scholarly journals Pathophysiological Relevance of Renal Medullary Conditions on the Behaviour of Red Cells From Patients With Sickle Cell Anaemia

2021 ◽  
Vol 12 ◽  
Author(s):  
David C.-Y. Lu ◽  
Rasiqh Wadud ◽  
Anke Hannemann ◽  
David C. Rees ◽  
John N. Brewin ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Renal Medulla ◽  
Red Cells ◽  
Red Cell ◽  
Sickle Cells ◽  
Hypoxic Conditions ◽  
Intracellular Ca ◽  
Concentrate Urine ◽  
Abnormal Haemoglobin

Red cells from patients with sickle cell anaemia (SCA) contain the abnormal haemoglobin HbS. Under hypoxic conditions, HbS polymerises and causes red cell sickling, a rise in intracellular Ca2+ and exposure of phosphatidylserine (PS). These changes make sickle cells sticky and liable to lodge in the microvasculature, and so reduce their lifespan. The aim of the present work was to investigate how the peculiar conditions found in the renal medulla – hypoxia, acidosis, lactate, hypertonicity and high levels of urea – affect red cell behaviour. Results show that the first four conditions all increased sickling and PS exposure. The presence of urea at levels found in a healthy medulla during antidiuresis, however, markedly reduced sickling and PS exposure and would therefore protect against red cell adherence. Loss of the ability to concentrate urine, which occurs in sickle cell nephropathy would obviate this protective effect and may therefore contribute to pathogenesis.

scholarly journals Yoda1 and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
R. Wadud ◽  
A. Hannemann ◽  
D. C. Rees ◽  
J. N. Brewin ◽  
J. S. Gibson
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Red Cells ◽  
Mechanosensitive Channel ◽  
Sickle Cells ◽  
Molecular Identity ◽  
Calphostin C ◽  
Intracellular Ca ◽  
Pkc Inhibitors ◽  
Low Levels

AbstractPhosphatidylserine (PS) exposure is increased in red cells from sickle cell anaemia (SCA) patients. Externalised PS is prothrombotic and attractive to phagocytes and activated endothelial cells and thus contributes to the anaemic and ischaemic complications of SCA. The mechanism of PS exposure remains uncertain but it can follow increased intracellular Ca2+ concentration ([Ca2+]i). Normally, [Ca2+]i is maintained at very low levels but in sickle cells, Ca2+ permeability is increased, especially following deoxygenation and sickling, mediated by a pathway sometimes called Psickle. The molecular identity of Psickle is also unclear but recent work has implicated the mechanosensitive channel, PIEZO1. We used Yoda1, an PIEZO1 agonist, to investigate its role in sickle cells. Yoda1 caused an increase in [Ca2+]i and PS exposure, which was inhibited by its antagonist Dooku1 and the PIEZO1 inhibitor GsMTx4, consistent with functional PIEZO1. However, PS exposure did not necessitate an increase in [Ca2+]i. Two PKC inhibitors were also tested, chelerytherine chloride and calphostin C. Both reduced PS exposure whilst chelerytherine chloride also reduced Yoda1-induced increases in [Ca2+]i. Findings are therefore consistent with the presence of PIEZO1 in sickle cells, able to mediate Ca2+ entry but that PKC was also involved in both Ca2+ entry and PS exposure.

scholarly journals The role of WNK in modulation of KCl cotransport activity in red cells from normal individuals and patients with sickle cell anaemia

2019 ◽  
Vol 471 (11-12) ◽  
pp. 1539-1549
Author(s):  
David C.-Y. Lu ◽  
Anke Hannemann ◽  
Rasiqh Wadud ◽  
David C. Rees ◽  
John N. Brewin ◽  
...  
Keyword(s):  
Oxygen Tension ◽  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Kinase Inhibitors ◽  
Red Cells ◽  
Red Cell ◽  
Sickle Cells ◽  
Kcl Cotransport ◽  
Pre Treatment

