Red blood cell survival: Normal values and measurement
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders
- Section Editor — Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
During its approximately four-month lifespan, the human red blood cell (RBC) travels approximately 300 miles, making approximately 170,000 circuits through the heart, enduring cycles of osmotic swelling and shrinkage while traveling through the kidneys and lungs, and an equal number of deformations while passing through capillary beds [1,2]. It has been speculated that accumulated damage to the RBC, especially to its membrane, renders the aging RBC unfit to circulate, leading to its destruction, via mechanisms that are poorly understood.
The normal time of RBC senescent (age-related) death in adults is approximately 110 to 120 days. Hemolysis can therefore be arbitrarily defined as a shortening in the survival of circulating RBCs to a value of less than 100 days.
This topic will review the mechanisms of normal RBC destruction and the methods used to measure RBC survival, which may be used in the evaluation of patients with suspected hemolysis . Approaches to the patient with hemolytic anemia and with anemia in general are presented separately. (See "Approach to the diagnosis of hemolytic anemia in the adult" and "Approach to the adult patient with anemia".)
MECHANISMS OF RBC DESTRUCTION
In normal subjects, RBCs are destroyed by two different mechanisms, one related to increasing RBC age (senescence) and the other to a random process that destroys intact RBCs, or portions of an intact RBC (eg, vesicles) independent of their age (random hemolysis). These two processes may not be fully independent of one another .
Senescence — Virtually all RBCs in normal subjects die of processes associated with "wear and tear" associated with prolonged circulation within the intravascular space. These processes include, but are not limited to :
- ALLISON AC. Turnovers of erythrocytes and plasma proteins in mammals. Nature 1960; 188:37.
- Lux SE. Spectrin-actin membrane skeleton of normal and abnormal red blood cells. Semin Hematol 1979; 16:21.
- Franco RS. The measurement and importance of red cell survival. Am J Hematol 2009; 84:109.
- Willekens FL, Werre JM, Groenen-Döpp YA, et al. Erythrocyte vesiculation: a self-protective mechanism? Br J Haematol 2008; 141:549.
- Landaw SA. Factors that accelerate or retard red blood cell senescence. Blood Cells 1988; 14:47.
- Arese P, Turrini F, Schwarzer E. Band 3/complement-mediated recognition and removal of normally senescent and pathological human erythrocytes. Cell Physiol Biochem 2005; 16:133.
- Kriebardis AG, Antonelou MH, Stamoulis KE, et al. Storage-dependent remodeling of the red blood cell membrane is associated with increased immunoglobulin G binding, lipid raft rearrangement, and caspase activation. Transfusion 2007; 47:1212.
- Karnchanaphanurach P, Mirchev R, Ghiran I, et al. C3b deposition on human erythrocytes induces the formation of a membrane skeleton-linked protein complex. J Clin Invest 2009; 119:788.
- Li CK, Li EK. Mechanical fatigue as a possible determinant of in vivo longevity of red blood cells. IEEE Trans Biomed Eng 1983; 30:226.
- Korolnek T, Hamza I. Macrophages and iron trafficking at the birth and death of red cells. Blood 2015.
- EADIE GS, BROWN IW Jr. The potential life span and ultimate survival of fresh red blood cells in normal healthy recipients as studied by simultaneous Cr51 tagging and differential hemolysis. J Clin Invest 1955; 34:629.
- CLINE MJ, BERLIN NI. Red blood cell life span using DFP as a cohort label. Blood 1962; 19:715.
- SHEMIN D, RITTENBERG D. The life span of the human red blood cell. J Biol Chem 1946; 166:627.
- Tartakover-Matalon S, Shoham-Kessary H, Foltyn V, Gershon H. Receptors involved in the phagocytosis of senescent and diamide-oxidized human RBCs. Transfusion 2000; 40:1494.
- Galili U, Flechner I, Knyszynski A, et al. The natural anti-alpha-galactosyl IgG on human normal senescent red blood cells. Br J Haematol 1986; 62:317.
- Kay MM, Wyant T, Goodman J. Autoantibodies to band 3 during aging and disease and aging interventions. Ann N Y Acad Sci 1994; 719:419.
- Kuypers FA, Yuan J, Lewis RA, et al. Membrane phospholipid asymmetry in human thalassemia. Blood 1998; 91:3044.
- Gifford SC, Derganc J, Shevkoplyas SS, et al. A detailed study of time-dependent changes in human red blood cells: from reticulocyte maturation to erythrocyte senescence. Br J Haematol 2006; 135:395.
- Marinkovic D, Zhang X, Yalcin S, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 2007; 117:2133.
- Khandelwal S, van Rooijen N, Saxena RK. Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation. Transfusion 2007; 47:1725.
- Burger P, Hilarius-Stokman P, de Korte D, et al. CD47 functions as a molecular switch for erythrocyte phagocytosis. Blood 2012; 119:5512.
- Franco RS, Puchulu-Campanella ME, Barber LA, et al. Changes in the properties of normal human red blood cells during in vivo aging. Am J Hematol 2013; 88:44.
