Hemoglobinopathy

{{Short description|Any of various genetic disorders of blood}} {{Infobox medical condition (new) | name = Hemoglobinopathy | synonyms = Hemoglobinopathies | image = File:Sickle cells.jpg | caption = Red blood cells from a person with sickle cell disease, illustrating abnormal 'sickle' shaped red blood cells - key characteristic of the disease. | symptoms = Chronic anemia | complications = Enlarged spleen, iron overload, death | onset = During fetal development or very early infancy | duration = | types = Relatively frequent: sickle cell disease, alpha thalassemia and beta thalassemia | causes = Usually inherited | risks = | diagnosis = Blood smear, ferritin test, hemoglobin electrophoresis, DNA sequencing | differential = Iron deficiency anemia | prevention = Genetic counselling of potential parents, termination of pregnancy | treatment = Blood transfusion, iron chelation, hematopoietic stem cell transplant | medication = | prognosis = | frequency = | deaths = }}

'''Hemoglobinopathy''' is the medical term for a group of inherited blood disorders involving the hemoglobin, the major protein of red blood cells.<ref name="CDC 2019">{{cite web | author=CDC | title=Hemoglobinopathies Research | website=Centers for Disease Control and Prevention | date=2019-02-08 | url=https://www.cdc.gov/ncbddd/hemoglobinopathies/index.html | access-date=2019-05-05}}</ref> They are generally single-gene disorders and, in most cases, they are inherited as autosomal recessive traits.<ref name=":2">{{cite journal | pmid = 11545326 | year = 2001 | last1 = Weatherall | first1 = D. J. | last2 = Clegg | first2 = J. B. | title = Inherited haemoglobin disorders: An increasing global health problem | journal = Bulletin of the World Health Organization | volume = 79 | issue = 8 | pages = 704–712 | pmc = 2566499 }}</ref><ref>{{Cite web |last=Shakeel |first=Hassan |date=25 March 2023 |title=Thalassaemia — Knowledge Hub |url=https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/thalassaemia/ |access-date=2025-01-01 |website=Genomics Education Programme and NHS England |language=en}}</ref>

There are two main groups: abnormal structural hemoglobin variants caused by mutations in the hemoglobin genes, and the thalassemias, which are caused by an underproduction of otherwise normal hemoglobin molecules. The main structural hemoglobin variants are HbS, HbE and HbC. The main types of thalassemia are alpha-thalassemia and beta thalassemia.<ref>{{cite web |url=http://www.medicalassistantonlineprograms.org/hemoglobinopathy/ |title=Hemoglobinopathies and Thalassemia |website=medicalassistantonlineprograms.org/ |access-date=2013-11-07 |archive-date=2015-01-09 |archive-url=https://web.archive.org/web/20150109010024/http://www.medicalassistantonlineprograms.org/hemoglobinopathy/ }}</ref><ref name=":2" />

==Hemoglobin functions== Hemoglobin is a protein containing iron that facilitates the transportation of oxygen in red blood cells.<ref>{{cite book |last1=Maton |first1=Anthea |url=https://archive.org/details/humanbiologyheal00scho |title=Human Biology and Health |author2=Jean Hopkins |author3=Charles William McLaughlin |author4=Susan Johnson |author5=Maryanna Quon Warner |author6=David LaHart |author7=Jill D. Wright |publisher=Prentice Hall |year=1993 |isbn=978-0-13-981176-0 |location=Englewood Cliffs, New Jersey, US}}</ref> Hemoglobin in the blood carries oxygen from the lungs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the metabolism. Normal levels of hemoglobin vary according to sex and age in the range 9.5 to 17.2 grams of hemoglobin in every deciliter of blood.<ref>{{Cite web |title=Hemoglobin: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/003645.htm |access-date=2025-01-02 |website=medlineplus.gov |language=en}}</ref>

