  in humans. [ 2 ]


The physiological effects of these variants can range from minor to severe. [ 3 ]  Mutations can caused impaired production of hemoglobin ( thalassemia ) or produce structurally altered hemoglobins. Some hemoglobin variants, such as HbS which causes  sickle-cell anemia , are responsible for severe diseases and are considered  hemoglobinopathies . Other variants cause no detectable  pathology , and are thus considered non-pathological variants. [ 4 ] [ 5 ]


Hemoglobin variants can be discovered through examination, routine laboratory testing, or evaluation of patients with severe anemia. [ 3 ]  In some countries, all newborns are tested for hemoglobinopathies, thalassemias, and HbS.  Isoelectric focusing  or  high-performance liquid chromatography  are used to identify structural abnormalities in hemoglobin.


There are in excess of 1,000 known hemoglobin variants. [ 2 ]  A research database of hemoglobin variants is maintained by  Penn State University . [ 6 ]  A few of these variants are listed below.


Hemoglobin G ,  Hemoglobin G-Philadelphia , or  hbG , is a  mutation  of the cells that  oxygenate   blood . The G-Philadelphia variant is most commonly found in African Americans, with carriers being every 1 in 5,000. [ 1 ]
The trait is normal-functioning and has no known negative effects. [ 2 ]


The mutation was first discovered in 1971, during the boom of research in to  hemoglobin . [ 3 ]  The push was backed by the desire to research the causes and possibly fight  sickle cell anemia  and other types of Anemia. Because the strict laws of clinical testing had not existed in the 1970s, clinical trials were conducted almost immediately upon the granting of the National Sickle Cell Act of 1971. [ 4 ]


Schwartz et al confirmed that Hemoglobin G is a normal mutation of the combination of S and A  alleles , which is reflected in the chart below. [ 2 ]


Over time the variant has been shown more commonly in people of African and of Asian descent. [ citation needed ]  The clinical presentations of the gene mutation are regarded as either  Microcytic  or  Hypochromic  if they are detectable at all. [ 5 ]  While the trait is not known to be abnormal on its own, the mutation of the gene can have an effect on the absorption of  alcohol . [ 6 ]  As well as physical difficulties with alcohol and other blood-altering substances, the hemoglobin has also been shown to effect the way the brain handles sleep disorders, like  insomnia . [ 6 ]  People with the G mutation are typically more likely to have issues oxygenating blood and because of this,  Anemia  was thought to be a side-effect of the mutation. [ 7 ]
  The overall consensus among clinicians is that the "G-Philadelphia" mutation is harmless and has no clinical consequences. [ 8 ]