AbstractAbnormal activity of red cell KCl cotransport (KCC) is involved in pathogenesis of sickle cell anaemia (SCA). KCC-mediated solute loss causes shrinkage, concentrates HbS, and promotes HbS polymerisation. Red cell KCC also responds to various stimuli including pH, volume, urea, and oxygen tension, and regulation involves protein phosphorylation. The main aim of this study was to investigate the role of the WNK/SPAK/OSR1 pathway in sickle cells. The pan WNK inhibitor WNK463 stimulated KCC with an EC50 of 10.9 ± 1.1 nM and 7.9 ± 1.2 nM in sickle and normal red cells, respectively. SPAK/OSR1 inhibitors had little effect. The action of WNK463 was not additive with other kinase inhibitors (staurosporine and N-ethylmaleimide). Its effects were largely abrogated by pre-treatment with the phosphatase inhibitor calyculin A. WNK463 also reduced the effects of physiological KCC stimuli (pH, volume, urea) and abolished any response of KCC to changes in oxygen tension. Finally, although protein kinases have been implicated in regulation of phosphatidylserine exposure, WNK463 had no effect. Findings indicate a predominant role for WNKs in control of KCC in sickle cells but an apparent absence of downstream involvement of SPAK/OSR1. A more complete understanding of the mechanisms will inform pathogenesis whilst manipulation of WNK activity represents a potential therapeutic approach.

scholarly journals Role of Emergency Automated Red Cell Exchange in Sickle Cell Crisis: A Case Report

2020 ◽  
Vol 13 ◽  
pp. 117954762097020
Author(s):  
Anubhav Gupta ◽  
Kiran Chaudhary ◽  
Rajnish Kaushik
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Symptomatic Improvement ◽  
Red Cells ◽  
Acute Chest Syndrome ◽  
Compound Heterozygous ◽  
Red Cell ◽  
Transfusion Therapy ◽  
Sickle Cell Crisis ◽  
Patient At Risk

For many years main stay of treatment for sickle cell anaemia was transfusion therapy. But repeated transfusions put the patient at risk of iron overload. Automated red cell exchange is an evolving and newer technique which rapidly removes the sickle cells and has benefit in decreasing sickle cell load and related complications. Red cell exchange is a therapeutic procedure in which the patient’s whole blood is processed centrifugally in cell separator. Patient’s red cells are separated from other blood components and removed and replaced with donor red cells and colloids. We report our first experience of automated red cell exchange in 24-year-old female diagnosed case of sickle cell anaemia presented to us with acute chest syndrome with septic shock. Red cell exchange was planned to tide over the acute sickle cell crisis and provide symptomatic improvement. We also highlight that compound heterozygous thalassaemia could be associated with sickle cell disease which could make the diagnosis difficult. New generation automated Apheresis equipment’s provides better monitoring of the procedure that can be useful in severely ill patients also.

scholarly journals New Observations on Sickle Cells

Blood ◽  
1954 ◽  
Vol 9 (1) ◽  
pp. 39-45 ◽  
Author(s):  
M. BESSIS ◽  
M. BRICKA ◽  
J. BRETON-GORIUS ◽  
J. TABUIS
Keyword(s):  
Electron Microscope ◽  
Sickle Cell ◽  
Special Form ◽  
Phase Contrast ◽  
Red Cells ◽  
Red Cell ◽  
Surface Layers ◽  
Characteristic Appearance ◽  
Sickle Cells

Abstract Observations made on sickle cells with phase contrast and with the electron microscope lead to the following conclusions. 1. When the red cell sickles, its oscillatory movements cease. 2. Spherical red cells give rise to a special form of sickle cell. 3. Myelin forms, whether attached to the cell or free, become rigid when the tension of oxygen is reduced. 4. The electron microscope, combined with the technic of moulage, shows that the sickle cell contains striated rod-like structures, which give a characteristic appearance to the surface of the sickle cell. 5. Agglutination by appropriate antisera does not occur to any extent in sickled cells, because these rigid structures do not form myelin forms. This is additional evidence of the importance of the formation of viscous surface layers already described as part of the mechanism of agglutination.

