On the other hand, clustering of Band 3 has bee reported to induce externalization of phosphatidylserine by a calcium- and oxidation-independent mechanism Koshkaryev et al. Eryptosis is the process of cell shrinkage and exposure of phosphatidylserine due influx of calcium ions that activates a scramblase resulting in redistribution of phospholipids in both leaflets Lang et al. Eryptosis may contribute to red cell clearance in diseased states, but its contribution to senescence-associated clearance is speculative.
Physiological processes that delay senescence may contribute to hypoxia-induced erythrocytosis Tang et al. The studies provided the first evidence suggesting that longer red cell survival, in addition to hypoxia stimulation of erythropoiesis contributes to hypoxia-induced erythrocytosis.
Lactadherin, also called milk fat globule epidermal growth factor 8, is an opsonin that binds to phosphatidylserine expressing cell, including red cells Hanayama et al. It has a phosphatidylserine binding domain, as well as an Arginine-Glycine-Aspartic acid RGD motif in one of its epidermal growth factor domains which mediates binding to integrins Andersen et al. Lactadherin-mediated erythrophagocytosis of phosphatidylserine expressing cells by integrins is proposed as a mechanism for clearance of senescent red cells by activated endothelial cells Fens et al.
However, red cell survival is normal in lactadherin deficient mice, and as discussed above, whether senescent red cells express greater amounts of phosphatidylserine is an issue of active debate Dasgupta et al. Physiologic response to hypoxia is the stimulation of red blood cell production.
Hypoxia-inducible factors HIFs orchestrate response to hypoxia and HIF-2 is the principal regulator of erythropoietin EPO production in kidney as underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis Prchal, Upon the rapid return to normoxia, the secondary erythrocytosis is overcorrected, as the accumulated, newly formed red cells undergo preferential destruction.
This process, termed neocytolysis , was originally observed in astronauts returning to earth after living in a zero gravity environment Rice et al. Return to normoxia from hypoxia results in generation of reactive oxygen species from increased mitochondrial mass that correlates with decreased expression of Bnip3L transcripts, a hypoxia regulated gene Sandoval et al. Bnip3L mediates removal of reticulocyte mitochondria that generate increased reactive oxygen species accompanied by reduced catalase activity mediated by hypoxia-regulated miR21 Song et al.
Rapid changes in hematocrit in human newborns also suggest that neocytolysis also occurs after birth. The hypoxic fetus has erythrocytosis at birth, but the neonate rapidly overcorrects its elevated red cell mass and becomes anemic in first 2 weeks of life Christensen et al.
In contrast to our limited understanding of the physiological red blood cell clearance of senescent red cells, the mechanisms involved in removal of abnormal erythrocytes hemolysis are understood in greater details. Premature destruction can occur in the circulation by lysis with the release of hemoglobin into the plasma intravascular hemolysis or by the macrophages in the spleen and liver extravascular hemolysis with little release of hemoglobin.
The spleen plays a major role here. Increased splenic clearance occurs due to injuries extrinsic events immunological targeting, mechanical or chemical injuries or due to intrinsic defects in red cells due to inherited defects in red cells cytoskeleton or enzymes.
Red cells with reduced deformability are unable to negotiate through narrow endothelial slits in the human spleen. Consequently, they are retained in the splenic cords and eventually destroyed by red pulp macrophages. The principal determinants of the red blood cell deformability are the ratio of cell surface area to volume determined by the shape , intracellular viscosity determined the physical properties of hemoglobin , and membrane elasticity determined by rheological properties of the membrane.
As discussed earlier, red cells traverse the interendothelial slit in splenic sinusoids. When normal deformity is compromised, sustained elongation results in loss of membrane due to vesiculation Li et al. Premature destruction occurs in many membrane disorders including hereditary spherocytosis, ovalocytosis, and pyropoikilocytosis. In addition to intrinsic membrane defects, the red cell membrane can be damaged by abnormalities in microcirculation due intravascular fibrin deposition and abnormal shearing due artificial heart valves, or severe aortic stenosis.
The fragment erythrocytes are rapidly removed by the reticuloendothelial system. Collectively these processes are called microangiopathic hemolytic anemia. Red cells efficiently transport oxygen throughout their lifespan unless they are damaged by ROS. Consequently, they have effective mechanism to quench ROS. Depletion of NADPH can occur in the G6PD deficiency, or structural hemoglobin abnormalities that predispose to hemoglobin oxidation, or exposure to oxidant drugs.