1A00 ,  1A01 ,  1A0U ,  1A0Z ,  1A3N ,  1A3O ,  1A9W ,  1ABW ,  1ABY ,  1AJ9 ,  1B86 ,  1BAB ,  1BBB ,  1BIJ ,  1BUW ,  1BZ0 ,  1BZ1 ,  1BZZ ,  1C7B ,  1C7C ,  1C7D ,  1CLS ,  1CMY ,  1COH ,  1DKE ,  1DXT ,  1DXU ,  1DXV ,  1FDH ,  1FN3 ,  1G9V ,  1GBU ,  1GBV ,  1GLI ,  1GZX ,  1HAB ,  1HAC ,  1HBA ,  1HBB ,  1HBS ,  1HCO ,  1HDB ,  1HGA ,  1HGB ,  1HGC ,  1HHO ,  1IRD ,  1J3Y ,  1J3Z ,  1J40 ,  1J41 ,  1J7S ,  1J7W ,  1J7Y ,  1JY7 ,  1K0Y ,  1K1K ,  1KD2 ,  1LFL ,  1LFQ ,  1LFT ,  1LFV ,  1LFY ,  1LFZ ,  1LJW ,  1M9P ,  1MKO ,  1NEJ ,  1NIH ,  1NQP ,  1O1I ,  1O1J ,  1O1K ,  1O1L ,  1O1M ,  1O1N ,  1O1O ,  1O1P ,  1QI8 ,  1QSH ,  1QSI ,  1QXD ,  1QXE ,  1R1X ,  1R1Y ,  1RPS ,  1RQ3 ,  1RQ4 ,  1RQA ,  1RVW ,  1SDK ,  1SDL ,  1SHR ,  1SI4 ,  1THB ,  1UIW ,  1VWT ,  1XXT ,  1XY0 ,  1XYE ,  1XZ2 ,  1XZ4 ,  1XZ5 ,  1XZ7 ,  1XZU ,  1XZV ,  1Y01 ,  1Y09 ,  1Y0A ,  1Y0C ,  1Y0D ,  1Y0T ,  1Y0W ,  1Y22 ,  1Y2Z ,  1Y31 ,  1Y35 ,  1Y45 ,  1Y46 ,  1Y4B ,  1Y4F ,  1Y4G ,  1Y4P ,  1Y4Q ,  1Y4R ,  1Y4V ,  1Y5F ,  1Y5J ,  1Y5K ,  1Y7C ,  1Y7D ,  1Y7G ,  1Y7Z ,  1Y83 ,  1Y85 ,  1Y8W ,  1YDZ ,  1YE0 ,  1YE1 ,  1YE2 ,  1YEN ,  1YEO ,  1YEQ ,  1YEU ,  1YEV ,  1YFF ,  1YG5 ,  1YGD ,  1YGF ,  1YH9 ,  1YHE ,  1YHR ,  1YIE ,  1YIH ,  1YVQ ,  1YVT ,  1YZI ,  1Z8U ,  2D5Z ,  2D60 ,  2DN1 ,  2DN2 ,  2DN3 ,  2DXM ,  2H35 ,  2HBC ,  2HBD ,  2HBE ,  2HBF ,  2HBS ,  2HCO ,  2HHD ,  2HHE ,  2M6Z ,  2W6V ,  2W72 ,  2YRS ,  3B75 ,  3D17 ,  3D7O ,  3DUT ,  3HXN ,  3IA3 ,  3IC0 ,  3IC2 ,  3KMF ,  3NL7 ,  3NMM ,  3ODQ ,  3ONZ ,  3OO4 ,  3OO5 ,  3OVU ,  3P5Q ,  3QJB ,  3QJC ,  3QJD ,  3QJE ,  3R5I ,  3S48 ,  3S65 ,  3S66 ,  3SZK ,  3WCP ,  3WHM ,  4FC3 ,  4HHB ,  4IJ2 ,  4L7Y ,  4M4A ,  4M4B ,  4MQC ,  4MQG ,  4MQH ,  4MQI ,  4MQJ ,  4MQK ,  4N7N ,  4N7O ,  4N7P ,  4N8T ,  4NI0 ,  4NI1 ,  4ROL ,  4ROM ,  4WJG ,  4X0L ,  4XS0 ,  6HBW ,  5E29 ,  5E6E ,  5EE4 ,  5HU6 ,  5JDO ,  5KDQ ,  5E83 ,%%s 1Y01 ,  1Z8U ,  1BZ1


NP_000508 NP_000508.1 NP_000549.1


Hemoglobin subunit alpha , Hemoglobin, alpha 1, [ 5 ]  is a  hemoglobin   protein  that in humans is encoded by the  HBA1   gene . [ 6 ]


The human alpha globin  gene cluster  located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 ( HBA2 ) and alpha-1 (HBA1; this gene) coding sequences are identical. These genes differ slightly over the  5' untranslated regions  and the  introns , but they differ significantly over the  3' untranslated regions . [ 6 ]


Two alpha chains plus two beta chains constitute  HbA , which in normal adult life accounts for about 97% of the total  hemoglobin ; alpha chains combine with delta chains to constitute  HbA-2 , which with  fetal hemoglobin  (HbF), composed of alpha and gamma chains, make up the remaining 3% of adult hemoglobin. [ 6 ]


Alpha  thalassemias  result from deletions of each of the alpha genes as well as deletions of both  HBA2  and  HBA1 ; some nondeletion alpha thalassemias have also been reported. [ 6 ]


Hemoglobin subunit alpha has been shown to  interact  with  hemoglobin subunit beta  (HBB). [ 7 ] [ 8 ]


Hemoglobin, alpha 2 [ 5 ]  also known as  HBA2  is a  gene  that in humans codes for the alpha globin chain of  hemoglobin . [ 6 ] [ 7 ]


The human alpha globin gene cluster is located on chromosome 16 and spans about 30 kb, including seven alpha like globin genes and pseudogenes: 5'-  HBZ  - HBZP1 -  HBM  - HBAP1 - HBA2 -  HBA1  -  HBQ1  -3'. The HBA2 (α 2 )  and   HBA1  (α 1 ) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions.


