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The ] of erythrocytes is rich in ], an ]-containing ] that can bind oxygen and is responsible for the red color of the cells. The ] is composed of ] and ], and this structure provides properties essential for physiological ] function such as ] and ] while traversing the circulatory system and specifically the ] network. The ] of erythrocytes is rich in ], an ]-containing ] that can bind oxygen and is responsible for the red color of the cells. The ] is composed of ] and ], and this structure provides properties essential for physiological ] function such as ] and ] while traversing the circulatory system and specifically the ] network.


In humans, mature red blood cells are flexible and oval biconcave disks. They lack a ] and most ]s, in order to accommodate maximum space for hemoglobin. Approximately 2.4 million new erythrocytes are produced per second in human adults.<ref name="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 ] and circulate for about 100–120 days in the body before their components are recycled by ]s. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are red blood cells.<ref name=dean>Laura Dean. </ref><ref name=pierige>{{cite journal |author=Pierigè F, Serafini S, Rossi L, Magnani M |title=Cell-based drug delivery |journal=Advanced Drug Delivery Reviews |volume=60 |issue=2 |pages=286–95 |date=January 2008 |pmid=17997501 |doi=10.1016/j.addr.2007.08.029}}</ref> In humans, mature red blood cells are flexible and oval biconcave disks. They lack a ] and most ]s, in order to accommodate maximum space for hemoglobin. Approximately 2.4 million new erythrocytes are produced per second in human adults.<ref name="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 ] and circulate for about 100–120 days in the body before their components are recycled by ]s. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are red blood cells.<ref name=dean>Laura Dean. </ref><ref name=pierige>{{cite journal |author=Pierigè F, Serafini S, Rossi L, Magnani M |title=Cell-based drug delivery |journal=Advanced Drug Delivery Reviews |volume=60 |issue=2 |pages=286–95 |date=January 2008 |pmid=17997501 |doi=10.1016/j.addr.2007.08.029|last2=Serafini |last3=Rossi |last4=Magnani }}</ref>


Red blood cells are also known as '''RBCs''', '''red cells''',<ref>{{cite book|title=Robbins Basic Pathology|edition=8th|publisher=Saunders|year=2007|author=Vinay Kumar, Abul K. Abbas, Nelson Fausto, Richard N. Mitchell}}</ref> '''red blood corpuscles''' (an archaic term), '''haematids''', '''erythroid cells''' or '''erythrocytes''' (from ] ''erythros'' for "red" and ''kytos'' for "hollow vessel", with ''-cyte'' translated as "cell" in modern usage). ] (pRBC) are red blood cells that have been donated, processed, and stored in a ] for ]. Red blood cells are also known as '''RBCs''', '''red cells''',<ref>{{cite book|title=Robbins Basic Pathology|edition=8th|publisher=Saunders|year=2007|author=Vinay Kumar, Abul K. Abbas, Nelson Fausto, Richard N. Mitchell}}</ref> '''red blood corpuscles''' (an archaic term), '''haematids''', '''erythroid cells''' or '''erythrocytes''' (from ] ''erythros'' for "red" and ''kytos'' for "hollow vessel", with ''-cyte'' translated as "cell" in modern usage). ] (pRBC) are red blood cells that have been donated, processed, and stored in a ] for ].
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===Nucleus=== ===Nucleus===
Erythrocytes in ]s are ''anucleate'' when mature, meaning that they lack a ]. In comparison, the erythrocytes of other ]s have nuclei; the only known exceptions are ]s of the '']'' genus and fish of the '']'' genus with closely related species.<ref>{{cite journal |doi=10.1007/BF01283036 |title=The cytomorphic system of anucleate non-mammalian erythrocytes |year=1982 |last1=Cohen |first1=W. D. |journal=Protoplasma |volume=113 |pages=23}}</ref><ref>{{cite journal |author=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 |doi_brokendate=2009-12-02 }}</ref> Erythrocytes in ]s are ''anucleate'' when mature, meaning that they lack a ]. In comparison, the erythrocytes of other ]s have nuclei; the only known exceptions are ]s of the '']'' genus and fish of the '']'' genus with closely related species.<ref>{{cite journal |doi=10.1007/BF01283036 |title=The cytomorphic system of anucleate non-mammalian erythrocytes |year=1982 |last1=Cohen |first1=W. D. |journal=Protoplasma |volume=113 |pages=23}}</ref><ref>{{cite journal |author=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 |doi_brokendate=2015-01-09 }}</ref>


The elimination of the nucleus in vertebrate erythrocytes has been offered as an explanation for the subsequent ].<ref>{{cite doi|10.1006/bcmd.2001.0457}}</ref> The argument runs as follows: Efficient gas transport requires erythrocytes 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. The elimination of the nucleus in vertebrate erythrocytes has been offered as an explanation for the subsequent ].<ref>{{cite doi|10.1006/bcmd.2001.0457}}</ref> The argument runs as follows: Efficient gas transport requires erythrocytes 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.