Hemoglobin also transports other gases. It carries off some of the body's respiratory carbon dioxide (about 20–25% of the total)<ref>{{cite book |last=Patton |first=Kevin T. |url=https://books.google.com/books?id=Ko2bBgAAQBAJ |title=Anatomy and Physiology |date=2015-02-10 |publisher=Elsevier Health Sciences |isbn=978-0-323-31687-3 |access-date=2016-01-09 |archive-url=https://web.archive.org/web/20160426205246/https://books.google.com/books?id=Ko2bBgAAQBAJ |archive-date=2016-04-26 |url-status=live}}</ref> as carbaminohemoglobin, in which CO₂ binds to the heme protein. The molecule also carries the important regulatory molecule nitric oxide bound to a thiol group in the globin protein, releasing it at the same time as oxygen.<ref name="Epstein-1998">{{cite journal |last1=Epstein |first1=F. H. |last2=Hsia |first2=C. C. W. |year=1998 |title=Respiratory Function of Hemoglobin |journal=New England Journal of Medicine |volume=338 |issue=4 |pages=239–47 |doi=10.1056/NEJM199801223380407 |pmid=9435331}}</ref>

== Hemoglobin structural biology == thumb|(a) schematic representation of a hemoglobin molecule, showing alpha and beta globins. (b) structure of the heme molecular component of hemoglobin Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α) globin and one beta-like (β) globin. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the α and the β chains is balanced so that their ratio is relatively constant and there is no excess of either type.<ref>Weatherall DJ. The New Genetics and Clinical Practice, Oxford University Press, Oxford 1991.</ref>

The specific α and β chains that are incorporated into Hb are highly regulated during development:<ref>{{Cite journal |last1=Cantú |first1=Ileana |last2=Philipsen |first2=Sjaak |date=2014-11-01 |title=Flicking the switch: adult hemoglobin expression in erythroid cells derived from cord blood and human induced pluripotent stem cells |url=https://haematologica.org/article/view/7190 |journal=Haematologica |language=en |volume=99 |issue=11 |pages=1647–1649 |doi=10.3324/haematol.2014.116483 |issn=1592-8721 |pmc=4222461 |pmid=25420279}}</ref> * Embryonic Hb are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb.<ref>Huisman TH. The structure and function of normal and abnormal haemoglobins. In: Baillière's Clinical Haematology, Higgs DR, Weatherall DJ (Eds), W.B. Saunders, London 1993. p.1.</ref><ref>Natarajan K, Townes TM, Kutlar A. Disorders of hemoglobin structure: sickle cell anemia and related abnormalities. In: Williams Hematology, 8th ed, Kaushansky K, Lichtman MA, Beutler E, et al. (Eds), McGraw-Hill, 2010. p.ch.48.</ref> Embryonic Hbs include: ** Hb Gower-1, composed of two ζ (zeta) globins and two ε (epsilon) globins, i.e., ζ₂ε₂ ** Hb Gower-2, composed of two α globins and two ε globins (α₂ε₂) ** Hb Portland, composed of two ζ globins and two γ (gamma) globins (ζ₂γ₂) * Fetal Hb (HbF) is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by early childhood. HbF is composed of two α globins and two γ globins (α₂γ₂).<ref name="Schechter2008">{{cite journal |vauthors=Schechter AN |date=November 2008 |title=Hemoglobin research and the origins of molecular medicine |journal=Blood |volume=112 |issue=10 |pages=3927–38 |doi=10.1182/blood-2008-04-078188 |pmc=2581994 |pmid=18988877 |doi-access=free}}</ref> * Adult Hb (HbA) is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two α globins and two β globins (α₂β₂).<ref name="urlHemoglobinopathies">{{cite web |date=17 April 2002 |title=Hemoglobinopathies |url=https://sickle.bwh.harvard.edu/hemoglobinopathy.html |access-date=2009-02-06 |website=Brigham and Women's Hospital}}</ref> * HbA2 is a minor adult Hb that normally accounts for approximately 2.5–3.5% of total Hb from six months of age onward. It is composed of two α globins and two δ (delta) globins (α₂δ₂).<ref name="urlHemoglobinopathies" />