Oxidation of hemoglobin alters the quaternary structure allowing them to precipitate within the red cell and to form aggregates called Heinz bodies. Heinz bodies attach to the red cell membrane decreasing deformability, thereby rendering the affected cells susceptible to engulfment by sinusoidal macrophages of the spleen and liver to membranes decreases the deformability and other physical properties pliable of red cell membrane, rendering them to engulfment by macrophages in rich sinusoids of spleen and liver.
Macrophage-mediated removal of Heinz bodies leaves a defect in the erythrocyte membrane structure that may be seen as bite cells on microscopic examination of the peripheral blood smear. Antibody-mediated intravascular hemolysis occurs due to complement activation by the classical pathway. IgM antibodies fix complement more avidly than IgG antibodies because of their they are pentavalent rather than bivalent. Hence, the antigen density is a critical determinate of complement activation in IgG-mediated immune hemolytic anemia Garratty, As the macrophages do not express IgM Fc receptors Kubagawa et al.
Immune complexes activate the classical complement pathway by binding the C1q portion of the C1 complex. Exposure of the collagen-like regions of C1q makes it recognizable by macrophage complement receptor 1 CR1 Eggleton et al. Rather, during complement activation, the third component of complement C3 is cleaved to C3b, which can bind covalently to cell surface carbohydrate and peptide moieties.
Bound C3b is rapidly cleaved to an inactivated form, iC3b. Cell bound iC3b is rapidly degraded enzymatically to C3dg and C3d. IgG-mediated extravascular hemolysis is mediated by macrophages in the spleen and liver Eggleton et al.
IgG antibodies bind red cell antigens, and the Fc portion of the bound immunoglobulin is recognized by specific macrophage receptors that mediate phagocytosis of the opsonized erythrocytes. Phagocytosed red cells are targeted to phagolysosomes Mosser and Zhang, ITAM-induced phosphorylation activates signaling pathways, including phosphatidylinositol kinase and MAP kinase that induces efficient erythrophagocytosis such that little free hemoglobin is released into the circulation.
Intravenous immunoglobulin IVIG is a modestly effective treatment for autoimmune hemolytic anemia Flores et al. This review provides an overview of our current knowledge of the mechanisms involved red cell clearance.
Despite the plethora of investigations, our understanding of the molecular details of red cell clearance is incomplete. Recent progresses in in vivo red cell labeling and availability of novel proteomic techniques should provide the means to enhance our understanding of the processes that underlie red cell senescence. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aderem, A. Mechanisms of phagocytosis in macrophages. Ahrens, N. Allen, L. Molecular definition of distinct cytoskeletal structures involved in complement- and Fc receptor-mediated phagocytosis in macrophages. Allison, A. Enzyme activity as a function of age in the human erythrocyte.
Aminoff, D. Role of sialic acid in survival of erythrocytes in the circulation: interaction of neuraminidase-treated and untreated erythrocytes with spleen and liver at the cellular level.
Andersen, M. Biochemistry 36, — Ando, K. Evidence for accumulation of lipid hydroperoxides during the aging of human red blood cells in the circulation. Anniss, A. Expression of CD47 integrin-associated protein decreases on red blood cells during storage. Anosa, V. Postsplenectomy blood values, marrow cytology, erythrocyte life-span, and sequestration in mice.
Arndt, P. Rh null red blood cells with reduced CD47 do not show increased interactions with peripheral blood monocytes. Badior, K. Molecular mechanism for the red blood cell senescence clock. Bernstein, R. Alterations in metabolic energetics and cation transport during aging of red cells. Boas, F. Phosphatidylserine exposure and red cell viability in red cell aging and in hemolytic anemia.
Borun, E. The distribution of Fe59 tagged human erythrocytes in centrifuged specimens as a function of cell age. Bosman, G. The proteome of red cell membranes and vesicles during storage in blood bank conditions. Transfusion 48, — Bournazos, S.
The role and function of fcgamma receptors on myeloid cells. Bratosin, D. Flow cytometric approach to the study of erythrophagocytosis: evidence for an alternative immunoglobulin-independent pathway in agammaglobulinemic mice. Methods , — Bratton, D. Apoptotic cell recognition: will the real phosphatidylserine receptor s please stand up?
Bretscher, M. Phosphatidyl-ethanolamine: differential labelling in intact cells and cell ghosts of human erythrocytes by a membrane-impermeable reagent. Browne, T. Bruhns, P. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses.
Blood , — Calvez, J. Asymmetric distribution of phospholipids in spectrin-poor erythrocyte vesicles. Biochemistry 27, — Caron, E. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science , — Carrell, R. Haemoglobin—a frustrated oxidase? Implications for red cell metabolism. Hemoglobin 1, — Christensen, R. Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system.