===Secondary functions=== ===Secondary functions===
When erythrocytes undergo shear stress in constricted vessels, they release ], which causes the vessel walls to relax and dilate so as to promote normal blood flow.<ref>{{cite journal |author=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=16432–7 |date=October 2008 |pmid=18922780 |pmc=2575437 |doi=10.1073/pnas.0805779105|bibcode = 2008PNAS..10516432W }}</ref> When erythrocytes undergo shear stress in constricted vessels, they release ], which causes the vessel walls to relax and dilate so as to promote normal blood flow.<ref>{{cite journal |author=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=16432–7 |date=October 2008 |pmid=18922780 |pmc=2575437 |doi=10.1073/pnas.0805779105|bibcode = 2008PNAS..10516432W |last2=Ristenpart |last3=Stone }}</ref>


When their hemoglobin molecules are deoxygenated, erythrocytes release ]s, which also act to dilate blood vessels,<ref>{{cite journal |author=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=545–53 |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. When their hemoglobin molecules are deoxygenated, erythrocytes release ]s, which also act to dilate blood vessels,<ref>{{cite journal |author=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=545–53 |date=August 2008 |pmid=18658051 |pmc=2763414 |doi=10.1161/CIRCRESAHA.108.176867|last2=Hess |last3=Stamler }}</ref> thus directing more blood to areas of the body depleted of oxygen.


Erythrocytes can also synthesize ] enzymatically, using ] as substrate, as do ]s.<ref>{{cite journal |author= Kleinbongard P |title= Red blood cells express a functional endothelial nitric oxide synthase |journal=Blood|volume=107 |pages=2943–51 |year=2006 |pmid= 16368881 |issue= 7 |doi= 10.1182/blood-2005-10-3992 |author-separator= , |author2= Schutz R |author3= Rassaf T |display-authors= 3 |last4= Lauer |first4= T |last5= Dejam |first5= A |last6= Jax |first6= T |last7= Kumara |first7= I |last8= Gharini |first8= P |last9= Kabanova |first9= S |first10= B |first11= HG |first14= M |first15= H |first16= W |first17= P |first18= M }}</ref> Exposure of erythrocytes to physiological levels of shear stress activates ] and export of nitric oxide,<ref>{{cite journal |author= 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 |pages=121–32 |year=2009 |pmid= 19458415 |issue= 2 |doi= 10.3233/BIR-2009-0532 }}</ref> which may contribute to the regulation of vascular tonus. Erythrocytes can also synthesize ] enzymatically, using ] as substrate, as do ]s.<ref>{{cite journal |author= Kleinbongard P |title= Red blood cells express a functional endothelial nitric oxide synthase |journal=Blood|volume=107 |pages=2943–51 |year=2006 |pmid= 16368881 |issue= 7 |doi= 10.1182/blood-2005-10-3992 |author-separator= , |author2= Schutz R |author3= Rassaf T |display-authors= 3 |last4= Lauer |first4= T |last5= Dejam |first5= A |last6= Jax |first6= T |last7= Kumara |first7= I |last8= Gharini |first8= P |last9= Kabanova |first9= S |first10= B |first11= HG |first14= M |first15= H |first16= W |first17= P |first18= M }}</ref> Exposure of erythrocytes to physiological levels of shear stress activates ] and export of nitric oxide,<ref>{{cite journal |author= 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 |pages=121–32 |year=2009 |pmid= 19458415 |issue= 2 |doi= 10.3233/BIR-2009-0532 |last2= Sati |last3= Celik-Ozenci |last4= Meiselman |last5= Baskurt |doi_brokendate= 2015-01-09 }}</ref> which may contribute to the regulation of vascular tonus.


Erythrocytes can also produce ], a signalling gas that acts to relax vessel walls. It is believed that the cardioprotective effects of ] are due to erythrocytes converting its sulfur compounds into hydrogen sulfide.<ref>{{Cite journal Erythrocytes can also produce ], a signalling gas that acts to relax vessel walls. It is believed that the cardioprotective effects of ] are due to erythrocytes converting its sulfur compounds into hydrogen sulfide.<ref>{{Cite journal
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| last = Benavides | last = Benavides
| first = Gloria A | first = Gloria A
| author2 = Victor M Darley-Usmar
| coauthors = Giuseppe L Squadrito, Robert W Mills, Hetal D Patel, T Scott Isbell, Rakesh P Patel, ], Jeannette E Doeller, David W Kraus
| title = Hydrogen sulfide mediates the vasoactivity of garlic | title = Hydrogen sulfide mediates the vasoactivity of garlic
| journal = Proceedings of the National Academy of Sciences of the United States of America | journal = Proceedings of the National Academy of Sciences of the United States of America
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| pmid = 17951430 | pmid = 17951430
| pmc = 2084282 | pmc = 2084282
|bibcode = 2007PNAS..10417977B }}</ref> |bibcode = 2007PNAS..10417977B | authorlink2 = Victor Darley-Usmar
| last3 = Mills
| first3 = R. W.
| last4 = Patel
| first4 = H. D.
| last5 = Isbell
| first5 = T. S.
| last6 = Patel
| first6 = R. P.
| last7 = Darley-Usmar
| first7 = V. M.
| last8 = Doeller
| first8 = J. E.
| last9 = Kraus
| first9 = D. W.
| display-authors = 9
}}</ref>


