Editing Red blood cell

{{Short description|Oxygen-delivering blood cell and the most common type of blood cell}}
{{Use dmy dates|date=December 2020}}
{{Infobox cell
| Name = Red blood cells
| Latin=
| Image = Blausen 0761 RedBloodCells.png
| Caption = 3D rendering of human red blood cells ({{c.|6–8 μm}} in diameter)
| Image2 =
| Caption2 =
| Precursor =
| Acronym = RBC
| System =
| Function = [[Oxygen]] transport
}}

'''Red blood cells''' ('''RBCs'''), referred to as '''erythrocytes''' ({{ety|grc|erythros|red||kytos|hollow vessel}}, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as '''red cells''',<ref>{{cite book|title=Robbins Basic Pathology| vauthors = Kumar V, Abbas AK, Fausto N, Mitchell RN |publisher=Saunders|year=2007|edition=8th}}</ref> '''erythroid cells''', and rarely '''haematids''', are the most common type of [[blood cell]] and the [[vertebrate]]'s principal means of delivering [[oxygen]] ({{chem2|O2}}) to the body [[tissue (biology)|tissues]]—via blood flow through the [[circulatory system]].<ref>{{cite web|title=Blood Cells|url=http://www.biosbcc.net/doohan/sample/htm/Blood%20cells.htm|url-status=dead|archive-url=https://web.archive.org/web/20160723113019/http://www.biosbcc.net/doohan/sample/htm/Blood%20cells.htm|archive-date=23 July 2016}}</ref> Erythrocytes take up oxygen in the [[lung]]s, or in fish the [[gill]]s, and release it into tissues while squeezing through the body's [[capillary|capillaries]].

The [[cytoplasm]] of a red blood cell is rich in [[hemoglobin]] (Hb), an [[iron]]-containing [[biomolecule]] that can bind oxygen and is responsible for the red color of the cells and the blood. Each human red blood cell contains approximately 270&nbsp;million hemoglobin molecules.<ref>{{cite journal | vauthors = D'Alessandro A, Dzieciatkowska M, Nemkov T, Hansen KC | title = Red blood cell proteomics update: is there more to discover? | journal = Blood Transfusion = Trasfusione del Sangue | volume = 15 | issue = 2 | pages = 182–187 | date = March 2017 | pmid = 28263177 | pmc = 5336341 | doi = 10.2450/2017.0293-16 }}</ref> The [[cell membrane]] is composed of [[proteins]] and [[lipids]], and this structure provides properties essential for physiological [[Cell (biology)|cell]] function such as [[erythrocyte deformability|deformability]] and [[erythrocyte fragility|stability]] of the blood cell while traversing the circulatory system and specifically the [[capillary]] network.

In humans, mature red blood cells are flexible [[biconcave disk]]s. They lack a [[cell nucleus]] (which is expelled during [[Erythropoiesis|development]]) and [[organelle]]s, to accommodate maximum space for hemoglobin; they can be viewed as sacks of hemoglobin, with a [[lipid bilayer|plasma membrane]] as the sack. Approximately 2.4&nbsp;million new erythrocytes are produced per second in human adults.<ref name="Sackmann">[[Erich Sackmann]], ''Biological Membranes Architecture and Function.'', Handbook of Biological Physics, (ed. R.Lipowsky and E.Sackmann, vol.1, Elsevier, 1995</ref> The cells develop in the [[bone marrow]] and circulate for about 100–120 days in the body before their components are recycled by [[macrophage]]s.  Each circulation takes about 60 seconds (one minute).<ref name="Blom20032">{{cite book|url=https://books.google.com/books?id=CJ4c6gbewfQC&pg=PA27|title=Monitoring of Respiration and Circulation|year= 2003|publisher=CRC Press|isbn=978-0-203-50328-7|page=27| vauthors = Blom JA }}</ref> Approximately 84% of the cells in the human body are the 20–30&nbsp;trillion red blood cells.<ref>{{cite journal | vauthors = Hatton IA, Galbraith ED, Merleau NS, Miettinen TP, Smith BM, Shander JA | title = The human cell count and size distribution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 120 | issue = 39 | pages = e2303077120 | date = September 2023 | pmid = 37722043 | pmc = 10523466 | doi = 10.1073/pnas.2303077120 | bibcode = 2023PNAS..12003077H }}</ref><ref>{{cite journal | vauthors = Sender R, Fuchs S, Milo R | title = Revised Estimates for the Number of Human and Bacteria Cells in the Body | journal = PLOS Biology | volume = 14 | issue = 8 | pages = e1002533 | date = August 2016 | pmid = 27541692 | pmc = 4991899 | doi = 10.1371/journal.pbio.1002533 | doi-access = free }}</ref><ref name="dean">{{Cite book| vauthors = Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK2261/?depth=2| title = Blood Groups and Red Cell Antigens|date=2005|publisher=National Center for Biotechnology Information (US)}}</ref><ref name="pierige">{{cite journal | vauthors = Pierigè F, Serafini S, Rossi L, Magnani M | title = Cell-based drug delivery | journal = Advanced Drug Delivery Reviews | volume = 60 | issue = 2 | pages = 286–295 | date = January 2008 | pmid = 17997501 | doi = 10.1016/j.addr.2007.08.029 }}</ref> Nearly half of the blood's volume ([[hematocrit|40% to 45%]]) is red blood cells.

[[Packed red blood cells]] are red blood cells that have been donated, processed, and stored in a [[blood bank]] for [[blood transfusion]].

== Structure ==

===Vertebrates===
[[Image:Erythrocytes in vertebrates.jpg|thumb|200px|There is an immense size variation in vertebrate red blood cells, as well as a correlation between cell and nucleus size. Mammalian red blood cells, which do not contain nuclei, are considerably smaller than those of most other vertebrates.<ref name="Gulliver1875">{{Cite journal | volume = 1875 | pages = 474–495 | vauthors = Gulliver G | title = On the size and shape of red corpuscles of the blood of vertebrates, with drawings of them to a uniform scale, and extended and revised tables of measurements | journal = Proceedings of the Zoological Society of London | year = 1875 }}</ref>]] [[File:Cytological abnormalities in peripheral blood erythrocytes of penguins Pygoscelis papua 5.jpg|thumb|Mature red blood cells of birds have a nucleus, however in the blood of adult females of penguin ''[[Gentoo penguin|Pygoscelis papua]]'' enucleated red blood cells ('''B''') have been observed, but with very low frequency. |222x222px]] The vast majority of vertebrates, including [[mammal]]s and humans, have red blood cells. These erythrocytes are cells present in blood to transport oxygen. The only known vertebrates without red blood cells are the crocodile icefish (family [[Channichthyidae]]); they live in very oxygen-rich cold water and transport oxygen freely dissolved in their blood.<ref>{{cite journal | vauthors = Ruud JT | title = Vertebrates without erythrocytes and blood pigment | journal = Nature | volume = 173 | issue = 4410 | pages = 848–850 | date = May 1954 | pmid = 13165664 | doi = 10.1038/173848a0 | bibcode = 1954Natur.173..848R | s2cid = 3261779 }}</ref> While they no longer use hemoglobin, remnants of hemoglobin genes can be found in their [[genome]].<ref>{{cite book|title=The Making of the Fittest|publisher=W.W. Norton|year=2006|isbn=978-0-393-06163-5| vauthors = Carroll S |author-link=Sean B. Carroll}}</ref>

Vertebrate red blood cells consist mainly of [[hemoglobin]], a complex [[metalloprotein]] containing [[heme]] groups whose iron atoms temporarily bind to oxygen molecules (O<sub>2</sub>) in the lungs or gills and release them throughout the body. Oxygen can easily [[diffusion|diffuse]] through the erythrocyte's [[cell membrane]]. Hemoglobin in the red blood cells also carries some of the waste product [[carbon dioxide]] back from the tissues; most waste carbon dioxide, however, is transported back to the [[alveolar-capillary barrier|pulmonary capillaries]] of the [[lung]]s as [[bicarbonate]] (HCO<sub>3</sub><sup>−</sup>) dissolved in the [[blood plasma]]. [[Myoglobin]], a compound related to hemoglobin, acts to store oxygen in [[muscle]] cells.<ref>{{cite book  | vauthors = Maton A, Hopkins J, McLaughlin CW, Johnson S, Warner MQ, LaHart D, Wright JD | title = Human Biology and Health  | publisher = Prentice Hall  | year = 1993  | location = Englewood Cliffs, New Jersey| isbn = 978-0-13-981176-0  | url-access = registration  | url = https://archive.org/details/humanbiologyheal00scho  }}</ref>