== Classification of hemoglobinopathies ==

=== A) Qualitative ===

==== Structural abnormalities ==== Hemoglobin structural variants manifest a change in the structure of the Hb molecule. The majority of hemoglobin variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. Hb variants can usually be detected by protein-based assay methods such as electrophoresis,<ref>{{Cite web |title=Hemoglobin Electrophoresis: MedlinePlus Medical Test |url=https://medlineplus.gov/lab-tests/hemoglobin-electrophoresis/ |access-date=2024-11-20 |website=medlineplus.gov |language=en}}</ref> isoelectric focusing,<ref>{{Citation |last=Garfin |first=David E. |title=[35] Isoelectric focusing |date=1990 |journal=Methods in Enzymology |volume=182 |pages=459–477 |editor-last=Deutscher |editor-first=Murray P. |url=https://linkinghub.elsevier.com/retrieve/pii/0076687990820373 |access-date=2024-11-20 |series=Guide to Protein Purification |publisher=Academic Press |doi=10.1016/0076-6879(90)82037-3 |isbn=978-0-12-182083-1 |pmid=2314254|url-access=subscription }}</ref> or high-performance liquid chromatography.<ref name="Arishi-2021">{{Cite journal |last1=Arishi |first1=Wjdan A. |last2=Alhadrami |first2=Hani A. |last3=Zourob |first3=Mohammed |date=2021-05-05 |title=Techniques for the Detection of Sickle Cell Disease: A Review |journal=Micromachines |language=en |volume=12 |issue=5 |page=519 |doi=10.3390/mi12050519 |pmc=8148117 |pmid=34063111 |doi-access=free}}</ref> Diagnosis is commonly confirmed by DNA sequencing.<ref name="Arishi-2021" />

The hemoglobin structural variants can be broadly classified as follows:<ref>{{Cite journal |last=Forget |first=Bernard G. |last2=Bunn |first2=H. Franklin |date=2013-02-01 |title=Classification of the Disorders of Hemoglobin |url=https://perspectivesinmedicine.cshlp.org/content/3/2/a011684 |journal=Cold Spring Harbor Perspectives in Medicine |language=en |volume=3 |issue=2 |article-number=a011684 |doi=10.1101/cshperspect.a011684 |issn=2157-1422 |pmc=3552344 |pmid=23378597}}</ref> * '''Sickle cell disorders''', which are the most prevalent form of hemoglobinopathy. Sickle hemoglobin (HbS) is prone to polymerize when deoxygenated, precipitating within the red blood cell. This damages the RBC membrane resulting in its premature destruction and consequent anemia.<ref>{{Cite journal | doi=10.1016/S0065-3233(08)60287-9| pmid=2195851| isbn=978-0-12-034240-2| title=Sickle Cell Hemoglobin Polymerization | journal=Advances in Protein Chemistry| year=1990| last1=Eaton| first1=William A.| last2=Hofrichter| first2=James| volume=40| pages=63–279}}</ref> * '''Unstable hemoglobin variants''' are mutations that cause the hemoglobin molecule to precipitate, spontaneously or upon oxidative stress, resulting in hemolytic anemia. Precipitated, denatured hemoglobin can attach to the inner layer of the plasma membrane of the red blood cell (RBC) forming Heinz bodies, leading to premature destruction of the RBC and anemia.<ref>{{cite journal | pmid = 7655024 | year = 1995 | last1 = Srivastava | first1 = P. | last2 = Kaeda | first2 = J. S. | last3 = Roper | first3 = D. | last4 = Vulliamy | first4 = T. J. | last5 = Buckley | first5 = M. | last6 = Luzzatto | first6 = L. | title = Severe hemolytic anemia associated with the homozygous state for an unstable hemoglobin variant (Hb Bushwick) | journal = Blood | volume = 86 | issue = 5 | pages = 1977–1982 | doi = 10.1182/blood.V86.5.1977.bloodjournal8651977 | doi-access = free }}</ref> * '''Change in oxygen affinity.''' High or low oxygen affinity hemoglobin molecules are more likely than normal to adopt the relaxed (R, oxy) state or the tense (T, deoxy) state, respectively. High oxygen affinity variants (R state) cause polycythemia (e.g., Hb Chesapeake, Hb Montefiore). Low oxygen affinity variants can cause cyanosis (e.g., Hb Kansas, Hb Beth Israel).<ref name="auto">{{cite journal | pmid = 19734427 | year = 2009 | last1 = Percy | first1 = M. J. | last2 = Butt | first2 = N. N. | last3 = Crotty | first3 = G. M. | last4 = Drummond | first4 = M. W. | last5 = Harrison | first5 = C. | last6 = Jones | first6 = G. L. | last7 = Turner | first7 = M. | last8 = Wallis | first8 = J. | last9 = McMullin | first9 = M. F. | title = Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis | journal = Haematologica | volume = 94 | issue = 9 | pages = 1321–1322 | doi = 10.3324/haematol.2009.008037 | pmc = 2738729 }}</ref>