Erythrocytes also play a part in the body's ]: when ] by pathogens such as bacteria, their hemoglobin releases ]s, which break down the pathogen's cell wall and membrane, killing it.<ref>{{cite news|last=Kesava|first=Shobana|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|accessdate=2013-03-26|newspaper=The Straits Times|date=2007-09-01}}</ref><ref>{{cite journal |author=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=1114–22 |date=October 2007 |pmid=17721536 |doi=10.1038/ni1501}}</ref> Erythrocytes also play a part in the body's ]: when ] by pathogens such as bacteria, their hemoglobin releases ]s, which break down the pathogen's cell wall and membrane, killing it.<ref>{{cite news|last=Kesava|first=Shobana|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|accessdate=2013-03-26|newspaper=The Straits Times|date=2007-09-01}}</ref><ref>{{cite journal |author=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=1114–22 |date=October 2007 |pmid=17721536 |doi=10.1038/ni1501|last2=Tan |last3=Ho |last4=Ding }}</ref>


==Mammalian erythrocytes== ==Mammalian erythrocytes==
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As a result of not containing ], these cells use none of the oxygen they transport; instead they produce the energy carrier ] by the ] of ] and ] on the resulting ]. As a result of not containing ], these cells use none of the oxygen they transport; instead they produce the energy carrier ] by the ] of ] and ] on the resulting ].


Because of the lack of nuclei and organelles, mature red blood cells do not contain ] and cannot synthesize any ], and consequently cannot divide and have limited repair capabilities.<ref name="Kabanova2009">{{cite journal |author=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=156–9 |year=2009 |pmid=19421340 |pmc=2677714 |url=http://www.medsci.org/v06p0156.htm |doi=10.7150/ijms.6.156}}</ref> This also ensures that no ] can evolve to target mammalian red blood cells.<ref>{{cite news|last=Zimmer|first=Carl|title=Scientists Explore Ways to Lure Viruses to Their Death|url=http://www.nytimes.com/2007/03/27/science/27viral.html|accessdate=2013-03-26|newspaper=The New York Times|date=2007-03-27}}</ref> Because of the lack of nuclei and organelles, mature red blood cells do not contain ] and cannot synthesize any ], and consequently cannot divide and have limited repair capabilities.<ref name="Kabanova2009">{{cite journal |author=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=156–9 |year=2009 |pmid=19421340 |pmc=2677714 |url=http://www.medsci.org/v06p0156.htm |doi=10.7150/ijms.6.156|last2=Kleinbongard |last3=Volkmer |last4=Andrée |last5=Kelm |last6=Jax }}</ref> This also ensures that no ] can evolve to target mammalian red blood cells.<ref>{{cite news|last=Zimmer|first=Carl|title=Scientists Explore Ways to Lure Viruses to Their Death|url=http://www.nytimes.com/2007/03/27/science/27viral.html|accessdate=2013-03-26|newspaper=The New York Times|date=2007-03-27}}</ref>


Mammalian erythrocytes are typically shaped as biconcave disks: flattened and depressed in the center, with a dumbbell-shaped cross section, and a ]-shaped rim on the edge of the disk. This distinctive biconcave shape optimises the flow properties of blood in the large vessels, such as maximization of ] and minimization of platelet scatter, which suppresses their ] activity in those large vessels.<ref>{{cite journal |author=Uzoigwe C |title=The human erythrocyte has developed the biconcave disc shape to optimise the flow properties of the blood in the large vessels |journal=Medical Hypotheses |volume=67 |issue=5 |pages=1159–63 |year=2006 |pmid=16797867 |doi=10.1016/j.mehy.2004.11.047}}</ref> However, there are some exceptions concerning shape in the ] order (even-toed ] including cattle, deer, and their relatives), which displays a wide variety of bizarre erythrocyte morphologies: small and highly ovaloid cells in ]s and ]s (family ]), tiny spherical cells in mouse deer (family ]), and cells which assume fusiform, lanceolate, crescentic, and irregularly polygonal and other angular forms in red deer and wapiti (family ]). Members of this order have clearly evolved a mode of red blood cell development substantially different from the ] norm.<ref name="Gulliver1875"/><ref>{{cite journal |author=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=830–43 |year=2001 |pmid=11783946 |doi=10.1006/bcmd.2001.0457}}</ref> Overall, mammalian erythrocytes are remarkably flexible and deformable so as to squeeze through tiny ], as well as to maximize their apposing surface by assuming a cigar shape, where they efficiently release their oxygen load.<ref>{{cite journal |author=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=1391–408 |date=December 2007 |pmid=18040063 |doi=10.3181/0706-MR-156}}</ref> Mammalian erythrocytes are typically shaped as biconcave disks: flattened and depressed in the center, with a dumbbell-shaped cross section, and a ]-shaped rim on the edge of the disk. This distinctive biconcave shape optimises the flow properties of blood in the large vessels, such as maximization of ] and minimization of platelet scatter, which suppresses their ] activity in those large vessels.<ref>{{cite journal |author=Uzoigwe C |title=The human erythrocyte has developed the biconcave disc shape to optimise the flow properties of the blood in the large vessels |journal=Medical Hypotheses |volume=67 |issue=5 |pages=1159–63 |year=2006 |pmid=16797867 |doi=10.1016/j.mehy.2004.11.047}}</ref> However, there are some exceptions concerning shape in the ] order (even-toed ] including cattle, deer, and their relatives), which displays a wide variety of bizarre erythrocyte morphologies: small and highly ovaloid cells in ]s and ]s (family ]), tiny spherical cells in mouse deer (family ]), and cells which assume fusiform, lanceolate, crescentic, and irregularly polygonal and other angular forms in red deer and wapiti (family ]). Members of this order have clearly evolved a mode of red blood cell development substantially different from the ] norm.<ref name="Gulliver1875"/><ref>{{cite journal |author=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=830–43 |year=2001 |pmid=11783946 |doi=10.1006/bcmd.2001.0457}}</ref> Overall, mammalian erythrocytes are remarkably flexible and deformable so as to squeeze through tiny ], as well as to maximize their apposing surface by assuming a cigar shape, where they efficiently release their oxygen load.<ref>{{cite journal |author=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=1391–408 |date=December 2007 |pmid=18040063 |doi=10.3181/0706-MR-156|last2=Kurdia |last3=Ammann |last4=Kakhniashvili |last5=Daescu }}</ref>