The color of red blood cells is due to the heme group of hemoglobin. The [[blood plasma]] alone is straw-colored, but the red blood cells change color depending on the state of the hemoglobin: when combined with oxygen the resulting oxyhemoglobin is scarlet, and when oxygen has been released the resulting deoxyhemoglobin is of a dark red burgundy color. However, blood can appear bluish when seen through the vessel wall and skin.<ref>{{Cite web|title = Why Are Veins Blue?|url = http://scienceblogs.com/scientificactivist/2008/04/17/why-are-veins-blue/|access-date = 23 April 2015|date = 17 April 2008|website = Scienceblogs| vauthors = Anthis N }}</ref> [[Pulse oximetry]] takes advantage of the hemoglobin color change to directly measure the [[artery|arterial]] blood [[oxygen saturation]] using [[colorimetric]] techniques. Hemoglobin also has a very high affinity for [[carbon monoxide]], forming carboxyhemoglobin which is a very bright red in color. Flushed, confused patients with a saturation reading of 100% on pulse oximetry are sometimes found to be suffering from carbon monoxide poisoning.{{citation needed|date=December 2021}}

Having oxygen-carrying proteins inside specialized cells (as opposed to oxygen carriers being dissolved in body fluid) was an important step in the evolution of vertebrates as it allows for less [[viscosity|viscous]] blood, higher concentrations of oxygen, and better diffusion of oxygen from the blood to the tissues. The size of red blood cells varies widely among vertebrate species; red blood cell width is on average about 25% larger than [[capillary]] diameter, and it has been hypothesized that this improves the oxygen transfer from red blood cells to tissues.<ref name=snyder>{{Cite journal |doi=10.1093/icb/39.2.189 |title=Red Blood Cells: Centerpiece in the Evolution of the Vertebrate Circulatory System |year=1999 | vauthors = Snyder GK, Sheafor BA |journal=Integrative and Comparative Biology |volume=39 |pages=189–198 |issue=2|doi-access=free }}</ref>

===Mammals===
[[Image:Gray453.png|thumb|300px|Typical mammalian red blood cells: (a) seen from surface; (b) in profile, forming rouleaux; (c) rendered spherical by water; (d) rendered crenate (shrunken and spiky) by salt. (c) and (d) do not normally occur in the body. The last two shapes are due to water being transported into, and out of, the cells, by [[osmosis]].]]

The red blood cells of [[mammal]]s are typically shaped as biconcave disks: flattened and depressed in the center, with a [[dumbbell]]-shaped cross section, and a [[torus]]-shaped rim on the edge of the disk. This shape allows for a high surface-area-to-volume (SA/V) ratio to facilitate diffusion of gases.<ref>{{Cite web|url=https://www.bbc.co.uk/education/guides/ztp9q6f/revision/2|title=BBC Bitesize – GCSE Biology – Blood – Revision 2|website=www.bbc.co.uk|language=en-GB|access-date=26 November 2017}}</ref> However, there are some exceptions concerning shape in the [[artiodactyl]] order (even-toed [[ungulates]] including cattle, deer, and their relatives), which displays a wide variety of bizarre red blood cell morphologies: small and highly ovaloid cells in [[llama]]s and camels (family [[Camelidae]]), tiny spherical cells in mouse deer (family [[Tragulidae]]), and cells which assume fusiform, lanceolate, crescentic, and irregularly polygonal and other angular forms in red deer and wapiti (family [[Cervidae]]). Members of this order have clearly evolved a mode of red blood cell development substantially different from the mammalian norm.<ref name="Gulliver1875" /><ref name="The bigger the C-value, the larger">{{cite journal | vauthors = Gregory TR | title = The bigger the C-value, the larger the cell: genome size and red blood cell size in vertebrates | journal = Blood Cells, Molecules & Diseases | volume = 27 | issue = 5 | pages = 830–843 | year = 2001 | pmid = 11783946 | doi = 10.1006/bcmd.2001.0457 | citeseerx = 10.1.1.22.9555 }}</ref> Overall, mammalian red blood cells are remarkably flexible and deformable so as to squeeze through tiny [[capillary|capillaries]], as well as to maximize their apposing surface by assuming a cigar shape, where they efficiently release their oxygen load.<ref>{{cite journal | vauthors = Goodman SR, Kurdia A, Ammann L, Kakhniashvili D, Daescu O | title = The human red blood cell proteome and interactome | journal = Experimental Biology and Medicine | volume = 232 | issue = 11 | pages = 1391–1408 | date = December 2007 | pmid = 18040063 | doi = 10.3181/0706-MR-156 | s2cid = 32326166 }}</ref>

Red blood cells in mammals are unique amongst vertebrates as they do not have nuclei when mature. They do have nuclei during early phases of [[erythropoiesis]], but extrude them during development as they mature; this provides more space for hemoglobin.  The red blood cells without nuclei, called [[reticulocytes]], subsequently lose all other cellular [[organelle]]s such as their [[mitochondrion|mitochondria]], [[Golgi apparatus]] and [[endoplasmic reticulum]].

The [[spleen]] acts as a reservoir of red blood cells, but this effect is somewhat limited in humans. In some other mammals such as dogs and horses, the spleen sequesters large numbers of red blood cells, which are dumped into the blood during times of exertion stress, yielding a higher oxygen transport capacity.

[[Image:Red White Blood cells.jpg|thumb|200px|Scanning electron micrograph of blood cells. From left to right: human red blood cell, [[Platelet|thrombocyte]] (platelet), [[leukocyte]].]]

===Human===
[[Image:NIK 3232-Drops of blood medium.JPG|thumb|200px|Two drops of blood are shown with a bright red oxygenated drop on the left and a darker red deoxygenated drop on the right.]]
[[Image:Erytrocyte deoxy to oxy v0.7.gif|thumb|200px|Animation of a typical human red blood cell cycle in the circulatory system. This animation occurs at a faster rate (~20 seconds of the average 60-second cycle) and shows the red blood cell deforming as it enters capillaries, as well as the bars changing color as the cell alternates in states of oxygenation along the circulatory system.]]

A typical human red blood cell has a disk diameter of approximately [[Orders of magnitude (length)#Cellular to human scale|6.2–8.2 μm]]<ref>{{cite book|title=Clinical Hematology: Theory and Procedures| vauthors = Turgeon ML |publisher=Lippincott Williams & Wilkins|year=2004|page=100|url=https://books.google.com/books?id=cHAjsUgegpQC&q=erythrocyte%20size&pg=PA100|isbn=9780781750073}}</ref> and a maximum thickness of 2–2.5&nbsp;μm and a minimum thickness in the centre of 0.8–1&nbsp;μm, being much smaller than most other [[List of distinct cell types in the adult human body|human cells]]. These cells have an average volume of about [[Femto-|90 fL]]<ref>{{cite journal | vauthors = McLaren CE, Brittenham GM, Hasselblad V | title = Statistical and graphical evaluation of erythrocyte volume distributions | journal = The American Journal of Physiology | volume = 252 | issue = 4 Pt 2 | pages = H857–H866 | date = April 1987 | pmid = 3565597 | doi = 10.1152/ajpheart.1987.252.4.H857 | citeseerx = 10.1.1.1000.348 }}</ref> with a surface area of about 136 μm<sup>2</sup>, and can swell up to a sphere shape containing 150 fL, without membrane distension.

Adult humans have roughly 20–30&nbsp;trillion red blood cells at any given time, constituting approximately 70% of all cells by number.<ref>{{cite journal | vauthors = Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R, Frabetti F, Vitale L, Pelleri MC, Tassani S, Piva F, Perez-Amodio S, Strippoli P, Canaider S | display-authors = 6 | title = An estimation of the number of cells in the human body | journal = Annals of Human Biology | volume = 40 | issue = 6 | pages = 463–471 | date = 1 November 2013 | pmid = 23829164 | doi = 10.3109/03014460.2013.807878 | s2cid = 16247166 | doi-access = free | hdl = 11585/152451 }}</ref> Women have about 4–5&nbsp;million red blood cells per microliter (cubic millimeter) of blood and men about 5–6&nbsp;million; [[Effects of high altitude on humans#Acclimatization|people living at high altitudes]] with low oxygen tension will have more. Red blood cells are thus much more common than the other blood particles: there are about 4,000–11,000 [[white blood cells]] and about 150,000–400,000 [[platelet]]s per microliter.