====Chemical abnormalities==== Methemoglobinemia is a condition caused by elevated levels of methemoglobin in the blood. Methaemoglobin is a form of hemoglobin that contains the ferric [Fe³⁺] form of iron, instead of the ferrous [Fe²⁺] form . Methemoglobin cannot bind oxygen, which means it cannot carry oxygen to tissues. In human blood a trace amount of methemoglobin is normally produced spontaneously; the enzyme methemoglobin reductase is responsible for converting methemoglobin back to hemoglobin.<ref name="Ludlow_2019">{{Cite book |title=StatPearls [Internet]. |vauthors=Ludlow JT, Wilkerson RG, Nappe TM |date=January 2019 |publisher=StatPearls Publishing |location=Treasure Island (FL) |chapter=Methemoglobinemia |pmid=30726002}}</ref><ref>{{cite journal |vauthors=Elahian F, Sepehrizadeh Z, Moghimi B, Mirzaei SA |date=June 2014 |title=Human cytochrome b5 reductase: structure, function, and potential applications |journal=Critical Reviews in Biotechnology |volume=34 |issue=2 |pages=134–143 |doi=10.3109/07388551.2012.732031 |pmid=23113554}}</ref> Methemoglobinemia can be hereditary but more commonly occurs as a side effect of certain medications or by abuse of recreational drugs.<ref>{{Cite web |title=Methemoglobinemia (MetHb): Symptoms, Causes & Treatment |url=https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia |archive-url=https://web.archive.org/web/20241229080906/https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia |archive-date=2024-12-29 |access-date=2025-01-01 |website=Cleveland Clinic |language=en |url-status=live }}</ref>

===B) Quantitative===

==== Production abnormalities ==== Red blood cells from a person with beta thalassemia|right|thumbThalassemias are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. This ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into normal hemoglobin can form non-functional aggregates that precipitate. This can lead to premature RBC destruction in the bone marrow and/or in the peripheral blood. Thalassemia subtypes of clinical significance are alpha thalassemia and beta thalassemia. A third subtype, delta thalassemia, affects production of HBA2 and is generally asymptomatic.<ref>{{Citation |last=Dasgupta |first=Amitava |title=Chapter 21 - Hemoglobinopathy |date=2014-01-01 |work=Clinical Chemistry, Immunology and Laboratory Quality Control |pages=363–390 |editor-last= |editor-first= |url=https://linkinghub.elsevier.com/retrieve/pii/B9780124078215000218 |access-date=2025-01-01 |place=San Diego |publisher=Elsevier |doi=10.1016/b978-0-12-407821-5.00021-8 |isbn=978-0-12-407821-5 |last2= |first2= |editor2-last= |editor2-first=|url-access=subscription }}</ref>