Two alpha chains plus two beta chains constitute  HbA , which in normal adult life accounts for about 97% of the total  hemoglobin ; alpha chains combine with delta chains to constitute  HbA-2 , which with  HbF  (fetal hemoglobin), composed of alpha and gamma chains, make up the remaining 3% of adult hemoglobin.


Alpha-thalassemias  most commonly result from deletions of any of the four alpha alleles, although some alpha thalassemias have been reported that are due to mutations other than deletion. Deletion of 1 or 2 alleles is clinically silent.  Deletion of 3 alleles causes HbH disease, resulting in anemia and hepatosplenomegaly.  Deletion of all 4 alleles is lethal because it renders the body unable to make fetal hemoglobin (HbF), adult hemoglobin (HbA) or adult variant hemoglobin (HbA2), and results in  hydrops fetalis . [ 8 ]


The  human β-globin  locus is composed of five  genes  located on a short region of  chromosome 11 , responsible for the creation of the beta parts (roughly half) of the oxygen transport protein  Haemoglobin . This locus contains not only the  beta globin gene  but also  delta ,  gamma-A ,  gamma-G , and  epsilon  globin.  Expression of all of these genes is controlled by single  locus control region  (LCR), and the genes are differentially expressed throughout development. [ 1 ]


The order of the genes in the beta-globin cluster is: 5' -  epsilon  –  gamma-G  –  gamma-A  –  delta  –  beta  - 3'. [ citation needed ]


The arrangement of the genes directly reflects the temporal differentiation of their expression during development, with the early-embryonic stage version of the gene located closest to the LCR. If the genes are rearranged, the gene products are expressed at improper stages of development. [ citation needed ]


Expression of these genes is regulated in embryonic  erythropoiesis  by many  transcription factors , including  KLF1 , [ 2 ]  which is associated with the upregulation of  adult hemoglobin  in adult definitive  erythrocytes , and  KLF2 , [ 3 ]  which is vital to the expression of  embryonic hemoglobin .


Many  CRMs  have been mapped within the cluster of genes encoding β-like globins expressed in embryonic (HBE1), fetal (HBG1 and HBG2), and adult (HBB and HBD) erythroid cells. All are marked by  DNase I hypersensitive sites  and  footprints , and many are bound by  GATA1  in  peripheral blood derived erythroblasts  (PBDEs). A DNA segment located between the HBG1 and HBD genes is one of the DNA segments bound by  BCL11A  and several other proteins to negatively regulate HBG1 and HBG2. It is sensitive to  DNase I  but is not conserved across  mammals . An  enhancer  located 3′ of the HBG1 gene is bound by several proteins in PBDEs and  K562 cells  and is sensitive to DNase I, but shows almost no signal for mammalian constraint. [ 4 ]


Methemoglobin  (British:  methaemoglobin , shortened  MetHb ) (pronounced "met-hemoglobin") is a  hemoglobin   in the form of  metalloprotein , in which the  iron  in the  heme  group is in the Fe 3+  ( ferric ) state, not the Fe 2+  ( ferrous ) of normal hemoglobin. Sometimes, it is also referred to as ferrihemoglobin. [ 2 ]  Methemoglobin cannot bind  oxygen , which means it cannot carry oxygen to tissues. It is bluish chocolate-brown in color. In human  blood  a trace amount of methemoglobin is normally produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown. The  NADH -dependent enzyme  methemoglobin reductase  ( a type of diaphorase ) is responsible for converting methemoglobin back to  hemoglobin .


Normally one to two percent of a person's hemoglobin is methemoglobin; a higher percentage than this can be genetic or caused by exposure to various chemicals and depending on the level can cause health problems known as  methemoglobinemia . A higher level of methemoglobin will tend to cause a  pulse oximeter  to read closer to 85% regardless of the true level of  oxygen saturation .


The word methemoglobin derives from the  Ancient Greek  prefix  μετα-  (meta-: behind, later, subsequent) and the word  hemoglobin .


The name  hemoglobin  is itself derived from the words  heme  and  globin , each  subunit  of hemoglobin being a  globular protein  with an embedded  heme  group.