Human red blood cells take on average 60 seconds to complete one cycle of circulation.<ref name="Blom20032" /><ref name=pierige/><ref>{{Cite book  | vauthors = Hillman RS, Ault KA, Rinder HM | year = 2005  | title = Hematology in Clinical Practice: A Guide to Diagnosis and Management  | edition = 4th | publisher = McGraw-Hill Professional  | page = 1  | isbn = 978-0-07-144035-6  }}</ref>

The blood's red color is due to the spectral properties of the [[heme|hemic]] iron [[ion]]s in [[hemoglobin]]. Each hemoglobin molecule carries four heme groups; hemoglobin constitutes about a third of the total cell volume. Hemoglobin is responsible for the transport of more than 98% of the oxygen in the body (the remaining oxygen is carried dissolved in the [[blood plasma]]). The red blood cells of an average adult human male store collectively about 2.5 grams of iron, representing about 65% of the total iron contained in the body.<ref>[http://www.med-ed.virginia.edu/courses/path/innes/nh/iron.cfm Iron Metabolism], University of Virginia Pathology. Accessed 22 September 2007.</ref><ref>{{Cite web|title=Transferrin and Iron Transport Physiology |url= https://sickle.bwh.harvard.edu/iron_transport.html |access-date= 26 March 2023 | vauthors = Bridges KR | work = Information Center for Sickle Cell and Thalassemic Disorders}}</ref>

==Microstructure==
===Nucleus===
Red blood cells in mammals are ''anucleate'' when mature, meaning that they lack a [[cell nucleus]]. In comparison, the red blood cells of other vertebrates have nuclei; the only known exceptions are [[salamander]]s of the family ''[[Plethodontidae]]'', where five different clades has evolved various degrees of enucleated red blood cells (most evolved in some species of the genus ''[[Batrachoseps]]''), and fish of the genus ''[[Maurolicus]]''.<ref>{{cite journal |doi=10.1007/BF01283036 |title=The cytomorphic system of anucleate non-mammalian erythrocytes |year=1982 | vauthors = Cohen WD |journal=Protoplasma |volume=113 |pages=23–32|s2cid=41287948 }}</ref><ref>{{cite journal | vauthors = Wingstrand KG | title = Non-nucleated erythrocytes in a teleostean fish Maurolicus mülleri (Gmelin) | journal = Zeitschrift für Zellforschung und Mikroskopische Anatomie | volume = 45 | issue = 2 | pages = 195–200 | year = 1956 | pmid = 13402080 | doi = 10.1007/BF00338830 | s2cid = 12916049 }}</ref><ref>{{cite journal | pmc=2435017 | date=2008 | last1=Mueller | first1=R. L. | last2=Gregory | first2=T. R. | last3=Gregory | first3=S. M. | last4=Hsieh | first4=A. | last5=Boore | first5=J. L. | title=Genome size, cell size, and the evolution of enucleated erythrocytes in attenuate salamanders | journal=Zoology | volume=111 | issue=3 | pages=218–230 | doi=10.1016/j.zool.2007.07.010 | pmid=18328681 | bibcode=2008Zool..111..218M }}</ref>

The elimination of the nucleus in vertebrate red blood cells has been offered as an explanation for the subsequent [[C-value enigma|accumulation of non-coding DNA in the genome]].<ref name="The bigger the C-value, the larger"/> The argument runs as follows: Efficient gas transport requires red blood cells to pass through very narrow capillaries, and this constrains their size. In the absence of nuclear elimination, the accumulation of repeat sequences is constrained by the volume occupied by the nucleus, which increases with genome size.

[[Nucleated red blood cell]]s in mammals consist of two forms: normoblasts, which are normal erythropoietic precursors to mature red blood cells, and megaloblasts, which are abnormally large precursors that occur in [[megaloblastic anemia]]s.

===Membrane composition===
Red blood cells are deformable, flexible, are able to adhere to other cells, and are able to interface with immune cells. Their [[cell membrane|membrane]] plays many roles in this. These functions are highly dependent on the membrane composition. The red blood cell membrane is composed of 3 layers: the [[glycocalyx]] on the exterior, which is rich in [[carbohydrates]]; the [[lipid bilayer]] which contains many [[transmembrane protein]]s, besides its lipidic main constituents; and the membrane skeleton, a structural network of proteins located on the inner surface of the lipid bilayer. Half of the membrane mass in human and most mammalian red blood cells are proteins.  The other half are lipids, namely [[phospholipid]]s and [[cholesterol]].<ref name="Yazdanbakhsh2000">{{cite journal | vauthors = Yazdanbakhsh K, Lomas-Francis C, Reid ME | title = Blood groups and diseases associated with inherited abnormalities of the red blood cell membrane | journal = Transfusion Medicine Reviews | volume = 14 | issue = 4 | pages = 364–374 | date = October 2000 | pmid = 11055079 | doi = 10.1053/tmrv.2000.16232 }}</ref>

====Membrane lipids====
[[Image:Erythrocyte Membrane lipids.jpg|thumb|250px|The most common red blood cell membrane lipids, schematically disposed as they are distributed on the bilayer. Relative abundances are not at scale.]]
The red blood cell membrane comprises a typical [[lipid bilayer]], similar to what can be found in virtually all human cells. Simply put, this lipid bilayer is composed of [[cholesterol]] and [[phospholipid]]s in equal proportions by weight. The lipid composition is important as it defines many physical properties such as membrane permeability and fluidity. Additionally, the activity of many membrane proteins is regulated by interactions with lipids in the bilayer.

Unlike cholesterol, which is evenly distributed between the inner and outer leaflets, the 5 major phospholipids are asymmetrically disposed, as shown below:

'''Outer monolayer'''
* [[Phosphatidylcholine]] (PC);
* [[Sphingomyelin]] (SM).

'''Inner monolayer'''
* [[Phosphatidylethanolamine]] (PE);
* [[Phosphoinositol]] (PI) (small amounts).
* [[Phosphatidylserine]] (PS);

This asymmetric phospholipid distribution among the bilayer is the result of the function of several energy-dependent and energy-independent [[phospholipid]] transport proteins. Proteins called "[[Flippase]]s" move phospholipids from the outer to the inner monolayer, while others called "[[floppase]]s" do the opposite operation, against a concentration gradient in an energy-dependent manner. Additionally, there are also "[[scramblase]]" proteins that move phospholipids in both directions at the same time, down their concentration gradients in an energy-independent manner. There is still considerable debate ongoing regarding the identity of these membrane maintenance proteins in the red cell membrane.

The maintenance of an asymmetric phospholipid distribution in the bilayer (such as an exclusive localization of PS and PIs in the inner monolayer) is critical for the cell integrity and function due to several reasons:
* [[Macrophages]] recognize and [[phagocytose]] red cells that expose PS at their outer surface. Thus the confinement of PS in the inner monolayer is essential if the cell is to survive its frequent encounters with macrophages of the [[reticuloendothelial system]], especially in the [[spleen]].
* Premature destruction of [[Thalassemia|thallassemic]] and sickle red cells has been linked to disruptions of lipid asymmetry leading to exposure of PS on the outer monolayer.
* An exposure of PS can potentiate adhesion of red cells to vascular endothelial cells, effectively preventing normal transit through the microvasculature. Thus it is important that PS is maintained only in the inner leaflet of the bilayer to ensure normal blood flow in microcirculation.
* Both PS and [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) can regulate membrane mechanical function, due to their interactions with skeletal proteins such as [[spectrin]] and [[Band 4.1|protein 4.1R]]. Recent studies have shown that binding of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of [[Band 4.1|protein band 4.1R]] to [[glycophorin C]] but decreases its interaction with [[Band 3|protein band 3]], and thereby may modulate the linkage of the bilayer to the membrane skeleton.