In large blood vessels, red blood cells sometimes occur as a stack, flat side next to flat side. This is known as ''] formation'', and it occurs more often if the levels of certain serum proteins are elevated, as for instance during ]. In large blood vessels, red blood cells sometimes occur as a stack, flat side next to flat side. This is known as ''] formation'', and it occurs more often if the levels of certain serum proteins are elevated, as for instance during ].
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] ]


A typical ] erythrocyte has a disk diameter of approximately ]<ref>{{cite book|title=Clinical Hematology: Theory and Procedures|author=Mary Louise Turgeon|publisher=Lippincott Williams & Wilkins|year=2004|page=100|url=http://books.google.com/?id=cHAjsUgegpQC&lpg=PA100&dq=erythrocyte%20size&pg=PA100#v=onepage&q=erythrocyte%20size&f=false|isbn=9780781750073}}</ref> and a thickness at the thickest point 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 ]. These cells have an average volume of about ]<ref>{{cite journal | pmid = 3565597 | volume=252 | issue=4 Pt 2 | title=Statistical and graphical evaluation of erythrocyte volume distributions |date=April 1987 | journal=Am. J. Physiol. | pages=H857–66 | author=McLaren CE, Brittenham GM, Hasselblad V}}</ref> with a surface of about 136 μm<sup>2</sup>, and can swell up to a sphere shape containing 150 fL, without membrane distension. A typical ] erythrocyte has a disk diameter of approximately ]<ref>{{cite book|title=Clinical Hematology: Theory and Procedures|author=Mary Louise Turgeon|publisher=Lippincott Williams & Wilkins|year=2004|page=100|url=http://books.google.com/?id=cHAjsUgegpQC&lpg=PA100&dq=erythrocyte%20size&pg=PA100#v=onepage&q=erythrocyte%20size&f=false|isbn=9780781750073}}</ref> and a thickness at the thickest point 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 ]. These cells have an average volume of about ]<ref>{{cite journal | pmid = 3565597 | volume=252 | issue=4 Pt 2 | title=Statistical and graphical evaluation of erythrocyte volume distributions |date=April 1987 | journal=Am. J. Physiol. | pages=H857–66 | author=McLaren CE, Brittenham GM, Hasselblad V| last2=Brittenham | last3=Hasselblad }}</ref> with a surface 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 trillion) red blood cells at any given time, comprising approximately one quarter of the total human body cell number (women have about 4 to 5 million erythrocytes per ] (cubic millimeter) of blood and men about 5 to 6 million; ] 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 ] and about 150,000–400,000 ]s in each microliter of human blood. Adult humans have roughly ] (20–30 trillion) red blood cells at any given time, comprising approximately one quarter of the total human body cell number (women have about 4 to 5 million erythrocytes per ] (cubic millimeter) of blood and men about 5 to 6 million; ] 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 ] and about 150,000–400,000 ]s in each microliter of human blood.


Human red blood cells take on average 20 seconds to complete one cycle of circulation.<ref name=dean/><ref name=pierige/><ref>{{Cite book | last = Hillman | first = Robert S. | last2 = Ault | first2 = Kenneth A. | last3 = Rinder | first3 = Henry M. | year = 2005 | title = Hematology in Clinical Practice: A Guide to Diagnosis and Management | edition = 4 | publisher = McGraw-Hill Professional | page = 1 | isbn = 0-07-144035-6 | accessdate = December 7, 2008 }}</ref> Human red blood cells take on average 20 seconds to complete one cycle of circulation.<ref name=dean/><ref name=pierige/><ref>{{Cite book | last = Hillman | first = Robert S. | last2 = Ault | first2 = Kenneth A. | last3 = Rinder | first3 = Henry M. | year = 2005 | title = Hematology in Clinical Practice: A Guide to Diagnosis and Management | edition = 4 | publisher = McGraw-Hill Professional | page = 1 | isbn = 0-07-144035-6 }}</ref>


