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Modulation of Erythrocyte Membrane Mechanical Stability by 2,3-Diphosphoglycerate in the Neonatal Poikilocytosis/Elliptocytosis Syndrome William C

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Modulation of Erythrocyte Membrane Mechanical Stability by 2,3-Diphosphoglycerate in the Neonatal Poikilocytosis/Elliptocytosis Syndrome William C Modulation of Erythrocyte Membrane Mechanical Stability by 2,3-Diphosphoglycerate in the Neonatal Poikilocytosis/Elliptocytosis Syndrome William C. Mentzer, Jr.,* Terri A. Iarocci,* Narla Mohandas,* Peter A. Lane,* Byron Smith,* Jack Lazerson,t and Taru Hays *Departments ofPediatrics and Laboratory Medicine, University ofCalifornia, San Francisco, California 94102; $The Department ofPediatrics, University ofCalifornia, Davis, California 95616; §Denver Children's Hospital and the Department ofPediatrics, University ofColorado School ofMedicine, Denver, Colorado 80220 Abstract fetal and adult red cells (7-9). We therefore considered it more likely that developmental changes in nonskeletal red cell com- To explain the transient anemia and poikilocytosis seen during ponents capable ofinteracting with the underlying skeletal pro- infancy in hereditary elliptocytosis (HE), we resealed erythrocyte tein abnormality were responsible for transient neonatal poi- (RBC) ghosts from affected children or their elliptocytic parents kilocytosis and hemolysis. In this report, we provide evidence with 2,-diphosphoglycerate (DPG) (0-8 mM), a compound that that 2,3-diphosphoglycerate (DPG)' can dissociate the flawed dissociates membrane skeletons, then measured ghost mechan- membrane skeleton of elliptocytic ghosts, causing such prepa- ical stability in the ektacytometer. Without added 2,3-DPG, rations to reach the extreme levels of mechanical fragility char- ghost mechanical stability was subnormal in infantile poikilo- acteristic of hereditary pyropoikilocyte ghosts. cytosis (IP) and HE but was even more abnormal in hereditary We propose that the uniquely high levels of free 2,3-DPG pyropoikilocytosis (HPP). Addition of 2,3-DPG (2.55 mM) to in fetal red cells, a consequence ofthe extremely limited ability IP or HE ghosts, decreased their stability to that of HPP ghosts ofhemoglobin F to bind 2,3-DPG, render cells with an inherited (without 2,3-DPG). Nonphysiological 2,3-DPG levels (6-8 mM) membrane skeletal abnormality particularly susceptible to in were required to elicit a similar effect in normal ghosts. The data vivo fragmentation and premature destruction. suggest that free 2,3-DPG, present in neonatal RBC as a con- sequence ofdiminished binding to HbF, may render HE suscep- Methods tible to in vivo fragmentation. The developmental switch from fetal to adult hemoglobin, by diminishing available free 2,3-DPG, Glycerate-2,3-diphosphate (pentacyclohexylammonium salt) was pur- may explain the abatement of poikilocytosis and hemolytic ane- chased from Boehringer Mannheim, Indianapolis, IN; electrophoresis mia that accompanies maturation. reagents from Bio-Rad Laboratories, Richmond, CA; Seakem ME agarose from FMC Corporation, Rockland, ME; DFP from Sigma Chemi- cal Co., St. Louis, MO; and Trypsin-N-tosyl-L-phenylalanine chloro- Introduction methyl ketone (TPCK) from Worthington/Cooper Biomedical, Inc., Malvern, PA. Transient hemolytic anemia and bizarre erythrocyte morphol- The study protocol was approved by the Committee on Human Re- ogy, resembling that seen in hereditary pyropoikilocytosis, may search of the University of California, San Francisco. occur in young infants from kindreds in which one parent has Routine hematology. Routine blood counts were measured by elec- elliptocytosis (1-5). Affected infants, who have usually been tronic particle counter. The percentage ofhemoglobin F was determined Black, often require transfusion in early infancy for anemia or by alkali denaturation or by densitometric scanning of cellulose acetate hyperbilirubinemia. At - 6 mo of age, hemolytic anemia dis- hemoglobin electrophoresis strips. The percentage of elliptocytes was appears or diminishes in severity and, thereafter, erythrocyte determined by counting 500 cells on well separated areas ofa peripheral morphology becomes more purely elliptocytic, like that of the blood smear. affected parent. Red cell thermalfragility. Morphologic changes such as membrane The cause of these transient hematologic abnormalities is distortions or budding were studied by Nomarski interference phase mi- croscopy after heating red cells suspended in BSKG buffer (132 mM unknown. One proposed explanation is that the skeletal abnor- NaCl, 5 mM KCI, 10 mM NaHPO4, 11 mM glucose, 290 mosM, pH mality responsible for elliptocytosis is itselfdifferent in fetal red 7.4) to various temperatures between 370 and 50°C for 10 min (10). cells than in adult cells. Although there are definite differences Fragmentation of heated erythrocytes was estimated by measuring the that distinguish the membrane