Amyl nitrite  is administered to treat  cyanide poisoning . It works by converting  hemoglobin  to methemoglobin, which allows for the binding of  cyanide  (CN – )  anions  by  ferric  (Fe 3+ )  cations  and the formation of  cyanomethemoglobin . The immediate goal of forming this cyanide adduct is to prevent the binding of free cyanide to the  cytochrome  a 3  group in  cytochrome c oxidase . [ 8 ]


Methemoglobin is expressed as a concentration or a percentage. Percentage of methemoglobin is calculated by dividing the concentration of methemoglobin by the concentration of total hemoglobin. Percentage of methemoglobin is likely a better indicator of illness severity than overall concentration, as underlying medical conditions play an important role. For example, a methemoglobin concentration of 1.5 g/dL may represent a percentage of 10% in an otherwise healthy patient with a baseline hemoglobin of 15 mg/dL, whereas the presence of the same concentration of 1.5 g/dL of methemoglobin in an anemic patient with a baseline hemoglobin of 8 g/dL would represent a percentage of 18.75%. The former patient will be left with a functional hemoglobin concentration of 13.5 g/dL and potentially remain asymptomatic while the latter patient with a functional hemoglobin concentration 6.5 g/dL may be severely symptomatic with a methemoglobin of less than 20%. [ 9 ]


This may be further compounded by the "functional hemoglobin's" decreased ability to release oxygen in the presence of methemoglobin.  Anemia ,  congestive heart failure ,  chronic obstructive pulmonary disease , and essentially any pathology that impairs the ability to deliver oxygen may worsen the symptoms of methemoglobinemia. [ 9 ]


Increased levels of methemoglobin are found in blood stains. Upon exiting the body,  bloodstains  transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO 2 ) to methemoglobin (met-Hb) and  hemichrome  (HC). [ 10 ]


Mu hemoglobin  is a  predicted  protein encoded in the  HBM   gene . The mRNA is expressed at moderate levels, but the protein has not been detected by mass spectrometry. [ 1 ] [ 2 ] [ 3 ]  The order of genes is: 5' -  zeta  - pseudozeta -  mu  - pseudoalpha-1 -  alpha-2  -  alpha-1  -  theta1  - 3'.


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Sulfhemoglobinemia   is a rare condition in which there is excess sulfhemoglobin (SulfHb) in the  blood . The pigment is a greenish derivative of  hemoglobin  which cannot be converted back to normal, functional hemoglobin. It causes  cyanosis  even at low blood levels.


It is a rare blood condition in which the β-pyrrole ring of the  hemoglobin  molecule has the ability to bind irreversibly to any substance containing a  sulfur   atom . [ 1 ] [ 2 ]  When  hydrogen sulfide  (H 2 S) (or  sulfide   ions ) and  ferrous  ions combine in the  heme  of hemoglobin, the  blood  is thus incapable of transporting  oxygen  to the tissues.


Symptoms  include a blueish or greenish coloration of the blood (cyanosis),  skin , and  mucous membranes , even though a blood count test may not show any abnormalities in the blood.
This discoloration is caused by greater than 5 grams per cent of deoxyhemoglobin, or 1.5 grams per cent of methemoglobin, or 0.5 grams per cent of sulfhemoglobin, all serious medical abnormalities. [ citation needed ]


Sulfhemoglobinemia is usually drug induced, with drugs associated with it including  sulphonamides , such as  sulfasalazine  or  sumatriptan . Another possible cause is occupational exposure to sulfur compounds. [ citation needed ]


It can also be caused by  phenazopyridine . [ 3 ]


The condition generally resolves itself with erythrocyte (red blood cell) turnover, although  blood transfusions  can be necessary in extreme cases. [ citation needed ]


Vitreoscilla  haemoglobin  ( VHb ) is a type of  haemoglobin  found in the  Gram-negative aerobic bacterium ,  Vitreoscilla . It is the first  haemoglobin  discovered from bacteria, but unlike classic haemoglobin it is composed only of a single  globin  molecule. [ 1 ]  Like typical haemoglobin, its primary role is binding oxygen, but it also performs other functions including delivery of oxygen to  oxygenases ,  detoxification  of  nitric oxide , sensing and relaying oxygen concentrations,  peroxidase -like activity by eliminating autoxidation-derived  H 2 O 2  that prevents  haeme  degradation and iron release. [ 2 ]