The presence of specialized structures named "[[lipid rafts]]" in the red blood cell membrane have been described by recent studies. These are structures enriched in [[cholesterol]] and [[sphingolipids]] associated with specific membrane proteins, namely [[FLOT1|flotillin]]s, [[STOM]]atins (band 7), [[G-proteins]], and [[Beta-adrenergic receptor|β-adrenergic receptor]]s. [[Lipid rafts]] that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate [[Beta-adrenergic receptor|β2-adregenic receptor]] signaling and increase [[Cyclic adenosine monophosphate|cAMP]] levels, and thus regulating entry of [[malaria]]l parasites into normal red cells.<ref name="Mohandas2008">{{cite journal | vauthors = Mohandas N, Gallagher PG | title = Red cell membrane: past, present, and future | journal = Blood | volume = 112 | issue = 10 | pages = 3939–3948 | date = November 2008 | pmid = 18988878 | pmc = 2582001 | doi = 10.1182/blood-2008-07-161166 }}</ref><ref>{{cite journal | vauthors = Rodi PM, Trucco VM, Gennaro AM | title = Factors determining detergent resistance of erythrocyte membranes | journal = Biophysical Chemistry | volume = 135 | issue = 1–3 | pages = 14–18 | date = June 2008 | pmid = 18394774 | doi = 10.1016/j.bpc.2008.02.015 | hdl-access = free | hdl = 11336/24825 }}</ref>

====Membrane proteins====
[[File:RBC Membrane Proteins SDS-PAGE gel.jpg|thumb|Red blood cell membrane proteins separated by [[Polyacrylamide gel electrophoresis|SDS-PAGE]] and [[Silver staining|silverstained]]<ref>{{cite journal |vauthors=Hempelmann E, Götze O | title =Characterization of membrane proteins by polychromatic silver staining| journal = Hoppe-Seyler's Z Physiol Chem| volume = 365| pages = 241–42| year = 1984 }}</ref>]]
The proteins of the membrane skeleton are responsible for the deformability, flexibility and durability of the red blood cell, enabling it to squeeze through capillaries less than half the diameter of the red blood cell (7–8 μm) and recovering the discoid shape as soon as these cells stop receiving compressive forces, in a similar fashion to an object made of rubber.

There are currently more than 50 known membrane proteins, which can exist in a few hundred up to a million copies per red blood cell. Approximately 25 of these membrane proteins carry the various blood group antigens, such as the A, B and Rh antigens, among many others. These membrane proteins can perform a wide diversity of functions, such as transporting ions and molecules across the red cell membrane, adhesion and interaction with other cells such as endothelial cells, as signaling receptors, as well as other currently unknown functions. The [[blood type]]s of humans are due to variations in surface [[glycoprotein]]s of red blood cells. Disorders of the proteins in these membranes are associated with many disorders, such as [[hereditary spherocytosis]], [[hereditary elliptocytosis]], [[hereditary stomatocytosis]], and [[paroxysmal nocturnal hemoglobinuria]].<ref name="Yazdanbakhsh2000"/><ref name="Mohandas2008"/>

The red blood cell membrane proteins organized according to their function:
[[File:RBC membrane major proteins.png|thumb|Red blood cell membrane major proteins]]
'''Transport'''
* [[Band 3]] – Anion transporter, also an important structural component of the red blood cell membrane, makes up to 25% of the cell membrane surface, each red cell contains approximately one million copies. Defines the [[Diego antigen system|Diego Blood Group]];<ref>{{cite journal | vauthors = Iolascon A, Perrotta S, Stewart GW | title = Red blood cell membrane defects | journal = Reviews in Clinical and Experimental Hematology | volume = 7 | issue = 1 | pages = 22–56 | date = March 2003 | pmid = 14692233 }}</ref>
* [[Aquaporin 1]] – water transporter, defines the [[Colton antigen system|Colton Blood Group]];
* [[Glut1]] – glucose and [[Dehydroascorbic acid|L-dehydroascorbic acid]] transporter;
* [[MCT1]] – [[Monocarboxylate transporter]] for exporting [[Lactic acid]] to the liver. See [[Cori cycle]].;<ref name="pmid29660777">{{cite journal | vauthors = Fisel P, Schaeffeler E, Schwab M | title = Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy | journal = Clinical and Translational Science | volume = 11 | issue = 4 | pages = 352–364 | date = July 2018 | pmid = 29660777 | pmc = 6039204 | doi = 10.1111/cts.12551 }}</ref>
* [[Kidd antigen system|Kidd antigen protein]] – urea transporter;
* [[RHAG]] – gas transporter, probably of carbon dioxide, defines Rh Blood Group and the associated unusual blood group phenotype Rh<sub>null</sub>;
* [[Na+/K+-ATPase|Na<sup>+</sup>/K<sup>+</sup> – ATPase]];
* [[Calcium ATPase|Ca<sup>2+</sup> – ATPase]];
* [[Na-K-2Cl cotransporter|Na<sup>+</sup> K<sup>+</sup> 2Cl<sup>−</sup> – cotransporter]];
* [[Sodium-chloride symporter|Na<sup>+</sup>-Cl<sup>−</sup> – cotransporter]];
* [[Na-H exchanger]];
* [[K-Cl cotransporter|K-Cl – cotransporter]];
* [[KCNN4|Gardos Channel]].

'''Cell adhesion'''
* [[ICAM4|ICAM-4]] – interacts with [[integrins]];
* [[Basal cell adhesion molecule|BCAM]]  – a glycoprotein that defines the [[lutheran antigen system|Lutheran blood group]] and also known as [[Lutheran antigen system|Lu]] or [[laminin]]-binding protein.

'''Structural role''' – The following membrane proteins establish linkages with skeletal proteins and may play an important role in regulating cohesion between the lipid bilayer and membrane skeleton, likely enabling the red cell to maintain its favorable membrane surface area by preventing the membrane from collapsing (vesiculating).
* [[Ankyrin]]-based macromolecular complex – proteins linking the bilayer to the membrane skeleton through the interaction of their cytoplasmic domains with [[Ankyrin]].
** [[Band 3]] – also assembles various [[Glycolysis|glycolytic]] enzymes, the presumptive CO<sub>2</sub> transporter, and [[carbonic anhydrase]] into a macromolecular complex termed a "[[metabolon]]," which may play a key role in regulating red cell metabolism and ion and gas transport [[#Role in CO2 transport|function]].
** [[RHAG]] – also involved in transport, defines associated unusual blood group phenotype Rh<sub>mod</sub>.
* [[Band 4.1|Protein 4.1R]]-based macromolecular complex – proteins interacting with [[Band 4.1|Protein 4.1R]].
** [[Band 4.1|Protein 4.1R]] – weak expression of [[Gerbich antigen system|Gerbich]] antigens;
** [[Glycophorin C]] and D – glycoprotein, defines [[Gerbich antigen system|Gerbich Blood Group]];
** [[XK protein|XK]] – defines the Kell Blood Group and the Mcleod unusual phenotype (lack of Kx antigen and greatly reduced expression of Kell antigens);
** [[Rh factor|RhD/RhCE]] – defines Rh Blood Group and the associated unusual blood group phenotype Rh<sub>null</sub>;
** [[Duffy antigen system|Duffy protein]] – has been proposed to be associated with [[chemokine]] clearance;<ref>{{cite journal | vauthors = Denomme GA | title = The structure and function of the molecules that carry human red blood cell and platelet antigens | journal = Transfusion Medicine Reviews | volume = 18 | issue = 3 | pages = 203–231 | date = July 2004 | pmid = 15248170 | doi = 10.1016/j.tmrv.2004.03.006 }}</ref>
** [[ADD1|Adducin]] – interaction with band 3;
** [[EPB49|Dematin]]- interaction with the Glut1 glucose transporter.
<ref name="Yazdanbakhsh2000"/><ref name="Mohandas2008"/>

===Surface electrostatic potential===
The [[zeta potential]] is an electrochemical property of cell surfaces that is determined by the net electrical charge of molecules exposed at the surface of cell membranes of the cell. The normal zeta potential of the red blood cell is −15.7&nbsp;milli[[volt]]s (mV).<ref name=Tokumasu2012>Tokumasu F, Ostera GR, Amaratunga C, Fairhurst RM (2012) Modifications in erythrocyte membrane zeta potential by ''Plasmodium falciparum'' infection. Exp Parasitol</ref> Much of this potential appears to be contributed by the exposed [[sialic acid]] residues in the membrane: their removal results in zeta potential of −6.06&nbsp;mV.