- Sosale NG, Rouhiparkouhi T, Bradshaw AM, et al. Cell rigidity and shape override CD47's "self"-signaling in phagocytosis by hyperactivating myosin-II. Blood 2015; 125:542.
- Willekens FL, Roerdinkholder-Stoelwinder B, Groenen-Döpp YA, et al. Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation. Blood 2003; 101:747.
- Ashby W. THE DETERMINATION OF THE LENGTH OF LIFE OF TRANSFUSED BLOOD CORPUSCLES IN MAN. J Exp Med 1919; 29:267.
- Khera PK, Smith EP, Lindsell CJ, et al. Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation. Am J Hematol 2015; 90:50.
- Zeiler T, Müller JT, Hasse C, et al. Flow cytometric determination of RBC survival in autoimmune hemolytic anemia. Transfusion 2001; 41:493.
- Strauss RG, Mock DM, Widness JA, et al. Posttransfusion 24-hour recovery and subsequent survival of allogeneic red blood cells in the bloodstream of newborn infants. Transfusion 2004; 44:871.
- Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 2009; 113:4094.
- OWREN PA. Congenital hemolytic jaundice; the pathogenesis of the hemolytic crisis. Blood 1948; 3:231.
- Mock DM, Lankford GL, Widness JA, et al. Measurement of red cell survival using biotin-labeled red cells: validation against 51Cr-labeled red cells. Transfusion 1999; 39:156.
- Cowley H, Wojda U, Cipolone KM, et al. Biotinylation modifies red cell antigens. Transfusion 1999; 39:163.
- Valeri CR, MacGregor H, Giorgio A, et al. Comparison of radioisotope methods and a nonradioisotope method to measure the RBC volume and RBC survival in the baboon. Transfusion 2003; 43:1366.
- Cohen RM, Franco RS, Khera PK, et al. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood 2008; 112:4284.
- Mock DM, Matthews NI, Zhu S, et al. Red blood cell (RBC) survival determined in humans using RBCs labeled at multiple biotin densities. Transfusion 2011; 51:1047.
- MOLLISON PL. Further observations on the normal survival curve of 51 Cr-labelled red cells. Clin Sci 1961; 21:21.
- Guis MS, Lande WM, Mohandas N, et al. Prolongation of sickle cell survival by dimethyl adipimidate is compromised by immune sensitization. Blood 1984; 64:161.
- McCurdy PR, Sherman AS. Irreversibly sickled cells and red cell survival in sickle cell anemia: a study with both DF32P and 51CR. Am J Med 1978; 64:253.
- Sebring ES, Polesky HF. Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects. Transfusion 1990; 30:344.
- Dziegiel MH, Koldkjaer O, Berkowicz A. Massive antenatal fetomaternal hemorrhage: evidence for long-term survival of fetal red blood cells. Transfusion 2005; 45:539.
- Najean Y, Cacchione R, Dresch C, Rain JD. Methods of evaluating the sequestration site of red cells labelled with 51Cr: a review of 96 cases. Br J Haematol 1975; 29:495.
- Recommended method for radioisotope red-cell survival studies. International Committee for Standardization in Haematology. Br J Haematol 1980; 45:659.
- Ferrant A, Cauwe F, Michaux JL, et al. Assessment of the sites of red cell destruction using quantitative measurements of splenic and hepatic red cell destruction. Br J Haematol 1982; 50:591.
- HUFF RL, HENNESSY TG, AUSTIN RE, et al. Plasma and red cell iron turnover in normal subjects and in patients having various hematopoietic disorders. J Clin Invest 1950; 29:1041.
- Ricketts C, Jacobs A, Cavill I. Ferrokinetics and erythropoiesis in man: the measurement of effective erythropoiesis, ineffective erythropoiesis and red cell lifespan using 59Fe. Br J Haematol 1975; 31:65.
- Pollycove M. Iron metabolism and kinetics. Semin Hematol 1966; 3:235.
- Landaw SA, Callahan EW Jr, Schmid R. Catabolism of heme in vivo: comparison of the simultaneous production of bilirubin and carbon monoxide. J Clin Invest 1970; 49:914.
- Berlin NI, Berk PD. Quantitative aspects of bilirubin metabolism for hematologists. Blood 1981; 57:983.
- Stevenson DK, Vreman HJ, Oh W, et al. Bilirubin production in healthy term infants as measured by carbon monoxide in breath. Clin Chem 1994; 40:1934.
- Mitlyng BL, Singh JA, Furne JK, et al. Use of breath carbon monoxide measurements to assess erythrocyte survival in subjects with chronic diseases. Am J Hematol 2006; 81:432.
- Landaw SA, Winchell HS. Endogenous production of 14CO: A method for calculation of RBC life-span in vivo. Blood 1970; 36:642.
- MECHANISMS OF RBC DESTRUCTION
- Random RBC death
- DETERMINATION OF RBC LIFESPAN
- Utility of RBC survival studies
- Estimation of red cell survival from the reticulocyte count
- Random label RBC survival method
- - RBC half-time
- Time of RBC senescence
- - Sites of RBC destruction
- Cohort labeling technique
- Quantitative erythrokinetic studies
- Endogenous carbon monoxide production