In 1986, a bacterial ( Vitreoscilla ) heme protein that had been studied by Webster and his colleagues, was sequenced and this amino acid sequence exhibited the globin folds of a haemoglobin. [ 3 ] [ 4 ]  It consists of a single domain which normally occurs as a dimer. The solution of its crystal structure confirmed that its 3-dimensional structure is remarkably similar to the classic globin fold. [ 5 ]  When the gene ( vgb ) for this haemoglobin was cloned into  E. coli [ 6 ]  it was found that it increased the growth of these cells under low oxygen conditions compared to control bacteria. [ 7 ]  The concentration of VHb drastically increased in  Vitreoscilla , a strict aerobe, grown under  hypoxic conditions , [ 8 ]  and it was proposed that it acted as an "oxygen storage trap" to feed oxygen to the terminal oxidase  (cytochrome bo ) under these conditions. [ 9 ]  Further evidence for this is that VHb is concentrated  in vivo  near the membrane of  Vitreoscilla  cells. [ 10 ]  It was also shown that VHb binds to subunit I of the cytochrome bo terminal oxidase, [ 11 ]  the heme-containing subunit that is also responsible for the unique sodium pumping function of this unique terminal oxidase. [ 12 ]


VHb is the best understood of all the bacterial haemoglobins, and is attributed to play a number of functions. Its main role is likely the binding of  oxygen  at low concentrations and its direct delivery to the terminal respiratory oxidase(s) such as cytochrome o. It is also involved in the delivery of oxygen to  oxygenases , [ 13 ]   detoxification  of  nitric oxide  by converting it to  nitrate , [ 14 ]  and sensing oxygen concentrations and passing this signal to  transcription factors . [ 15 ] [ 16 ]  It has a  peroxidase -like activity and effectively eliminates autoxidation-derived  H 2 O 2 , which is a cause of  haeme  degradation and iron release. [ 2 ]


The VHb gene,  vgb , exists as a single copy in  Vitreoscilla  and exhibits complete agreement with the primary sequence of VHb. [ 6 ] [ 17 ]  The downstream region adjacent to  vgb  carries a gene in the opposite direction having close similarity with the  uvrA  gene of  E. coli , indicating that  vgb  is not part of a multigene  operon . [ 18 ]  Biosynthesis of VHb is regulated at the transcriptional level and is induced under hypoxia in its native host. [ 19 ]   vgb  is expressed strongly in  E. coli  through its native promoter and a similar increase in its transcript level occurs under hypoxia; this suggests a close similarity in the transcriptional machinery of  Vitreoscilla  and  E. coli . [ 20 ]  The promoter region of vgb is crowded with overlapping binding sites for several redox-sensitive transcriptional regulators, involving the fumarate and nitrate reduction (Fnr) system as primary regulator. [ 15 ]  The catabolite repression (Crp) system is an additional control [ 21 ]  along with the aerobic respiration control (Arc) system as a third oxygen-dependent controller. [ 22 ]  Another binding site for the oxidative stress response regulator (OxyR) is also present within the vgb promoter; all these transcriptional regulators appear to work in coordination with each other to control the biosynthesis of VHb in a redox dependent manner. [ 15 ]


Since it was shown that VHb stimulated the growth of  E. coli  under hypoxic conditions,  vgb  was cloned into a variety of organisms, including various bacteria, yeast, fungi, and even higher plants and animals to test its effects on growth and production of products of potential commercial importance, the degradation of toxic compounds, the enhancement of nitrification in wastewater treatment, and other environmental applications. [ 23 ]


Examples of increased productivity include increased yield of a variety of biochemicals including antibiotics, an insecticide, a surfactant, and potential plastic feedstocks. They also include enzymes [ 24 ]  (including one which might have anti-leukemic properties), and fuels (including ethanol, [ 25 ]  butanediol, [ 26 ] [ 27 ]  and biodiesel [ 28 ] ). The toxic compounds studied have been aromatics including 2-chlorobenzoic acid and 2,4-dinitrotolene. [ 29 ] [ 30 ]  In these cases, increases in degradation are thought to be due both to the effects of VHb enhancing respiration to provide cells with additional ATP for growth and production of degrading enzymes, and delivery of oxygen directly to the oxygenases required for early steps in the degradative pathways.