scholarly journals Physical Properties of Red Cells as Related to Effects in Vivo. II. Effect of Thermal Treatment on Rigidity of Red Cells, Stroma and the Sickle Cell

Blood ◽  
1968 ◽  
Vol 32 (6) ◽  
pp. 862-871 ◽  
Author(s):  
THOMAS HALE HAM ◽  
RICHARD W. SAYRE ◽  
REBECCA F. DUNN ◽  
JOHN R. MURPHY
Keyword(s):  
Thermal Treatment ◽  
Sickle Cell ◽  
Osmotic Fragility ◽  
Red Cells ◽  
Red Cell ◽  
Sickle Cells ◽  
Sonic Treatment ◽  
Physiologic Saline ◽  
Shape Changes

Abstract Heating of human or dog red cells at 49 C. for 15 minutes or 60 minutes increased resistance to packing by a centrifugal force, increased viscosity and deformed them. After 15 minutes of heating, osmotic fragility was usually normal but was elevated after 60 minutes with the formation of spheroidal cells. The increase in viscosity caused by heating red cells at 49 C. for 60 minutes did not appear to result from the effect of heat on the hemoglobin or the hemolysis products of red cells disrupted by sonic treatment. The heating of intact human or dog red cell stroma in serum, or stroma washed multiple times in physiologic saline however, regularly increased their viscosity and produced buds and microstroma. The rigidity of stroma was increased by heating, probably accounting for the increased viscosity of heated intact red cells. The rigidity of heated stroma of red cells was further demonstrated by showing that the shape changes of the sickling process could be prevented in large part by the heating of sickle cells. Heating did not, however, prevent tactoid formation in stroma-free sickle-cell hemoglobin solutions.

scholarly journals Vaso-occlusion by sickle cells: evidence for selective trapping of dense red cells

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1162-1166 ◽  
Author(s):  
DK Kaul ◽  
ME Fabry ◽  
RL Nagel
Keyword(s):  
Density Gradient ◽  
Sickle Cell ◽  
Morphological Analysis ◽  
Microvascular Obstruction ◽  
Perfusion Pressure ◽  
Peripheral Resistance ◽  
Red Cells ◽  
Arterial Perfusion ◽  
Sickle Cells ◽  
Sickle Cell Crisis

We have characterized the type of red cells from sickle cell patients that were trapped in the course of sickle-cell vaso-occlusion. In addition, the perfusion conditions (arterial perfusion pressure [Pa] and oxygen tension [PO2]) leading to experimentally induced vaso- occlusion in the artificially perfused, innervated mesocecum microvascular preparation were determined. Microvascular obstruction was induced by decrease in Pa; the lower the Pa, the greater the peripheral resistance as well as the extent of obstruction. The cells involved in the obstruction were recovered by vasodilation (secondary to denervation) and increase in Pa. Densitometric analysis of density gradient-separated infused and trapped cells was supplemented with morphological analysis to ascertain the involvement of density classes as well as morphological types seen in oxy and deoxy sickle blood. The trapping phenomenon was sensitive to PO2. Percentage of densest gradient classes, ie, fraction 3 (F3; mainly dense unsicklable SS discocytes [USDs]) and fraction 4 (F4; irreversibly sickled cells [ISCs] and the densest discocytes), showed a significant increase in trapping when perfusion was switched from oxy to deoxy perfusate. Morphological analysis revealed that unsicklable SS discocytes are more effectively trapped when deoxygenated. The deoxygenation of infused cells did not further change the percentage of ISCs trapped, suggesting that ISCs are equally capable of sequestration in the oxy and the deoxy states. The venous effluent showed a selective and significant depletion of dense cells (F4) and ISC counts at all Pa. We conclude that the progressive obstruction of the microcirculation by sickle cells involves selective sequestration of the densest classes of cells and that this mechanism might explain their partial disappearance during painful sickle cell crisis.

scholarly journals Reticulocyte Survival in Sickle Cell Anemia: Effect of Cyanate