== Function ==

===Role in {{CO2}} transport===

Recall that [[Respiration (physiology)|respiration]], as illustrated schematically here with a unit of carbohydrate, produces about as many molecules of carbon dioxide, CO<sub>2</sub>, as it consumes of oxygen, O<sub>2</sub>.<ref name="guyton">{{cite book | vauthors = Guyton AC |title=Textbook of Medical Physiology |date=1976 |publisher=W. B. Saunders |location=Philadelphia, PA |isbn=0-7216-4393-0 |pages=556 |edition=Fifth |chapter=Ch. 41 Transport of Oxygen and Carbon Dioxide in the Blood and Body Fluids |quote=The Respiratory Exchange Ratio is 1:1 when carbohydrate is consumed, it is as low as 0.7 when fat is consumed.}}</ref>

:<chem>HCOH + O2 -> CO2 + H2O</chem>

Thus, the function of the circulatory system is as much about the transport of carbon dioxide as about the transport of oxygen.
As stated elsewhere in this article, most of the carbon dioxide in the blood is in the form of bicarbonate ion. The bicarbonate provides a [[Bicarbonate buffer system|critical pH buffer]].<ref name="west1">{{cite book | vauthors = West JB |title=Respiratory Physiology – the essentials |date=1974 |publisher=Williams & Wilkens |location=Baltimore, MD |isbn=0-683-08932-3 |page=80 |chapter=Gas Transport to the Periphery |quote=Acid Base Status: The transport of CO2 has a profound effect on the acid-base status of blood and the body as a whole. The lung excretes over 10,000 mEq of carbonic acid per day compared to less than 100 mEq of fixed acids by the kidney.}}</ref> Thus, unlike hemoglobin for O<sub>2</sub> transport, there is a physiological advantage to not having a specific CO<sub>2</sub> transporter molecule.

Red blood cells, nevertheless, play a key role in the CO<sub>2</sub> transport process, for two reasons.
First, because, besides hemoglobin, they contain a large number of copies of the enzyme [[carbonic anhydrase]] on the inside of their cell membrane.<ref name="guyton6">{{cite book | vauthors = Guyton AC |title=Textbook of Medical Physiology |date=1976 |publisher=W. B. Saunders |location=Philadelphia, PA |isbn=0-7216-4393-0 |pages=553–554 |edition=Fifth |chapter=Ch. 41 Transport of Oxygen and Carbon Dioxide in the Blood and Body Fluids |quote=Reaction of Carbon Dioxide with Water in the Red Blood Cells - Effect of Carbonic Anhydrase}}</ref> Carbonic anhydrase, as its name suggests, acts as a catalyst of the exchange between [[carbonic acid]] and carbon dioxide (which is the [[acid anhydride|anhydride]] of carbonic acid). Because it is a catalyst, it can affect many CO<sub>2</sub> molecules, so it performs its essential role without needing as many copies as are needed for O<sub>2</sub> transport by hemoglobin.
In the presence of this catalyst carbon dioxide and carbonic acid reach an [[Henderson–Hasselbalch equation|equilibrium]] very rapidly, while the red cells are still moving through the capillary. Thus it is the RBC that ensures that most of the CO<sub>2</sub> is transported as bicarbonate.<ref name="guyton3">{{cite book | vauthors = Guyton AC |title=Textbook of Medical Physiology |date=1976 |publisher=W. B. Saunders |location=Philadelphia, PA |isbn=0-7216-4393-0 |pages=553–554 |edition=Fifth |chapter=Ch. 41 Transport of Oxygen and Carbon Dioxide in the Blood and Body Fluids |quote=carbonic anhydrase catalyzes the reaction between carbon dioxide and water.}}</ref><ref name="comroe">{{cite book | vauthors = Comroe Jr JH |title=Physiology of Respiration |date=1965 |publisher=Year Book Medical Publishers |location=Chicago, IL |isbn=0-8151-1824-4 |page=176 |edition=1971 |chapter=Transport and elimination of carbon dioxide |quote=[carbonic anhdrase] makes the reaction go to the right about 13000 times as fast}}</ref>
At physiological pH the equilibrium strongly favors carbonic acid, which is mostly dissociated into bicarbonate ion.<ref name="documenta">{{cite book | veditors = Diem K, Lentner C |title=Documenta Geigy Scientific Tables |date=1970 |publisher=Ciba-Geigy Limited |location=Basle, Switzerland |pages=570–571 |edition=7th |chapter=Blood Gasses |quote=In plasma about 5% of CO2 is in physical solution 94% as bicarbonate and 1% as carbamino compounds; in the erythrocytes the corresponding figures are 7%, 82% and 11%.}}</ref>

:<chem>CO2 + H2O <=>> H2CO3 <=>> HCO3- + H+ </chem>

The H+ ions released by this rapid reaction within RBC, while still in the capillary, act to reduce the oxygen binding affinity of hemoglobin, the [[Bohr effect]].

The second major contribution of RBC to carbon dioxide transport is that carbon dioxide directly reacts with globin protein components of hemoglobin to form [[carbaminohemoglobin]] compounds.
As oxygen is released in the tissues, more CO<sub>2</sub> binds to hemoglobin, and as oxygen binds in the lung, it displaces the hemoglobin bound CO<sub>2</sub>, this is called the [[Haldane effect]]. Despite the fact that only a small amount of the CO<sub>2</sub> in blood is bound to hemoglobin in venous blood, a greater proportion of the change in CO<sub>2</sub> content between venous and arterial blood comes from the change in this bound CO<sub>2</sub>.<ref name="guyton4">{{cite book | vauthors = Guyton AC |title=Textbook of Medical Physiology |date=1976 |publisher=W. B. Saunders |location=Philadelphia, PA |isbn=0-7216-4393-0 |page=554 |edition=Fifth |chapter=Ch. 41 Transport of Oxygen and Carbon Dioxide in the Blood and Body Fluids |quote=from figure 41-5 Hgb.CO2 is about 23% and bicarbonate is about 70% of the total carbon dioxide transported to the lungs.}}</ref> That is, there is always an abundance of bicarbonate in blood, both venous and arterial, because of its aforementioned role as a pH buffer.

In summary, carbon dioxide produced by cellular respiration diffuses very rapidly to areas of lower concentration, specifically into nearby capillaries.<ref name="comroe2">{{cite book | vauthors = Comroe J |title=Physiology of Respiration |date=1965 |publisher=Year Book Medical Publishers |location=Chicago, IL |isbn=0-8151-1824-4 |page=140 |edition=1971 |ref=comroe |chapter=Pulmonary Gas Diffusion |quote=Despite being a heavier molecule, because it is more soluble, the relative rate of diffusion of CO2 is about 20 times the rate of O2}}</ref><ref name="guyton5">{{cite book | vauthors = Guyton AC |title=Textbook of Medical Physiology |date=1976 |publisher=W. B. Saunders |location=Philadelphia, PA |isbn=0-7216-4393-0 |page=553 |edition=Fifth |chapter=Ch. 41 Transport of Oxygen and Carbon Dioxide in the Blood and Body Fluids |quote=carbon dioxide diffuses out of the tissue cells in the gaseous form (but not to a significant effect in the bicarbonate form because the cell membrane is far less permeable to bicarbonate than to the dissolved gas.}}</ref>
When it diffuses into a RBC, CO<sub>2</sub> is rapidly converted by the carbonic anhydrase found on the inside of the RBC membrane into bicarbonate ion. The bicarbonate ions in turn leave the RBC in exchange for [[chloride shift|chloride ions]] from the plasma, facilitated by the [[band 3 anion transport protein]] colocated in the RBC membrane. The bicarbonate ion does not diffuse back out of the capillary, but is carried to the lung. In the lung the lower [[partial pressure]] of carbon dioxide in the alveoli causes carbon dioxide to diffuse rapidly from the capillary into the alveoli. The carbonic anhydrase in the red cells keeps the bicarbonate ion in equilibrium with carbon dioxide. So as carbon dioxide leaves the capillary, and CO<sub>2</sub> is displaced by O<sub>2</sub> on hemoglobin, sufficient bicarbonate ion converts rapidly to carbon dioxide to maintain the equilibrium.<ref name="guyton6"/><ref name="comroe3">{{cite book | vauthors = Comroe Jr JH|title=Physiology of Respiration |date=1965 |publisher=Year Book Medical Publishers |location=Chicago, IL |isbn=0-8151-1824-4 |pages=175–177 |edition=1971 |ref=comroe |chapter=Transport and elimination of carbon dioxide |quote=the buffering occurred in the red cell}}</ref><ref name="west">{{cite book | vauthors = West JB |title=Respiratory Physiology – the essentials |date=1974 |publisher=Williams & Wilkens |location=Baltimore, MD |isbn=0-683-08932-3 |pages=77–79 |chapter=Gas Transport to the Periphery |quote=CO<sub>2</sub> Transport}}</ref><ref name="brobeck2">{{cite book | vauthors = Stone WE | veditors = Brobeck JR |title=Best & Taylor's Physiological basis of medical practice. |date=1973 |publisher=Williams & Wilkins |location=Baltimore, MD |isbn=0-683-10160-9 |pages=6.16–6.18 |edition=9th |ref=brobeck |chapter=Ch. 6-1 Uptake and Delivery of the Respiratory Gasses |quote=Transport of CO<sub>2</sub> as Bicarbonate}}</ref>