Other environmental investigations include those related to heavy metal remediation and provision of soil phosphate to plants. [ 28 ]  Expression of  vgb  in  Nitrosomonas europaea , a bacterium involved of  conversion of ammonia to nitrite  in wastewater, enhanced, to some degree, its ability in this conversion. [ 31 ]  Furthermore, it was shown that the mechanism of haeme protein expression to enhance oxygen supply to the monooxygenase in nitrification under hypoxic conditions is similar to VHb function seen in other applications. [ 32 ]


Amino acid residues in several sections of VHb in proximity to the haeme were altered using genetic engineering to change VHb’s affinity for oxygen and to examine the effects on the biotechnological properties of some of the systems studied. [ 23 ]  Many of the mutations did not have large effects on the ligand binding properties of VHb, or provided at best a modest increase in cell growth compared with cells harboring wild type VHb. [ 23 ] [ 33 ]  Two of the mutant VHb’s, however, provided substantial increases in growth and aromatic compound degradation compared to wild type VHb in  Pseudomonas  and  Burkholderia  bacteria transformed to contain  vgb . [ 34 ]


American Journal of Hematology  is an  academic journal  devoted to the coverage of  blood diseases . It has been published since 1976. The editor-in-chief is Carlo Brugnara ( Harvard Medical School ). [ 1 ]  According to the  Journal Citation Reports , the journal has a 2022  impact factor  of 12.8, ranking it 7th out of 76 journals in the category "Hematology". [ 2 ]


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See tips for writing articles about academic journals . Further suggestions might be found on the article's  talk page .


The  Asian Journal of Transfusion Science  is a  peer-reviewed   open-access   medical journal  published on behalf of the Indian Society of Blood Transfusion and Immunohematology. The journal publishes articles on the subjects of  blood transfusion  and  immunohematology .


The journal is indexed with Abstracts on Hygiene and Communicable Diseases, CAB Abstracts, Caspur, CINAHL,  DOAJ ,  Scopus ,  EBSCO , EMCARE, Expanded Academic ASAP,  JournalSeek , Global Health,  Google Scholar , Health & Wellness Research Center, Health Reference Center Academic,  Hinari , Index Copernicus, OpenJGate,  PubMed , SCOLOAR, SIIC databases, Tropical Diseases Bulletin, and  Ulrich's Periodicals Directory .


Blood  is a  peer-reviewed   medical journal  published by the  American Society of Hematology . It was established by  William Dameshek  in 1946. The journal changed from semimonthly (24 times annually) to weekly publication at the start of 2009. It covers clinical and basic research in all areas of  hematology , including disorders of  leukocytes , both benign and malignant,  erythrocytes ,  platelets ,  hemostatic mechanisms ,  vascular biology ,  immunology , and  hematologic oncology .


Blood  is indexed and abstracted by:


According to the  Journal Citation Reports , the journal has a 2021  impact factor  of 25.476, and has a Journal Impact Factor rank of 1/76 in the Hematology category. [ 1 ]


Blood Cells, Molecules and Diseases  is a  peer-reviewed   medical journal  covering  hematology . It was established in 1975 as  Blood Cells  and obtained its current title in 1995. The  editor-in-chief  is  Mohandus Narla . It is published eight times per year by  Elsevier .


The journal is abstracted and indexed in:


According to the  Journal Citation Reports , the journal had a 2013  impact factor  of 2.331, ranking it 39th out of 68 journals in the category "Hematology". [ 5 ]


Blood Reviews  is a quarterly  peer-reviewed   medical journal  that publishes  review articles  in the field of  hematology . It was established in 1987 and is published by  Elsevier . The  editors-in-chief  are Hillard Lazarus ( University Hospitals Case Medical Center ) and Drew Provan ( Royal London Hospital ). According to the  Journal Citation Reports , the journal has a 2017  impact factor  of 6.600. [ 1 ]


Blood Transfusion  is an English-language, bimonthly  peer-reviewed   academic journal . It is published by the Italian Society of Transfusion Medicine and Immunohematology ( Società Italiana di Medicina Trasfusionale e Immunoematologia , SIMTI). [ 1 ]  As of 2024, the editor-in-chief is Serelina Coluzzi. [ 2 ] [ 3 ]


As an online open-access [ 4 ]  publication,  Blood Transfusion  covers a range of topics including  blood donation  and donor recruitment;  immunohematology ;  transfusion medicine ,  patient blood management , collection, production and storage of blood components, transfusion transmitted diseases, hemovigilance, therapeutic apheresis,  cellular therapy  and  regenerative medicine ,  hematopoietic stem cell transplantation  and  cord blood banking ,  immunogenetics , hemostasis and thrombosis,  hematology , organization and quality systems in transfusion medicine, legal and ethical aspects of transfusion medicine.