As red blood cells contain no nucleus, ] is currently assumed to be absent in these cells, although a recent study indicates the presence of all the necessary biomachinery in the cells to do so.<ref name="Kabanova2009"/> As red blood cells contain no nucleus, ] is currently assumed to be absent in these cells, although a recent study indicates the presence of all the necessary biomachinery in the cells to do so.<ref name="Kabanova2009"/>
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====Senescence==== ====Senescence====
The aging erythrocyte undergoes changes in its ], making it susceptible to selective recognition by ]s and subsequent ] in the ] (], ] and ]s), thus removing old and defective cells and continually purging the blood. This process is termed eryptosis, erythrocyte programmed cell death.<ref name=Lang2012>{{cite journal|year=2012|title=Physiology and pathophysiology of eryptosis|journal=Transfusion Medicine and Hemotherapy|volume=39|pages=308–314|pmc=3678267|author=Lang F, Lang E, Föller M|issue=5|doi=10.1159/000342534|pmid=23801921}}</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 ], ], ], ], beta-], ], phosphate depletion, iron deficiency and ]. Eryptosis can be elicited by osmotic shock, oxidative stress, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is observed in erythrocytes lacking the cGMP-dependent protein kinase type I or the AMP-activated protein kinase AMPK. ]s of eryptosis include ], ], ]s and high concentrations of ]. The aging erythrocyte undergoes changes in its ], making it susceptible to selective recognition by ]s and subsequent ] in the ] (], ] and ]s), thus removing old and defective cells and continually purging the blood. This process is termed eryptosis, erythrocyte programmed cell death.<ref name=Lang2012>{{cite journal|year=2012|title=Physiology and pathophysiology of eryptosis|journal=Transfusion Medicine and Hemotherapy|volume=39|pages=308–314|pmc=3678267|author=Lang F, Lang E, Föller M|issue=5|doi=10.1159/000342534|pmid=23801921|last2=Lang|last3=Föller}}</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 ], ], ], ], beta-], ], phosphate depletion, iron deficiency and ]. Eryptosis can be elicited by osmotic shock, oxidative stress, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is observed in erythrocytes lacking the cGMP-dependent protein kinase type I or the AMP-activated protein kinase AMPK. ]s of eryptosis include ], ], ]s and high concentrations of ].


Much of the resulting breakdown products are recirculated in the body. The heme constituent of hemoglobin are broken down into Fe<sup>3+</sup> and ]. The biliverdin is reduced to ], which is released into the plasma and recirculated to the liver bound to ]. The iron is released into the plasma to be recirculated by a carrier protein called ]. Almost all erythrocytes are removed in this manner from the circulation before they are old enough to ]. Hemolyzed hemoglobin is bound to a protein in plasma called ], which is not excreted by the kidney.<ref>{{cite journal |author=Föller M, Huber SM, Lang F |title=Erythrocyte programmed cell death |journal=IUBMB Life |volume=60 |issue=10 |pages=661–8 |date=October 2008 |pmid=18720418 |doi=10.1002/iub.106}}</ref> Much of the resulting breakdown products are recirculated in the body. The heme constituent of hemoglobin are broken down into Fe<sup>3+</sup> and ]. The biliverdin is reduced to ], which is released into the plasma and recirculated to the liver bound to ]. The iron is released into the plasma to be recirculated by a carrier protein called ]. Almost all erythrocytes are removed in this manner from the circulation before they are old enough to ]. Hemolyzed hemoglobin is bound to a protein in plasma called ], which is not excreted by the kidney.<ref>{{cite journal |author=Föller M, Huber SM, Lang F |title=Erythrocyte programmed cell death |journal=IUBMB Life |volume=60 |issue=10 |pages=661–8 |date=October 2008 |pmid=18720418 |doi=10.1002/iub.106|last2=Huber |last3=Lang }}</ref>


===Membrane composition=== ===Membrane composition===
The ] of the red blood cell plays many roles that aid in regulating their surface deformability, flexibility, adhesion to other cells and immune recognition. These functions are highly dependent on its composition, which defines its properties. The red blood cell membrane is composed of 3 layers: the ] on the exterior, which is rich in ]; the ] which contains many ]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 erythrocytes are proteins. The other half are lipids, namely ]s and ].<ref name="Yazdanbakhsh2000">{{cite journal |author=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=364–74 |date=October 2000 |pmid=11055079 |doi=10.1053/tmrv.2000.16232}}</ref> The ] of the red blood cell plays many roles that aid in regulating their surface deformability, flexibility, adhesion to other cells and immune recognition. These functions are highly dependent on its composition, which defines its properties. The red blood cell membrane is composed of 3 layers: the ] on the exterior, which is rich in ]; the ] which contains many ]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 erythrocytes are proteins. The other half are lipids, namely ]s and ].<ref name="Yazdanbakhsh2000">{{cite journal |author=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=364–74 |date=October 2000 |pmid=11055079 |doi=10.1053/tmrv.2000.16232|last2=Lomas-Francis |last3=Reid }}</ref>


====Membrane lipids==== ====Membrane lipids====
Line 134: Line 150:
* Both PS and ] (PIP2) can regulate membrane mechanical function, due to their interactions with skeletal proteins such as ] and ]. Recent studies have shown that binding of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of ] to ] but decreases its interaction with ], and thereby may modulate the linkage of the bilayer to the membrane skeleton. * Both PS and ] (PIP2) can regulate membrane mechanical function, due to their interactions with skeletal proteins such as ] and ]. Recent studies have shown that binding of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of ] to ] but decreases its interaction with ], and thereby may modulate the linkage of the bilayer to the membrane skeleton.