===Secondary functions===
When red blood cells undergo [[shear stress]] in constricted vessels, they release [[adenosine triphosphate|ATP]], which causes the vessel walls to relax and dilate so as to promote normal blood flow.<ref>{{cite journal | vauthors = Wan J, Ristenpart WD, Stone HA | title = Dynamics of shear-induced ATP release from red blood cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 43 | pages = 16432–16437 | date = October 2008 | pmid = 18922780 | pmc = 2575437 | doi = 10.1073/pnas.0805779105 | doi-access = free | bibcode = 2008PNAS..10516432W }}</ref>

When their hemoglobin molecules are deoxygenated, red blood cells release [[S-Nitrosothiol]]s, which also act to dilate blood vessels,<ref>{{cite journal | vauthors = Diesen DL, Hess DT, Stamler JS | title = Hypoxic vasodilation by red blood cells: evidence for an s-nitrosothiol-based signal | journal = Circulation Research | volume = 103 | issue = 5 | pages = 545–553 | date = August 2008 | pmid = 18658051 | pmc = 2763414 | doi = 10.1161/CIRCRESAHA.108.176867 }}</ref> thus directing more blood to areas of the body depleted of oxygen.

Red blood cells can also synthesize [[nitric oxide]] enzymatically, using [[L-arginine]] as substrate, as do [[endothelial cell]]s.<ref>{{cite journal | vauthors = Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax T, Kumara I, Gharini P, Kabanova S, Ozüyaman B, Schnürch HG, Gödecke A, Weber AA, Robenek M, Robenek H, Bloch W, Rösen P, Kelm M | display-authors = 6 | title = Red blood cells express a functional endothelial nitric oxide synthase | journal = Blood | volume = 107 | issue = 7 | pages = 2943–2951 | date = April 2006 | pmid = 16368881 | doi = 10.1182/blood-2005-10-3992 | name-list-style = vanc | s2cid = 38270024 | doi-access = free }}</ref> Exposure of red blood cells to physiological levels of shear stress activates [[nitric oxide synthase]] and export of nitric oxide,<ref>{{cite journal | vauthors = Ulker P, Sati L, Celik-Ozenci C, Meiselman HJ, Baskurt OK | title = Mechanical stimulation of nitric oxide synthesizing mechanisms in erythrocytes | journal = Biorheology | volume = 46 | issue = 2 | pages = 121–132 | year = 2009 | pmid = 19458415 | doi = 10.3233/BIR-2009-0532 }}</ref> which may contribute to the regulation of vascular tonus.

Red blood cells can also produce [[hydrogen sulfide]], a signalling gas that acts to relax vessel walls. It is believed that the cardioprotective effects of garlic are due to red blood cells converting its sulfur compounds into hydrogen sulfide.<ref>{{cite journal | vauthors = Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW | display-authors = 6 | title = Hydrogen sulfide mediates the vasoactivity of garlic | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 46 | pages = 17977–17982 | date = November 2007 | pmid = 17951430 | pmc = 2084282 | doi = 10.1073/pnas.0705710104 | author-link2 = Victor Darley-Usmar | doi-access = free | bibcode = 2007PNAS..10417977B }}</ref>

Red blood cells also play a part in the body's [[immune response]]: when [[lysis|lysed]] by pathogens such as bacteria, their hemoglobin releases [[free radical]]s, which break down the pathogen's cell wall and membrane, killing it.<ref>{{cite news| vauthors = Kesava S |title=Red blood cells do more than just carry oxygen; New findings by NUS team show they aggressively attack bacteria too|url=http://www.dbs.nus.edu.sg/events/media/info/2007/dingSTsep07.pdf|access-date=26 March 2013|newspaper=The Straits Times|date=1 September 2007}}</ref><ref>{{cite journal | vauthors = Jiang N, Tan NS, Ho B, Ding JL | title = Respiratory protein-generated reactive oxygen species as an antimicrobial strategy | journal = Nature Immunology | volume = 8 | issue = 10 | pages = 1114–1122 | date = October 2007 | pmid = 17721536 | doi = 10.1038/ni1501 | s2cid = 11359246 }}</ref>

=== Cellular processes ===
As a result of not containing [[mitochondrion|mitochondria]], red blood cells use none of the oxygen they transport; instead they produce the energy carrier [[Adenosine triphosphate|ATP]] by the [[glycolysis]] of [[glucose]] and [[lactic acid fermentation]] on the resulting [[pyruvate]].<ref>{{cite book|title=Biochemistry|date=2012|publisher=W.H. Freeman|isbn=9781429229364|edition=7th|location=New York|pages=455, 609| vauthors = Berg JM, Tymoczko JL, Stryer L }}</ref><ref>{{cite journal | vauthors = Tilton WM, Seaman C, Carriero D, Piomelli S | title = Regulation of glycolysis in the erythrocyte: role of the lactate/pyruvate and NAD/NADH ratios | journal = The Journal of Laboratory and Clinical Medicine | volume = 118 | issue = 2 | pages = 146–152 | date = August 1991 | pmid = 1856577 }}</ref> Furthermore, the [[pentose phosphate pathway]] plays an important role in red blood cells; see [[glucose-6-phosphate dehydrogenase deficiency]] for more information.

As red blood cells contain no nucleus, [[protein biosynthesis]] is currently assumed to be absent in these cells.

Because of the lack of nuclei and organelles, mature red blood cells do not contain [[DNA]] and cannot synthesize any [[RNA]] (although it does contain RNAs),<ref name="Kabanova2009">{{cite journal | vauthors = Kabanova S, Kleinbongard P, Volkmer J, Andrée B, Kelm M, Jax TW | title = Gene expression analysis of human red blood cells | journal = International Journal of Medical Sciences | volume = 6 | issue = 4 | pages = 156–159 | year = 2009 | pmid = 19421340 | pmc = 2677714 | doi = 10.7150/ijms.6.156 }}</ref><ref name="Jain2022">{{cite journal | vauthors = Jain V, Yang WH, Wu J, Roback JD, Gregory SG, Chi JT | title = Single Cell RNA-Seq Analysis of Human Red Cells | journal = Frontiers in Physiology | volume = 13 | page = 828700 | year = 2022 | pmid = 35514346 | pmc = 9065680 | doi = 10.3389/fphys.2022.828700 | doi-access = free }}</ref> and consequently cannot divide and have limited repair capabilities.<ref name=Molecular_biology_of_the_cell>{{cite book|first1=Bruce|last1=Alberts|first2=Alexander|last2= Johnson|first3= Julian |last3=Lewis|first4= Martin|last4= Raff|first5= Keith|last5=Roberts|first6=Peter|last6= Walter |title=Molecular biology of the cell|chapter = Erythropoiesis Depends on the Hormone Erythropoietin|date=2002|publisher=Garland|location=New York|isbn=0-8153-4072-9|edition=4th|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK26919/#_A4157_|access-date=30 November 2023}}</ref> The inability to carry out [[protein synthesis]] means that no virus can evolve to target mammalian red blood cells.<ref>{{cite news|url=https://www.nytimes.com/2007/03/27/science/27viral.html|title=Scientists Explore Ways to Lure Viruses to Their Death| vauthors = Zimmer C |date=27 March 2007|newspaper=The New York Times|access-date=26 March 2013}}</ref> However, infection with [[parvovirus]]es (such as human [[parvovirus B19]]) can affect erythroid precursors while they still have DNA, as recognized by the presence of giant [[pronormoblast]]s with viral particles and [[inclusion bodies]], thus temporarily depleting the blood of reticulocytes and causing [[anemia]].<ref>{{cite journal | vauthors = Heegaard ED, Brown KE | title = Human parvovirus B19 | journal = Clinical Microbiology Reviews | volume = 15 | issue = 3 | pages = 485–505 | date = July 2002 | pmid = 12097253 | pmc = 118081 | doi = 10.1128/CMR.15.3.485-505.2002 | name-list-style = amp }}</ref>

==Life cycle==
Human red blood cells are produced through a process named [[erythropoiesis]], developing from committed [[stem cell]]s to mature red blood cells in about 7 days. When matured, in a healthy individual these cells live in blood circulation for about 100 to 120 days (and 80 to 90 days in a full term [[infant]]).<ref>{{cite journal | vauthors = Harrison KL | title = Fetal erythrocyte lifespan | journal = Australian Paediatric Journal | volume = 15 | issue = 2 | pages = 96–97 | date = June 1979 | pmid = 485998 | doi = 10.1111/j.1440-1754.1979.tb01197.x | s2cid = 5370064 }}</ref> At the end of their lifespan, they are removed from circulation. In many chronic diseases, the lifespan of the red blood cells is reduced.