The journal is indexed and abstracted in:


According to the  Journal Citation Reports , the journal's  impact factor  for 2023 is 2.4. [ 8 ] [ 9 ]


Blood Transfusion  was founded in 1956 with Lorenzo Lapponi as its founding editor-in-chief. [ 10 ]


Bone Marrow Transplantation  is a  peer-reviewed   medical journal  covering  transplantation  of  bone marrow  in humans. It is published monthly by  Nature Research . The scope of the journal includes  stem cell biology ,  transplantation immunology ,  translational research , and clinical results of specific transplant protocols. [ 1 ]


According to the  Journal Citation Reports ,  Bone Marrow Transplantation  has a 2020  impact factor  of 5.483. [ 2 ]


Bone Marrow Transplantation  is abstracted and indexed in  BIOBASE /Current Awareness in Biological Sciences,   BIOSIS ,  Current Contents /Clinical Medicine, Current Contents/Life Sciences,  EMBASE/Excerpta Medica ,  MEDLINE / Index Medicus , and  Science Citation Index .


This article about an  oncology   journal  is a  stub . You can help Wikipedia by  expanding it .


This article about a  surgery   journal  is a  stub . You can help Wikipedia by  expanding it .


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The  British Journal of Haematology  is a  peer-reviewed   medical journal  focusing on  hematology  and other  blood -related topics, such as  blood diseases  and their treatment.  It is published by [Wiley] on behalf of the  British Society for Haematology .


According to the  Journal Citation Reports , the  British Journal of Haematology  had a 2016  impact factor  of 5.67, ranking it 10th out of 70 in the category "Hematology". [ 1 ]  In addition, the journal is indexed in:


Clinical and Applied Thrombosis/Hemostasis  is a  peer-reviewed   medical journal  covering research in the field of  hematology . The  editor-in-chief  is Charles A. Carter. It was established in 1995 and is published by  SAGE Publications .


Clinical and Applied Thrombosis/Hemostasis  is abstracted and indexed in  Scopus  and the  Social Sciences Citation Index . According to the  Journal Citation Reports , its 2022  impact factor  is 2.9. [ 1 ]


Clinical Lymphoma, Myeloma & Leukemia  is a  peer-reviewed   medical journal  published by  Elsevier  (previously by  CIG Media Group ). It was established as  Clinical Lymphoma  in 2000, renamed to  Clinical Lymphoma & Myeloma  in 2005 and obtained its current name in 2010. The journal covers research on detection, diagnosis, prevention, and treatment of  lymphoma ,  myeloma ,  leukemia , and related disorders, including  macroglobulinemia ,  amyloidosis , and plasma-cell  dyscrasias .


The journal is abstracted and indexed in  Index Medicus / MEDLINE / PubMed ,  EMBASE ,  Excerpta Medica ,  Current Contents /Clinical Medicine,  CINAHL ,  Chemical Abstracts ,  Scopus , and the  Science Citation Index Expanded . According to the  Journal Citation Reports , the journal has a 2014  impact factor  of 2.02. [ 1 ]


Experimental Hematology  is a  peer-reviewed   medical journal  of  hematology , which publishes  original research  articles and reviews, as well as the abstracts of the annual proceedings of the  Society for Hematology and Stem Cells  (formerly known as the International Society for Experimental Hematology). The journal is published monthly by  Elsevier , and the annual proceedings are published in a supplement issue. The journal is  edited  by  Connie J. Eaves .


Expert Review of Hematology  is a  MEDLINE -indexed,  peer-reviewed , international  medical journal  publishing review articles and original papers on all aspects of  hematology . It is part of the  Expert Review  series, published by  Informa .


The journal provides commentary and analysis to elucidate best clinical practice in hematology and to translate advances in research – in areas such as  immunology ,  stem cell  research, and cell and gene therapy – into the clinical context. Each review includes an ‘expert commentary’ and a 'five-year view' section, in which authors are asked to provide their personal view on the current status and future direction of the research discussed.


The journal is aided by an international editorial advisory board of experts practicing within the field.


Expert Review of Hematology  is currently in its 7th year of publication, has an  Impact Factor [ 1 ]  of 2.07, and is available online or is published in paper format 12 times a year.


Haematologica  is a monthly  peer-reviewed   open access   medical journal  published by the Ferrata Storti Foundation. The  editor-in-chief  is Jacob M. Rowe (Rambam Medical Center, Haifa, Israel). The journal covers all topics related to  experimental and clinical hematology . It was established in 1920 by  Adolfo Ferrata .