The severity of alpha thalassemia depends on how many of the four genes that code for alpha globin are faulty. In the fetus, a deficiency of alpha globin results in the production of Hemoglobin Barts - a dysfunctional hemoglobin that consists of four gamma globins. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth.<ref>{{Cite web |title=Pathophysiology of alpha thalassemia |url=http://www.uptodate.com/contents/pathophysiology-of-alpha-thalassemia |access-date=2016-08-30 |website=www.uptodate.com}}</ref> In adults alpha thalassemia manifests as HbH disease. In this, excess beta-globin forms β<small>4</small>-tetramers, which accumulate and precipitate in red blood cells, damaging their membranes. Damaged RBCs are removed by the spleen resulting in moderate to severe anemia.<ref name=":12">{{Cite journal |last1=Fucharoen |first1=Suthat |last2=Viprakasit |first2=Vip |date=2009-01-01 |title=Hb H disease: clinical course and disease modifiers |journal=Hematology |volume=2009 |issue=1 |pages=26–34 |doi=10.1182/asheducation-2009.1.26 |issn=1520-4391 |pmid=20008179 |doi-access=free}}</ref>

In beta thalassemia, reduced production of beta globin, combined with a normal synthesis of alpha globin, results in an accumulation of excess unmatched alpha globin. This precipitates in the red cell precursors in the bone marrow, triggering their premature destruction. Anemia in beta thalassemia results from a combination of ineffective production of RBCs, peripheral hemolysis, and an overall reduction in hemoglobin synthesis.<ref>{{Cite journal |last=Thein |first=Swee Lay |date=2005-01-01 |title=Pathophysiology of β Thalassemia—A Guide to Molecular Therapies |url=https://ashpublications.org/hematology/article/2005/1/31/19297/Pathophysiology-of-Thalassemia-A-Guide-to |journal=Hematology |volume=2005 |issue=1 |pages=31–37 |doi=10.1182/asheducation-2005.1.31 |issn=1520-4391}}</ref>

== Combination hemoglobinopathies == A combination hemoglobinopathy occurs when someone inherits two different abnormal hemoglobin genes. If these are different versions of the same gene, one having been inherited from each parent it is an example of compound heterozygosity.

Both alpha- and beta- thalassemia can coexist with other hemoglobinopathies. Combinations involving alpha thalassemia are generally benign.<ref>{{Cite journal |last1=Khatri |first1=Govinda |last2=Sahito |first2=Abdul Moiz |last3=Ansari |first3=Saboor Ahmed |date=2021-12-31 |title=Shared molecular basis, diagnosis, and co-inheritance of alpha and beta thalassemia |journal=Blood Research |language=en |volume=56 |issue=4 |pages=332–333 |doi=10.5045/br.2021.2021128 |pmc=8721464 |pmid=34776416}}</ref><ref>{{Cite journal |last1=Wambua |first1=Sammy |last2=Mwacharo |first2=Jedidah |last3=Uyoga |first3=Sophie |last4=Macharia |first4=Alexander |last5=Williams |first5=Thomas N. |date=2006 |title=Co-inheritance of α+-thalassaemia and sickle trait results in specific effects on haematological parameters |journal=British Journal of Haematology |language=en |volume=133 |issue=2 |pages=206–209 |doi=10.1111/j.1365-2141.2006.06006.x |issn=1365-2141 |pmc=4394356 |pmid=16611313}}</ref>

Some examples of clinically significant combinations involving beta thalassemia include:

* Hemoglobin C/ beta thalassemia: common in Mediterranean and African populations generally results in a moderate form of anemia with splenomegaly.<ref>{{Cite web |date=February 2011 |title=Hemoglobin C |url=https://doh.wa.gov/sites/default/files/legacy/Documents/5220/HbCFactSheet.pdf |website=Washington State Department of Health}}</ref> * Hemoglobin D/ beta thalassemia: common in the northwestern parts of India and Pakistan (Punjab region).<ref>{{cite journal |vauthors=Torres Lde S |date=March 2015 |title=Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis |journal=Revista Brasileira de Hematologia e Hemoterapia |volume=37 |issue=2 |pages=120–126 |doi=10.1016/j.bjhh.2015.02.007 |pmc=4382585 |pmid=25818823}}</ref>

* Hemoglobin E/ beta thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or β thalassemia intermedia.<ref>{{Cite journal |last1=Olivieri |first1=Nancy F. |last2=Muraca |first2=Giulia M. |last3=O'Donnell |first3=Angela |last4=Premawardhena |first4=Anuja |last5=Fisher |first5=Christopher |last6=Weatherall |first6=David J. |date=May 2008 |title=Studies in haemoglobin E beta-thalassaemia |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.07126.x |journal=British Journal of Haematology |language=en |volume=141 |issue=3 |pages=388–397 |doi=10.1111/j.1365-2141.2008.07126.x |pmid=18410572 |issn=0007-1048|url-access=subscription }}</ref> * Hemoglobin S/ beta thalassemia: common in African and Mediterranean populations, it is clinically similar to sickle-cell anemia.<ref name=":0">{{Cite web |last=Gerber |first=Gloria F. |date=April 2024 |title=Hemoglobin S–Beta-Thalassemia Disease - Hematology and Oncology |url=https://www.msdmanuals.com/professional/hematology-and-oncology/anemias-caused-by-hemolysis/hemoglobin-s-beta-thalassemia-disease |access-date=2024-12-24 |website=MSD Manual Professional Edition |language=en}}</ref> * Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of both the delta and beta globins. It is generally asymptomatic.<ref>{{cite book |last1=Pal |first1=G. K. & |url=https://books.google.com/books?id=XpUAihQ7Ib4C&q=microcytosis+definition&pg=PA53 |title=Textbook Of Practical Physiology - 2Nd Edn. |date=2005 |publisher=Orient Blackswan |isbn=978-81-250-2904-5 |page=53 |language=en |access-date=17 September 2016}}</ref>

There are two clinically significant combinations involving the sickle cell gene:

* Hemoglobin S/ beta thalassemia: (see above).<ref name=":0" /> * Hemoglobin S/ hemoglobin C (Hemoglobin SC disease) occurs when an individual inherits one gene for hemoglobin S (sickle cell) and one gene for hemoglobin C, The symptoms are very similar to sickle cell disease.<ref>{{Cite web |last=Pitone |first=Melanie L. |title=Hemobglobin SC Disease (for Parents) |url=https://kidshealth.org/en/parents/hbsc-disease.html |access-date=2024-12-24 |website=Nemours Foundation |language=english}}</ref>

== Hemoglobin variants == Hemoglobin variants are not necessarily pathological. For example, Hb Lepore-Boston and G-Waimanalo are two variants which are non-pathological.<ref>{{Cite journal |last=DiGeorge |first=Nicholas W. |last2=Lahey |first2=Colleen F. |last3=Vigilante |first3=John A. |date=2014-03-01 |title=Fitness for Duty: Two Cases of Rare Hemoglobin Variants in U.S. Navy Recruits |url=https://academic.oup.com/milmed/article-abstract/179/3/e354/4160756?redirectedFrom=fulltext |journal=Military Medicine |volume=179 |issue=3 |pages=e354–e356 |doi=10.7205/MILMED-D-13-00383 |issn=0026-4075|url-access=subscription }}</ref> There are in excess of 1,000 known hemoglobin variants.<ref name=":1">{{Cite web |date=6 July 2018 |title=Understanding haemoglobinopathies |url=https://www.gov.uk/government/publications/handbook-for-sickle-cell-and-thalassaemia-screening/understanding-haemoglobinopathies |access-date=2024-12-28 |website=Public Health England |language=en}}</ref> A research database of hemoglobin variants is maintained by Penn State University.<ref>{{Cite web |date=December 2024 |title=A Database of Human Hemoglobin Variants and Thalassemia mutations |url=https://globin.bx.psu.edu/hbvar/menu.html |website=Penn State University}}</ref> A few of these variants are listed below.