===Creation===

[[Erythropoiesis]] is the process by which new red blood cells are produced; it lasts about 7 days. Through this process red blood cells are continuously produced in the red [[bone marrow]] of large bones. (In the [[embryo]], the [[liver]] is the main site of red blood cell production.) The production can be stimulated by the [[hormone]] [[erythropoietin]] (EPO), synthesised by the kidney. Just before and after leaving the bone marrow, the developing cells are known as [[reticulocyte]]s; these constitute about 1% of circulating red blood cells.

===Functional lifetime===

The functional lifetime of a red blood cell is about 100–120 days, during which time the red blood cells are continually moved by the blood flow push (in [[arteries]]), pull (in [[veins]]) and a combination of the two as they squeeze through microvessels such as capillaries. They are also recycled in the bone marrow.<ref>{{cite journal | vauthors = Higgins JM | title = Red blood cell population dynamics | journal = Clinics in Laboratory Medicine | volume = 35 | issue = 1 | pages = 43–57 | date = March 2015 | pmid = 25676371 | pmc = 4717490 | doi = 10.1016/j.cll.2014.10.002 }}</ref>

===Senescence===

The aging red blood cell undergoes changes in its [[plasma membrane]], making it susceptible to selective recognition by [[macrophage]]s and subsequent [[phagocytosis]] in the [[mononuclear phagocyte system]] ([[spleen]], [[liver]] and [[lymph node]]s), thus removing old and defective cells and continually purging the blood. This process is termed [[eryptosis]], red blood cell programmed death.<ref name=Lang2012>{{cite journal | vauthors = Lang F, Lang E, Föller M | title = Physiology and pathophysiology of eryptosis | journal = Transfusion Medicine and Hemotherapy | volume = 39 | issue = 5 | pages = 308–314 | date = October 2012 | pmid = 23801921 | pmc = 3678267 | doi = 10.1159/000342534 }}</ref> This process normally occurs at the same rate of production by erythropoiesis, balancing the total circulating red blood cell count. Eryptosis is increased in a wide variety of diseases including [[sepsis]], [[haemolytic uremic syndrome]], [[malaria]], [[sickle cell anemia]], beta-[[thalassemia]], [[glucose-6-phosphate dehydrogenase deficiency]], phosphate depletion, iron deficiency and [[Wilson's disease]]. Eryptosis can be elicited by osmotic shock, oxidative stress, and energy depletion, as well as by a wide variety of endogenous mediators and [[xenobiotic]]s. Excessive eryptosis is observed in red blood cells lacking the cGMP-dependent protein kinase type I or the AMP-activated protein kinase AMPK. [[Enzyme inhibitor|Inhibitor]]s of eryptosis include [[erythropoietin]], [[nitric oxide]], [[catecholamine]]s and high concentrations of [[urea]].

Much of the resulting breakdown products are recirculated in the body. The heme constituent of hemoglobin are broken down into iron (Fe<sup>3+</sup>) and [[biliverdin]]. The biliverdin is reduced to [[bilirubin]], which is released into the plasma and recirculated to the liver bound to [[albumin]].  The iron is released into the plasma to be recirculated by a carrier protein called [[transferrin]].  Almost all red blood cells are removed in this manner from the circulation before they are old enough to [[Hemolysis|hemolyze]]. Hemolyzed hemoglobin is bound to a protein in plasma called [[haptoglobin]], which is not excreted by the kidney.<ref>{{cite journal | vauthors = Föller M, Huber SM, Lang F | title = Erythrocyte programmed cell death | journal = IUBMB Life | volume = 60 | issue = 10 | pages = 661–668 | date = October 2008 | pmid = 18720418 | doi = 10.1002/iub.106 | s2cid = 41603762 | doi-access = free }}</ref>

==Clinical significance==

=== Disease ===
[[Image:Sicklecells.jpg|frame|right|Affected by [[Sickle-cell disease]], red blood cells alter shape and threaten to damage internal organs.]]

[[Blood diseases]] involving the red blood cells include:
* [[Anemia]]s (or anaemias) are diseases characterized by low oxygen transport capacity of the blood, because of low red cell count or some abnormality of the red blood cells or the hemoglobin.

:* [[Iron deficiency anemia]] is the most common anemia; it occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin, which contains iron, cannot be formed.

:* [[Pernicious anemia]] is an [[autoimmune disease]] wherein the body lacks [[intrinsic factor]], required to absorb [[vitamin B12|vitamin B<sub>12</sub>]] from food. Vitamin B<sub>12</sub> is needed for the production of red blood cells and hemoglobin.

:* [[Sickle-cell disease]] is a genetic disease that results in abnormal hemoglobin molecules. When these release their oxygen load in the tissues, they become insoluble, leading to mis-shaped red blood cells. These sickle shaped red cells are less deformable and [[Blood Viscoelasticity|viscoelastic]], meaning that they have become rigid and can cause blood vessel blockage, pain, strokes, and other tissue damage.

:* [[Thalassemia]] is a genetic disease that results in the production of an abnormal ratio of hemoglobin subunits.

:*[[Hereditary spherocytosis]] syndromes are a group of inherited disorders characterized by defects in the red blood cell's [[cell membrane]], causing the cells to be small, sphere-shaped, and fragile instead of donut-shaped and flexible. These abnormal red blood cells are destroyed by the [[spleen]]. Several other hereditary disorders of the red blood cell membrane are known.<ref>{{cite journal | vauthors = An X, Mohandas N | title = Disorders of red cell membrane | journal = British Journal of Haematology | volume = 141 | issue = 3 | pages = 367–375 | date = May 2008 | pmid = 18341630 | doi = 10.1111/j.1365-2141.2008.07091.x | s2cid = 7313716 }}</ref>

:* [[Aplastic anemia]] is caused by the inability of the [[bone marrow]] to produce blood cells.

:* [[Pure red cell aplasia]] is caused by the inability of the bone marrow to produce only red blood cells.

[[Image:Osmotic pressure on blood cells diagram.svg|thumb| right|Effect of [[osmotic pressure]] on blood cells]]
[[File:Human Erythrocytes OsmoticPressure PhaseContrast Plain.svg|thumb|right|Micrographs of the effects of osmotic pressure]]
* [[Hemolysis]] is the general term for excessive breakdown of red blood cells. It can have several causes and can result in [[hemolytic anemia]].

:* The [[malaria]] parasite spends part of its life-cycle in red blood cells, feeds on their hemoglobin and then breaks them apart, causing fever. Both [[sickle-cell disease]] and [[thalassemia]] are more common in malaria areas, because these mutations convey some protection against the parasite.
* [[Polycythemia]]s (or erythrocytoses) are diseases characterized by a surplus of red blood cells. The increased viscosity of the blood can cause a number of symptoms.

:* In [[polycythemia vera]] the increased number of red blood cells results from an abnormality in the bone marrow.
* Several [[microangiopathy|microangiopathic diseases]], including [[disseminated intravascular coagulation]] and [[thrombotic microangiopathies]], present with [[pathognomonic]] (diagnostic) red blood cell fragments called [[schistocyte]]s. These pathologies generate [[fibrin]] strands that sever red blood cells as they try to move past a [[thrombus]].