Blood Cells Mol. Clark, M. Senescence of red blood cells: progress and problems. Cohen, N. Biochemical characterization of density-separated human erythrocytes. Acta , — The average life span of healthy red blood cells RBCs is days, but that can be shortened in pathologic conditions including sepsis and in illnesses like sickle cell disease that interfere with normal production of RBCs. The cells also can become damaged during coronary bypass surgery or dialysis, and blood transfusions may contain RBCs that were damaged in the process of collection, storage and administration.
Damaged RBCs can release unbound forms of iron-carrying hemoglobin, which can cause kidney injury, and can lead to anemia, reducing the delivery of oxygen to tissues. If disease-associated RBC damage overwhelms the body's ability to clear aged RBCs, toxic levels of free iron can be released.
In the current study, the research team used several different models of RBC damage, including blood from human bypass patients, to investigate the mechanisms involved in clearance of the cells and the recycling of their iron. Experiments in mice revealed that the presence of damaged RBCs in the bloodstream led to a rapid increase in a specific population of monocytes that took up the damaged cells and traveled to both the liver and the spleen.
But several hours later almost all of those RBCs were located within a population of specialized macrophages -- cells produced by monocytes that engulf and dispose of debris, damaged cells, and microbes -- that were observed only in the liver.
Those macrophages eventually disappeared once they were no longer needed. What are the changes associated with red cell maturation, adulthood and senescence? What are the determinants of red cell life span What are the determinants of red cell life span and clearance? What are the mechanisms in control of red cell mass in healthy humans and patients with various forms of anemia?
What are the markers of circulating red cell senescence and in cells during storage and transfusion? Blood loss anemias are fairly straightforward. In addition to bleeding from wounds or other lesions, these forms of anemia may be due to ulcers, hemorrhoids, inflammation of the stomach gastritis , and some cancers of the gastrointestinal tract.
The excessive use of aspirin or other nonsteroidal anti-inflammatory drugs such as ibuprofen can trigger ulceration and gastritis.
Excessive menstruation and loss of blood during childbirth are also potential causes. Anemias caused by faulty or decreased RBC production include sickle cell anemia, iron deficiency anemia, vitamin deficiency anemia, and diseases of the bone marrow and stem cells. Figure 5. Sickle Cells Sickle cell anemia is caused by a mutation in one of the hemoglobin genes.
Erythrocytes produce an abnormal type of hemoglobin, which causes the cell to take on a sickle or crescent shape. It can occur transiently in a person who is dehydrated; when water intake is inadequate or water losses are excessive, the plasma volume falls. As a result, the hematocrit rises. For reasons mentioned earlier, a mild form of polycythemia is chronic but normal in people living at high altitudes. Some elite athletes train at high elevations specifically to induce this phenomenon. Polycythemia vera can dangerously elevate the viscosity of blood, raising blood pressure and making it more difficult for the heart to pump blood throughout the body.
It is a relatively rare disease that occurs more often in men than women, and is more likely to be present in elderly patients those over 60 years of age. The most abundant formed elements in blood, erythrocytes are red, biconcave disks packed with an oxygen-carrying compound called hemoglobin. The hemoglobin molecule contains four globin proteins bound to a pigment molecule called heme, which contains an ion of iron.
In the bloodstream, iron picks up oxygen in the lungs and drops it off in the tissues; the amino acids in hemoglobin then transport carbon dioxide from the tissues back to the lungs. Erythrocytes live only days on average, and thus must be continually replaced. Worn-out erythrocytes are phagocytized by macrophages and their hemoglobin is broken down. The breakdown products are recycled or removed as wastes: Globin is broken down into amino acids for synthesis of new proteins; iron is stored in the liver or spleen or used by the bone marrow for production of new erythrocytes; and the remnants of heme are converted into bilirubin, or other waste products that are taken up by the liver and excreted in the bile or removed by the kidneys.
Answer the question s below to see how well you understand the topics covered in the previous section. Show Answers. Skip to main content. Module 2: The Cardiovascular System: Blood. Search for:. Erythrocytes Learning Objectives By the end of this section, you will be able to: Describe the anatomy of erythrocytes Discuss the various steps in the lifecycle of an erythrocyte Explain the composition and function of hemoglobin.
Figure 1. Summary of Formed Elements in Blood. Critical Thinking Questions young woman has been experiencing unusually heavy menstrual bleeding for several years. She follows a strict vegan diet no animal foods. She is at risk for what disorder, and why?
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