The presence of specialized structures named "]" in the erythrocyte membrane have been described by recent studies. These are structures enriched in ] and ] associated with specific membrane proteins, namely ]s, ]s (band 7), ], and ]s. ] that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate ] signaling and increase ] levels, and thus regulating entry of ]l parasites into normal red cells.<ref name="Mohandas2008">{{cite journal |author=Mohandas N, Gallagher PG |title=Red cell membrane: past, present, and future |journal=Blood |volume=112 |issue=10 |pages=3939–48 |date=November 2008 |pmid=18988878 |pmc=2582001 |doi=10.1182/blood-2008-07-161166}}</ref><ref>{{cite journal |author=Rodi PM, Trucco VM, Gennaro AM |title=Factors determining detergent resistance of erythrocyte membranes |journal=Biophysical Chemistry |volume=135 |issue=1–3 |pages=14–8 |date=June 2008 |pmid=18394774 |doi=10.1016/j.bpc.2008.02.015}}</ref> The presence of specialized structures named "]" in the erythrocyte membrane have been described by recent studies. These are structures enriched in ] and ] associated with specific membrane proteins, namely ]s, ]s (band 7), ], and ]s. ] that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate ] signaling and increase ] levels, and thus regulating entry of ]l parasites into normal red cells.<ref name="Mohandas2008">{{cite journal |author=Mohandas N, Gallagher PG |title=Red cell membrane: past, present, and future |journal=Blood |volume=112 |issue=10 |pages=3939–48 |date=November 2008 |pmid=18988878 |pmc=2582001 |doi=10.1182/blood-2008-07-161166|last2=Gallagher }}</ref><ref>{{cite journal |author=Rodi PM, Trucco VM, Gennaro AM |title=Factors determining detergent resistance of erythrocyte membranes |journal=Biophysical Chemistry |volume=135 |issue=1–3 |pages=14–8 |date=June 2008 |pmid=18394774 |doi=10.1016/j.bpc.2008.02.015|last2=Trucco |last3=Gennaro }}</ref>


====Membrane proteins==== ====Membrane proteins====
Line 145: Line 161:
] ]
'''Transport''' '''Transport'''
* ] – Anion transporter, also an important structural component of the erythrocyte cell membrane, makes up to 25% of the cell membrane surface, each red cell contains approximately one million copies. Defines the ];<ref>{{cite journal |author=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> * ] – Anion transporter, also an important structural component of the erythrocyte cell membrane, makes up to 25% of the cell membrane surface, each red cell contains approximately one million copies. Defines the ];<ref>{{cite journal |author=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|last2=Perrotta |last3=Stewart }}</ref>
* ] – water transporter, defines the ]; * ] – water transporter, defines the ];
* ] – glucose and ] transporter; * ] – glucose and ] transporter;
Line 202: Line 218:
:* ] is a genetic disease that results in the production of an abnormal ratio of hemoglobin subunits. :* ] is a genetic disease that results in the production of an abnormal ratio of hemoglobin subunits.


:*] syndromes are a group of inherited disorders characterized by defects in the red blood cell's ], 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 ]. Several other hereditary disorders of the red blood cell membrane are known.<ref>{{cite journal |author=An X, Mohandas N |title=Disorders of red cell membrane |journal=British Journal of Haematology |volume=141 |issue=3 |pages=367–75 |date=May 2008 |pmid=18341630 |doi=10.1111/j.1365-2141.2008.07091.x}}</ref> :*] syndromes are a group of inherited disorders characterized by defects in the red blood cell's ], 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 ]. Several other hereditary disorders of the red blood cell membrane are known.<ref>{{cite journal |author=An X, Mohandas N |title=Disorders of red cell membrane |journal=British Journal of Haematology |volume=141 |issue=3 |pages=367–75 |date=May 2008 |pmid=18341630 |doi=10.1111/j.1365-2141.2008.07091.x|last2=Mohandas }}</ref>


:* ] is an ] wherein the body lacks ], required to absorb ] from food. Vitamin B<sub>12</sub> is needed for the production of hemoglobin. :* ] is an ] wherein the body lacks ], required to absorb ] from food. Vitamin B<sub>12</sub> is needed for the production of hemoglobin.

Revision as of 02:49, 9 January 2015

Scanning electron micrograph of human red blood cells (ca. 6–8 μm in diameter)

Red blood cells (RBCs), also called erythrocytes, are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen (O2) to the body tissues--via blood flow through the circulatory system. RBCs take up oxygen in the lungs or gills and release it into tissues while squeezing through the body's capillaries.

The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing biomolecule that can bind oxygen and is responsible for the red color of the cells. The cell membrane is composed of proteins and lipids, and this structure provides properties essential for physiological cell function such as deformability and stability while traversing the circulatory system and specifically the capillary network.

In humans, mature red blood cells are flexible and oval biconcave disks. They lack a cell nucleus and most organelles, in order to accommodate maximum space for hemoglobin. Approximately 2.4 million new erythrocytes are produced per second in human adults. The cells develop in the bone marrow and circulate for about 100–120 days in the body before their components are recycled by macrophages. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are red blood cells.

Red blood cells are also known as RBCs, red cells, red blood corpuscles (an archaic term), haematids, erythroid cells or erythrocytes (from Greek erythros for "red" and kytos for "hollow vessel", with -cyte translated as "cell" in modern usage). Packed red blood cells (pRBC) are red blood cells that have been donated, processed, and stored in a blood bank for blood transfusion.

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. 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 1901, Karl Landsteiner published his discovery of the three main blood groups—A, B, and C (which he later renamed to O). Landsteiner described the regular patterns in which reactions occurred when 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, Dr. Max Perutz was able to unravel the structure of hemoglobin, the red blood cell protein that carries oxygen.

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.