=== Transfusion ===
{{main|Blood transfusion}}
Red blood cells may be given as part of a [[blood transfusion]]. Blood may be [[blood donation|donated]] from another person, or stored by the recipient at an earlier date. Donated blood usually requires [[screening (medicine)|screening]] to ensure that donors do not contain risk factors for the presence of blood-borne diseases, or will not suffer themselves by giving blood. Blood is usually collected and tested for common or serious [[blood-borne disease]]s including [[Hepatitis B]], [[Hepatitis C]] and HIV. The [[blood type]] (A, B, AB, or O) or the blood product is identified and matched with the recipient's blood to minimise the likelihood of [[acute hemolytic transfusion reaction]], a type of [[transfusion reaction]]. This relates to the presence of [[antigen]]s on the cell's surface. After this process, the blood is stored, and within a short duration is used. Blood can be given as a whole product or the red blood cells separated as [[packed red blood cells]].

Blood is often transfused when there is known anaemia, active bleeding, or when there is an expectation of serious blood loss, such as prior to an operation. Before blood is given, a small sample of the recipient's blood is tested with the transfusion in a process known as [[cross-matching]].

In 2008 it was reported that human [[embryonic stem cell]]s had been successfully coaxed into becoming red blood cells in the lab. The difficult step was to induce the cells to eject their nucleus; this was achieved by growing the cells on [[stromal cell]]s from the bone marrow. It is hoped that these artificial red blood cells can eventually be used for blood transfusions.<ref>{{Cite web| vauthors = Coghlan A |date=2008-08-19 |title=First red blood cells grown in the lab|url=https://www.newscientist.com/article/dn14565-first-red-blood-cells-grown-in-the-lab/|access-date=2023-03-26|website=New Scientist|language=en-US}}</ref>

A human trial is conducted in 2022, using blood cultured from stem cells obtained from donor blood.<ref>
{{ Cite web
 | url          = https://www.medicalnewstoday.com/articles/researchers-are-trialing-lab-grown-blood-transfusions-what-to-know#Transfusing-lab-made-red-blood-cells
 | title        = Researchers are trialing lab-grown blood transfusions: What to know
 | website      = medicalnewstoday.com
 | date = 11 November 2022
 | publisher    = MedicalNewsToday
 | access-date  = 2022-11-17
 | url-status   = live
 | language     = en
 | archive-url  = https://web.archive.org/web/20221115050210/https://www.medicalnewstoday.com/articles/researchers-are-trialing-lab-grown-blood-transfusions-what-to-know
 | archive-date = 2022-11-15
 | quote        = A team of researchers led by the National Health Service (NHS) Blood and Transplant unit recently launched the first clinical trial to transfuse lab-grown red blood cells into a live human.
}}
</ref>

=== Tests ===
[[File:Poikilocytes - Red blood cell types.jpg|thumb|Variations of red blood cell shape, overall termed [[poikilocytosis]]]]
Several [[blood test]]s involve red blood cells. These include a ''RBC count'' (the number of red blood cells per volume of blood), calculation of the [[hematocrit]] (percentage of blood volume occupied by red blood cells), and the [[erythrocyte sedimentation rate]]. The [[blood type]] needs to be determined to prepare for a [[blood transfusion]] or an [[organ transplantation]].

Many diseases involving red blood cells are diagnosed with a [[blood film]] (or peripheral blood smear), where a thin layer of blood is smeared on a microscope slide. This may reveal [[poikilocytosis]], which are variations in red blood cell shape. When red blood cells sometimes occur as a stack, flat side next to flat side. This is known as ''[[rouleaux]] formation'', and it occurs more often if the levels of certain serum proteins are elevated, as for instance during [[inflammation]].

=== Separation and blood doping ===
Red blood cells can be obtained from [[whole blood]] by [[centrifugation]], which separates the cells from the [[blood plasma]] in a process known as [[blood fractionation]]. [[Packed red blood cells]], which are made in this way from whole blood with the plasma removed, are used in [[transfusion medicine]].<ref>{{cite web|url=http://www.aabb.org/resources/bct/Documents/coi0809r.pdf|title=Circular of Information for Blood and Blood Products|publisher=American Association of Blood Banks, American Red Cross, America's Blood Centers|access-date=1 November 2010|url-status=dead|archive-url=https://web.archive.org/web/20111030212757/http://www.aabb.org/resources/bct/Documents/coi0809r.pdf|archive-date=30 October 2011}}</ref> During [[blood donation|plasma donation]], the red blood cells are pumped back into the body right away and only the plasma is collected.

Some athletes have tried to improve their performance by [[blood doping]]: first about 1&nbsp;litre of their blood is extracted, then the red blood cells are isolated, frozen and stored, to be reinjected shortly before the competition. (Red blood cells can be conserved for 5 weeks at {{convert|−79|C|F|disp=or}}, or over 10 years using cryoprotectants<ref>{{cite book | vauthors = Valeri CR | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK233117/| chapter = Frozen Red Cell Technology| veditors = Sparacino L, Manning FJ | title = Blood Groups and Red Cell Antigens |date=8 February 1996|publisher=National Academies Press (US)|via=www.ncbi.nlm.nih.gov}}</ref>) This practice is hard to detect but may endanger the human [[cardiovascular system]] which is not equipped to deal with blood of the resulting higher [[viscosity]]. Another method of blood doping involves injection with [[erythropoietin]] to stimulate production of red blood cells.  Both practices are banned by the [[World Anti-Doping Agency]].

== History ==
The first person to describe red blood cells was the young Dutch biologist [[Jan Swammerdam]], who had used an early [[microscope]] in 1658 to study the blood of a frog.<ref>"Swammerdam, Jan (1637–1680)", McGraw Hill AccessScience, 2007. Accessed 27 December 2007.</ref> Unaware of this work, [[Anton van Leeuwenhoek]] provided another microscopic description in 1674, this time providing a more precise description of red blood cells, even approximating their size, "25,000 times smaller than a fine grain of sand".

In the 1740s, [[Vincenzo Menghini]] in Bologna was able to demonstrate the presence of iron by passing magnets over the powder or ash remaining from heated red blood cells.

In 1901, [[Karl Landsteiner]] published his discovery of the three main [[ABO blood group system|blood groups]]—A, B, and C (which he later renamed to O). Landsteiner described the regular patterns in which reactions occurred when [[blood serum|serum]] was mixed with red blood cells, thus identifying compatible and conflicting combinations between these blood groups. A year later Alfred von Decastello and Adriano Sturli, two colleagues of Landsteiner, identified a fourth blood group—AB.

In 1959, by use of [[X-ray crystallography]], [[Max Perutz]] was able to unravel the [[Hemoglobin#Structure of heme|structure of hemoglobin]], the red blood cell protein that carries oxygen.<ref>{{cite web |title=Max F. Perutz – Biographical |url=https://www.nobelprize.org/prizes/chemistry/1962/perutz/biographical/ |website=NobelPrize.org |access-date=23 October 2018}}</ref>

The oldest intact red blood cells ever discovered were found in [[Ötzi]] the Iceman, a natural mummy of a man who died around 3255 BCE. These cells were discovered in May 2012.<ref>{{cite news |title='Iceman' mummy holds world's oldest blood cells | vauthors = Pappas S |date=2 May 2012 |work=Fox News |url=http://www.foxnews.com/scitech/2012/05/02/iceman-mummy-holds-world-oldest-blood-cells/ |archive-url=https://web.archive.org/web/20120502232209/http://www.foxnews.com/scitech/2012/05/02/iceman-mummy-holds-world-oldest-blood-cells/ |url-status=dead |archive-date=2 May 2012 |access-date=2 May 2012}}</ref>

== See also ==
* [[List of distinct cell types in the adult human body]]
* [[Altitude training]]
* [[Blood substitute]]
* [[Red blood cell indices]]
* [[Serum (blood)]]
* [[Er blood group collection]]

== References ==
{{reflist}}

== External links ==
{{commons category|Red blood cells}}
* [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=rbcantigen.TOC&depth=2 ''Blood Groups and Red Cell Antigens''] by Laura Dean. Searchable and downloadable online textbook in the public domain.
* [http://www.genomesize.com/cellsize/ Database of vertebrate erythrocyte sizes].
* [https://www.pbs.org/wnet/redgold Red Gold], [[Public Broadcasting Service|PBS]] site containing facts and history

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[[Category:Human cells]]
[[Category:Blood cells]]
[[Category:Respiration]]
[[Category:1658 in science]]