Blood ◽  
1972 ◽  
Vol 40 (5) ◽  
pp. 733-739 ◽  
Author(s):  
Blanche P. Alter ◽  
Yuet Wai Kan ◽  
David G. Nathan
Keyword(s):  
Cell Survival ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Red Cells ◽  
Red Cell ◽  
Hemoglobin Molecule ◽  
Red Cell Survival ◽  
And Control

Abstract Cyanate prevents sickling in vitro and apparently prolongs the survival of 51Cr-tagged sickle erythrocytes in vivo. Cautious interpretation is required because the effects of cyanate on 51Cr binding to sickle and fetal hemoglobin-containing red cells are unknown, and comparison of the effect of cyanate on sickle red cell survival to control red cell survival must be performed sequentially. We have studied the survival of sickle reticulocytes utilizing radioactive amino acids that are incorporated into hemoglobin. Two informed adult patients with sickle cell disease were studied. In each study, two 50-ml samples of blood were incubated separately with 14C- and 3H-leucine for 2 hr, after which 50 mM cyanate was added to one aliquot for 1 hr. The cells were then washed and reinfused. Frequent venous samples were obtained, and the specific activities of 14C and 3H in the hemoglobin were followed. The t ½ of the carbamylated cells was tripled, but remained below normal. This method provides a generally useful measurement of the influence of drugs bound to red cells on reticulocyte lifespan. The labels are incorporated into the hemoglobin molecule of the reticulocyte, and simultaneous comparison of the survivals of the same cohort of drug-treated and control cells is achieved.

scholarly journals Increased Ca++, Mg++, and Na+ + K+ ATPase activities in erythrocytes of sickle cell anemia

Blood ◽  
1982 ◽  
Vol 60 (6) ◽  
pp. 1332-1336 ◽  
Author(s):  
MG Luthra ◽  
DA Sears
Keyword(s):  
Enzyme Activity ◽  
Blood Cell ◽  
Atpase Activity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Red Blood Cell ◽  
Calcium Binding ◽  
Red Cells ◽  
Low Density ◽  
Red Cell

Abstract To determine whether diminished activity of the Ca++ extrusion pump could account for the high levels of red blood cell (RBC) Ca++ in sickle cell anemia (SS), we measured calmodulin-sensitive Ca++ ATPase activity in normal and SS RBC. Hemolysates prepared with saponin were compared, since such preparations expressed maximum ATPase activities, exceeding isolated membranes or reconstituted systems of membranes plus cytosol, SS RBC hemolysates had greater Ca++ ATPase activity than normal hemolysates; they exhibited higher Mg++ and Na+ + K+ ATPase activities as well. Assays on density (age) fractions of SS and normal red cells demonstrated that all ATPase activities were highest in low density (young) cells, and activities in SS red cells exceeded those in normals in all fractions studied. Thus, when studied under conditions that maximize enzyme activity, Ca++ ATPase activity, like Mg++ and Na+ + K+ ATPase, is actually increased in SS RBC, probably due to the young red cell population present. The elevated Ca++ levels in these cells are more likely due to an increased Ca++ leak or abnormal calcium binding than to defective extrusion by the ATPase pump.

scholarly journals Red cells in sickle cell crisis: observations on the pathophysiology of crisis

Blood ◽  
1977 ◽  
Vol 49 (6) ◽  
pp. 967-979 ◽  
Author(s):  
EE Rieber ◽  
G Veliz ◽  
S Pollack
Keyword(s):  
Sickle Cell ◽  
Red Cells ◽  
Red Cell ◽  
Molecular Abnormality ◽  
Sickle Cell Crisis ◽  
Sickle Cell Crises

Abstract The pathophysiology of the occurrence and resolution of sickle cell crisis is unknown. The molecular abnormality is constant, while crisis is episodic. In the present study, red cell filterability and sickling with deoxygenation have been measured during sickle cell crises. Recovery from sickle crisis is associated with an increased filterability of the circulating red cell and a decreased susceptibility of the red cell to sickle with deoxygenation (p less than 0.05). The possibility that these changes are responsible for the resolution of crisis is suggested.

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