Vertebrate erythrocytes

There is an immense size variation in vertebrate erythrocytes, as well as a correlation between cell and nucleus size. Mammalian erythrocytes, which do not contain nuclei, are considerably smaller than those of most other vertebrates.

Erythrocytes consist mainly of hemoglobin, a complex metalloprotein containing heme groups whose iron atoms temporarily bind to oxygen molecules (O2) in the lungs or gills and release them throughout the body. Oxygen can easily diffuse through the red blood cell's cell membrane. Hemoglobin in the erythrocytes also carries some of the waste product carbon dioxide back from the tissues; most waste carbon dioxide, however, is transported back to the pulmonary capillaries of the lungs as bicarbonate (HCO3) dissolved in the blood plasma. Myoglobin, a compound related to hemoglobin, acts to store oxygen in muscle cells.

The color of erythrocytes 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, appearing bluish through the vessel wall and skin. Pulse oximetry takes advantage of this color change to directly measure the arterial blood oxygen saturation using colorimetric techniques. Hemoglobin also has a very high affinity for carbon monoxide, forming carboxyhaemoglobin 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.

The sequestration of 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 viscous blood, higher concentrations of oxygen, and better diffusion of oxygen from the blood to the tissues. The size of erythrocytes varies widely among vertebrate species; erythrocyte width is on average about 25% larger than capillary diameter, and it has been hypothesized that this improves the oxygen transfer from erythrocytes to tissues.

The only known vertebrates without erythrocytes are the crocodile icefishes (family Channichthyidae); they live in very oxygen-rich cold water and transport oxygen freely dissolved in their blood. While they do not use hemoglobin anymore, remnants of hemoglobin genes can be found in their genome.

Nucleus

Erythrocytes in mammals are anucleate when mature, meaning that they lack a cell nucleus. In comparison, the erythrocytes of other vertebrates have nuclei; the only known exceptions are salamanders of the Batrachoseps genus and fish of the Maurolicus genus with closely related species.

The elimination of the nucleus in vertebrate erythrocytes has been offered as an explanation for the subsequent accumulation of non-coding DNA in the genome. The argument runs as follows: Efficient gas transport requires erythrocytes 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.

Secondary functions

When erythrocytes undergo shear stress in constricted vessels, they release ATP, which causes the vessel walls to relax and dilate so as to promote normal blood flow.

When their hemoglobin molecules are deoxygenated, erythrocytes release S-nitrosothiols, which also act to dilate blood vessels, thus directing more blood to areas of the body depleted of oxygen.

Erythrocytes can also synthesize nitric oxide enzymatically, using L-arginine as substrate, as do endothelial cells. Exposure of erythrocytes to physiological levels of shear stress activates nitric oxide synthase and export of nitric oxide, which may contribute to the regulation of vascular tonus.

Erythrocytes 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 erythrocytes converting its sulfur compounds into hydrogen sulfide.

Erythrocytes also play a part in the body's immune response: when lysed by pathogens such as bacteria, their hemoglobin releases free radicals, which break down the pathogen's cell wall and membrane, killing it.

Mammalian erythrocytes

Typical mammalian erythrocytes: (a) seen from surface; (b) in profile, forming rouleaux; (c) rendered spherical by water; (d) rendered crenate by salt. (c) and (d) do not normally occur in the body.

Mammalian erythrocytes are unique among the vertebrates as they are non-nucleated cells in their mature form. These cells have nuclei during early phases of erythropoiesis, but extrude them during development as they mature in order to provide more space for hemoglobin. In mammals, erythrocytes also lose all other cellular organelles such as their mitochondria, Golgi apparatus and endoplasmic reticulum.

As a result of not containing mitochondria, these cells use none of the oxygen they transport; instead they produce the energy carrier ATP by the glycolysis of glucose and lactic acid fermentation on the resulting pyruvate.

Because of the lack of nuclei and organelles, mature red blood cells do not contain DNA and cannot synthesize any RNA, and consequently cannot divide and have limited repair capabilities. This also ensures that no virus can evolve to target mammalian red blood cells.

Mammalian erythrocytes 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 distinctive biconcave shape optimises the flow properties of blood in the large vessels, such as maximization of laminar flow and minimization of platelet scatter, which suppresses their atherogenic activity in those large vessels. 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 erythrocyte morphologies: small and highly ovaloid cells in llamas 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. Overall, mammalian erythrocytes are remarkably flexible and deformable so as to squeeze through tiny capillaries, as well as to maximize their apposing surface by assuming a cigar shape, where they efficiently release their oxygen load.

In large blood vessels, 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.

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.

Scanning electron micrograph of blood cells. From left to right: human erythrocyte, thrombocyte (platelet), leukocyte.

Human erythrocytes

Two drops of blood are shown with a bright red oxygenated drop on the left and a deoxygenated drop on the right.
An animation of a typical human red blood cell cycle in the circulatory system. This animation occurs at real time (20 seconds of cycle) and shows the red blood cell deform as it enters capillaries, as well as changing color as it alternates in states of oxygenation along the circulatory system.

A typical human erythrocyte has a disk diameter of approximately 6.2–8.2 µm and a thickness at the thickest point of 2–2.5 µm and a minimum thickness in the centre of 0.8–1 µm, being much smaller than most other human cells. These cells have an average volume of about 90 fL with a surface of about 136 μm, and can swell up to a sphere shape containing 150 fL, without membrane distension.