=== Normal hemoglobins === Source:<ref name=":2" /> ; Embryonic

* HbE Gower 1 (ζ₂ε₂) present in the normal embryo.<ref name=":3">{{Cite journal |last=Manning |first=Lois R. |last2=Russell |first2=J. Eric |last3=Padovan |first3=Julio C. |last4=Chait |first4=Brian T. |last5=Popowicz |first5=Anthony |last6=Manning |first6=Robert S. |last7=Manning |first7=James M. |date=2007 |title=Human embryonic, fetal, and adult hemoglobins have different subunit interface strengths. Correlation with lifespan in the red cell |url=https://onlinelibrary.wiley.com/doi/abs/10.1110/ps.072891007 |journal=Protein Science |language=en |volume=16 |issue=8 |pages=1641–1658 |doi=10.1110/ps.072891007 |issn=1469-896X |pmc=2203358 |pmid=17656582}}</ref> * HbE Gower 2 (α₂ε₂) present in the normal embryo.<ref name=":3" /> * HbE Portland I (ζ₂γ₂) present in the normal embryo.<ref name=":3" />

; Fetal

* HbF/Fetal (α₂γ₂) dominating during pregnancy and reducing close to zero a few weeks after birth * HbA (α₂β₂) Adult hemoglobin, present in small quantities during pregnancy

; Adult

* HbA (α₂β₂) comprising approximately 97% of adult hemoglobin * HbA₂ (α₂δ₂) comprising approximately 3% of adult hemoglobin * HbF/Fetal (α₂γ₂) dominating during pregnancy and reducing close to zero after birth

=== Relatively common abnormal hemoglobins === Source:<ref name=":2" />

* HbS (α₂β^S₂) causing sickle cell disease * HbC (α₂β^C₂) causing mild anemia if homozygous * HbE (α₂β^E₂) causing mild anemia if homozygous * HbD causing mild anemia if homozygous * HbH formed from 4 beta globins in severe alpha thalassemia causing severe anemia

==Evolutionary advantage== thumb|Historical distribution of red blood cell abnormalities {{Main|Malaria resistance}} Some hemoglobinopathies seem to have given an evolutionary benefit, especially to heterozygotes, in areas where malaria is endemic. Malaria parasites infect red blood cells, but subtly disturb normal cellular function and subvert the immune response. A number of mechanisms have been proposed to explain the increased chance of survival for the carrier of an abnormal hemoglobin trait.<ref>{{Cite journal |last1=Taylor |first1=Steve M. |last2=Cerami |first2=Carla |last3=Fairhurst |first3=Rick M. |date=2013-05-16 |title=Hemoglobinopathies: Slicing the Gordian Knot of Plasmodium falciparum Malaria Pathogenesis |journal=PLOS Pathogens |language=en |volume=9 |issue=5 |article-number=e1003327 |doi=10.1371/journal.ppat.1003327 |doi-access=free |issn=1553-7374 |pmc=3656091 |pmid=23696730}}</ref>

==References== {{reflist}}

{{Medical resources | DiseasesDB = 19674 | ICD10 = {{ICD10|D|58|2|d|55}} | ICD9 = {{ICD9|282.7}} | ICDO = | OMIM = | MedlinePlus = 001291 | eMedicineSubj = | eMedicineTopic = | MeshID = D006453 | Orphanet = 68364 }} {{Diseases of RBCs}}

Category:Hereditary hemolytic anemias Category:Disorders of globin and globulin proteins Category:Blood disorders