The journal is abstracted and indexed in  Biological Abstracts , [ 1 ]   BIOSIS Previews , [ 1 ]   Current Contents /Clinical Medicine, [ 1 ]  Current Contents/Life Sciences, [ 1 ]   Embase , [ 2 ]   Science Citation Index Expanded , [ 1 ]  and  Scopus . [ 3 ]  According to the  Journal Citation Reports , the journal has a 2021  impact factor  of 11.049. [ 4 ]


International Journal of Hematology  is the official  journal  of the  Japanese Society of Hematology . [ 1 ]  Since 2008, it has been published by  Springer Japan , but used to be published by  Carden Jennings . [ 2 ]


International Journal of Hematology  is indexed in the following databases:


The  Journal of Thrombosis and Haemostasis  is a monthly  peer-reviewed   medical journal  covering research on  thrombosis  and  hematology  in general. It is published by  Wiley-Blackwell  and the  editors-in-chief  are David Lillicrap and James Morrissey. Former editors-in-chief include Frits Rosendaal, Pieter Reitsma, Mike Greaves, David Lane, Pier Mannucci, Jos Vermylen, Jan Sixma, Francois Duckert, and  Rosemary Biggs . It is an official journal of the  International Society on Thrombosis and Haemostasis .


According to the  Journal Citation Reports , the journal has a 2021  impact factor  of 16.036. [ 1 ]


Leukemia  is a  peer-reviewed   medical journal  published by the  Nature Publishing Group . It was established in 1987 by  Nicole Muller-Bérat Killman  and  Sven-Aage Killman , and is currently edited by Professors Andreas Hochhaus and Robert Peter Gale. The journal covers research on all aspects of  leukemia .


According to the  Journal Citation Reports , the journal had a 2020  impact factor  of 11.528. [ 1 ]  In the past, the journal has been accused of practicing  coercive citation . [ 2 ]


Leukemia & Lymphoma  is a  peer-reviewed   medical journal  published by  Informa Healthcare . It covers basic and clinical aspects of hematologic malignancies ( leukemias  and  lymphomas ). The  editors-in-chief  are Aaron Polliack ( Hadassah University Hospital ), Koen Van Besien ( Weill Cornell Medical Center ), and John Seymour ( Peter MacCallum Cancer Centre ).


According to the  Journal Citation Reports , the journal has a 2014  impact factor  of 2.891. [ 1 ]


Leukemia Research  is a monthly  peer-reviewed   medical journal  covering research on  hematologic malignancies . It was established in 1977 and is published by  Elsevier . The  editor-in-chief  is Clive S. Zent ( James P. Wilmot Cancer Center ).


The journal is abstracted and indexed by: [ 1 ]


According to the  Journal Citation Reports , the journal has a 2017  impact factor  of 2.319. [ 2 ]


memo - Magazine of European Medical Oncology   is a  peer-reviewed   medical journal  published by  Springer  and covering the fields of  hematology  and  oncology .  memo  is the official journal of the  Central European Cooperative Oncology Group . [ 1 ]


memo  includes editorials and comments, peer-reviewed original reports, short reviews, case reports and controversies, articles explaining the  biology  of  neoplasia , and congress reports.


The journal is abstracted and indexed by  EMBASE , Expanded Academic,  Google Scholar , and Summon by Serial Solutions.


The Central European Cooperative Oncology Group groups centers of clinical oncology from Central and Southeastern Europe as well as  Israel  that conduct of clinical trials. It also provides postgraduate education in oncology.


Pediatric Blood & Cancer  is a  peer-review  online-only  medical journal  covering  pediatric oncology  and  hematology . It was established in 1975 as  Medical and Pediatric Oncology , obtaining its current name in 2004. [ 1 ] [ 2 ]  Starting in January 2014, it stopped publishing its print edition and moved to an exclusively online format. [ 3 ]  The  editor-in-chief  is Peter E. Newburger ( University of Massachusetts Medical School ). According to the  Journal Citation Reports , the journal has a 2021  impact factor  of 3.838, ranking it 30th out of 130 journals in the category "Pediatrics", [ 4 ]  39th out of 78 journals in the category "Hematology", [ 5 ]  and 141st out of 245 journals in the category "Oncology". [ 6 ]


This article about a  pediatrics   journal  is a  stub . You can help Wikipedia by  expanding it .