ofthe fetal red cell from that of accumulation of small particles using a Coulter Counter (model ZBI, adult erythrocytes (6), most available evidence indicates that the Coulter Electronics, Hialeah, FL) equipped with a channelizer 11(10). membrane skeleton and its component proteins are identical in Deformability measurements. The deformability of intact red cells was measured in the ektacytometer, a couette viscometer, which applies a well-defined laminar shear stress to the cell, while simultaneously mon- Address reprint requests to Dr. Mentzer, Room 2108, Building 20, San itoring the extent of cell deformation by laser defractometry (11). To Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA obtain information about initial cell surface area, surface area to volume 94110. ratio, and cell water content, the deformability of red cells was contin- Presented in part to the American Society of Hematology, Miami, FL, December 1984. Receivedfor publication 4 March 1986 and in revisedform 10 No- 1. Abbreviations used in this paper: DFP, diisopropyl fluorophosphate; vember 1986. DI, deformability index; DPG, diphosphoglycerate; HE, hereditary el- liptocytosis; HPP, hereditary pyropoikilocytosis; IP, infantile poikilo- J. Clin. Invest. cytosis; MCHC, mean corpuscular hemoglobin concentration; MCV, © The American Society for Clinical Investigation, Inc. mean corpuscular volume; PAGE, polyacrylamide gel electrophoresis; 0021-9738/87/03/0943/07 $ 1.00 PMSF, phenylmethylsulfonyl fluoride; TPCK, N-tosyl-L-phenylalanine Volume 79, March 1987, 943-949 chloromethyl ketone; T60, index ofred cell or ghost mechanical stability. Neonatal Poikilocytosis 943 uously recorded as the suspending medium osmolarity was linearly in- without any change in mechanical stability. All measurements were creased from 50 to 500 mosM/kg (1 1). completed in < 1 h from completion of ghost preparation. For deter- Membrane stability assay. We measured membrane resistance to mination of2,3-DGP levels, an aliquot ofthe packed ghosts were washed shear induced fragmentation by subjecting resealed ghosts to a constant and suspended in saline at a hematocrit of 30-40%, then extracted with shear stress of 575 dynes per square centimeter in the ektacytometer perchloric acid. To prepare the extracts, an aliquot (0.5 ml) of ghosts (12). Toward the end of 1984, the original analogue processing ektacy- was added to 1 ml of ice-cold 1% perchloric acid. The clear supernatant tometer was replaced by a second generation digital processing machine. was neutralized with 5 M potassium carbonate and stored for subsequent Ghost mechanical stability assays were run at a higher shear stress (650 assay. 2,3-DPG was assayed spectrophotometrically by the method of or 785 dyne/cm2) on this instrument. The major difference between the Keitt (18). two instruments was the geometric location ofthe areas ofthe diffraction pattern selected for scattered light intensity measurements to generate Case histories the deformability index (DI). In the earlier system, the DI values generated Family B. A.B., a Black infant born at term (birthweight, 3,525 g), re- were higher than in the later system. Because of these design changes, quired a two volume exchange transfusion at 48 h of life for hyperbili- the relative DI changes during membrane stability measurements were rubinemia. On the first day of life the hemoglobin was 13.4 g/dl, the different in the two systems. Ghosts were suspended in a dextran solution mean corpuscular volume (MCV) 79 fl, and the reticulocyte count 5%. of 97 centipoise (cp) viscosity and the ektacytometer chamber rotated Bizarre poikilocytes and elliptocytes were noted on the peripheral blood at a speed of 110-150 rpm to generate the desired shear stress. A decrease smear. At 19 wk ofage the hemoglobin reached a nadir of 7.4 g/dl. The in the DI generated by the ektacytometer has been shown to reflect frag- reticulocyte count was 12.8% and the spleen tip was palpable. At 51 wk mentation ofthe intact membranes into small, undeformable spherical ofage, the hemoglobin was normal (10.9 g/dl) but the reticulocyte count particles. As an index ofthe rate ofthis fragmentation process we selected remained elevated (3.8%), and the red cell indices were abnormal (MCV the time required for the DI to fall to 60% of its highest value (T60). 65 fl, [mean corpuscular hemoglobin count] MCHC 36.2%). At the age The 60% level was chosen because the rate offall in DI that accompanied of2 yr, following 2 d offever (1040) and diarrhea, he required transfusions fragmentation exhibited greater variability at lower levels. To minimize for an episode of severe anemia (Hb = 5.9 g/dl). Red cell morphology small, day-to-day variation in the absolute value ofthe T60 due to fluc- continued to resemble that ofhereditary pyropoikilocytosis and the spleen tuations in such uncontrolled variables as room temperature, we always was now palpable 2 cm below the left
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