Adult humans have roughly 20–30 × 10 (20–30 trillion) red blood cells at any given time, comprising approximately one quarter of the total human body cell number (women have about 4 to 5 million erythrocytes per microliter (cubic millimeter) of blood and men about 5 to 6 million; 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 platelets in each microliter of human blood.

Human red blood cells take on average 20 seconds to complete one cycle of circulation.

As red blood cells contain no nucleus, protein biosynthesis is currently assumed to be absent in these cells, although a recent study indicates the presence of all the necessary biomachinery in the cells to do so.

The blood's red color is due to the spectral properties of the hemic iron ions in hemoglobin. Each human red blood cell contains approximately 270 million of these hemoglobin biomolecules, each carrying four heme groups; hemoglobin comprises about a third of the total cell volume. This protein is responsible for the transport of more than 98% of the oxygen (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. (See Human iron metabolism.)

Life cycle

Human erythrocytes are produced through a process named erythropoiesis, developing from committed stem cells to mature erythrocytes 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). At the end of their lifespan, they become senescent, and are removed from circulation. In many chronic diseases, the lifespan of the erythrocytes is markedly reduced (e.g. patients requiring haemodialysis).

Erythropoiesis

Erythropoiesis is the development process by which new erythrocytes are produced; it lasts about 7 days. Through this process erythrocytes are continuously produced in the red bone marrow of large bones, at a rate of about 2 million per second in a healthy adult. (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 reticulocytes; these comprise about 1% of circulating red blood cells.

Functional lifetime

The functional lifetime of an erythrocyte is about 100–120 days, during which time the erythrocytes 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.

Senescence

The aging erythrocyte undergoes changes in its plasma membrane, making it susceptible to selective recognition by macrophages and subsequent phagocytosis in the mononuclear phagocyte system (spleen, liver and lymph nodes), thus removing old and defective cells and continually purging the blood. This process is termed eryptosis, erythrocyte programmed cell death. 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, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is observed in erythrocytes lacking the cGMP-dependent protein kinase type I or the AMP-activated protein kinase AMPK. Inhibitors of eryptosis include erythropoietin, nitric oxide, catecholamines 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 Fe 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 erythrocytes are removed in this manner from the circulation before they are old enough to hemolyze. Hemolyzed hemoglobin is bound to a protein in plasma called haptoglobin, which is not excreted by the kidney.

Membrane composition

The membrane of the red blood cell plays many roles that aid in regulating their surface deformability, flexibility, adhesion to other cells and immune recognition. These functions are highly dependent on its composition, which defines its properties. 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 proteins, 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 erythrocytes are proteins. The other half are lipids, namely phospholipids and cholesterol.

Membrane lipids

The most common erythrocyte cell membrane lipids, schematically disposed as they are distributed on the bilayer. Relative abundances are not at scale.

The erythrocyte 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 phospholipids 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

Inner monolayer

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 “Flippases” move phospholipids from the outer to the inner monolayer, while others called “floppases” 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 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.

The presence of specialized structures named "lipid rafts" in the erythrocyte membrane have been described by recent studies. These are structures enriched in cholesterol and sphingolipids associated with specific membrane proteins, namely flotillins, stomatins (band 7), G-proteins, and β-adrenergic receptors. Lipid rafts that have been implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate β2-adregenic receptor signaling and increase cAMP levels, and thus regulating entry of malarial parasites into normal red cells.

Membrane proteins

Red blood cell membrane proteins separated by SDS-Page and silverstained

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 erythrocyte (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 erythrocyte. 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 types of humans are due to variations in surface glycoproteins of erythrocytes. Disorders of the proteins in these membranes are associated with many disorders, such as hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, and paroxysmal nocturnal hemoglobinuria.

The red blood cell membrane proteins organized according to their function:

Red Blood Cell membrane major proteins

Transport

Cell adhesion

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 glycolytic enzymes, the presumptive CO2 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 function);
    • RhAG – also involved in transport, defines associated unusual blood group phenotype Rhmod.

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 erythrocyte is −15.7 millivolts (mV). 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 mV.

Clinical notes

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. During 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 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 −79 °C or −110 °F) 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 in order to stimulate production of red blood cells. Both practices are banned by the World Anti-Doping Agency.

Artificially grown red blood cells

In 2008 it was reported that human embryonic stem cells had been successfully coaxed into becoming erythrocytes in the lab. The difficult step was to induce the cells to eject their nucleus; this was achieved by growing the cells on stromal cells from the bone marrow. It is hoped that these artificial erythrocytes can eventually be used for blood transfusions.

Diseases and diagnostic tools

Affected by Sickle-cell disease, red blood cells alter shape and threaten to damage internal organs.

Blood diseases involving the red blood cells include:

  • Anemias (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
  • 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 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.
Effect of osmotic pressure on blood cells
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.
  • Polycythemias (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.
  • Hemolytic transfusion reaction is the destruction of donated red blood cells after a transfusion, mediated by host antibodies, often as a result of a blood type mismatch.

Several blood tests involve red blood cells, including the RBC count (the number of red blood cells per volume of blood), the hematocrit (percentage of blood volume occupied by red blood cells), and the erythrocyte sedimentation rate. 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. The blood type needs to be determined to prepare for a blood transfusion or an organ transplantation.

See also

References

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