Sickle cell membranes

In sickle cell membranes, ascorbic acid proved to be an effective antioxidant (Rice-Evans et al. 1986). It is possible that the mechanism of action of ascorbate may involve the scavenging of alkoxy or peroxy radicals by a chain-termination reaction (Halliwell and Gutteridge 1984) or the decreased initiation of lipid peroxidation. 

Hemolytic anemia results from decreased RBC survival time due to destruction in the spleen or circulation. The most common etiologies are RBC membrane defects (e.g., hereditary spherocytosis), altered Hb solubility or stability (e.g., sickle cell anemia [see Chap. 34] and thalassemias), and changes in intracellular metabolism (e.g., glucose-6-phosphate dehydrogenase deficiency). Some drugs cause direct oxidative damage to RBCs (see Appendix 3). 

Polymerization allows deoxygenated hemoglobin to exist as a semisolid gel that protrudes into the cell membrane, distorting RBCs into sickle shapes. Sickle-shaped RBCs increase blood viscosity and encourage sludging in the capillaries and small vessels. Such obstructive events lead to local tissue hypoxia and accentuate the pathologic process. 

In the majority of patients with sickle cell disease, anemia is not the major problem the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20-30%), a low serum hemoglobin level (7-10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes... 

Reported applications of DMA include the cross-linking of bovine pancreatic ribonuclease A (Hartman and Wold, 1967), treatment of erythrocyte membranes to reduce the effects of sickle cell anemia (Waterman et al., 1975), conjugation and analysis of the outer membrane proteins of Neisseria gonorrhoeae (Newhall et al., 1980), protein structural studies of bovine a-crystalline (Siezen et al., 1980), cross-linking of hemoglobin S (Pennathur-Das et al., 1982), and forming S-carbomethoxy-valeramidine during hydrolysis of DMA (Mentzer et al., 1982). 

An investigation of the role played by zinc in sickle cell anaemia has shown264 that zinc decreases the amount of haemoglobin associated with red-cell membranes and inhibits the effect of calcium in causing haemoglobin retention by membranes. 

Figure 2-5. Pathologic changes in sickle cell diseases. Vaso-occlusion is a combination of exposure of phosphatidylserine on the red cell membrane, activation of vascular endothelial cells, activation of leukocytes, and a state of increased coagulability. From Steinberg, 1999. Copyright 1999, Massachusetts Medical Society. All rights reserved.

The test is illustrated with results taken from experiments on membranes of erythrocytes from patients with sickle cell anaemia, which tend to retain increased levels of membrane-associated iron, compared with those of normal erythrocytes. Some results are shown in Table 4.2. 

As a result of impaired antioxidant activity in erythrocytes, there may be increased fragility of erythrocyte membranes or reduced membrane fluidity. As in sickle cell trait, which also protects against malaria, this may result in ... 

In limited uncontrolled studies, zinc appears to have been effective in decreasing symptoms and crises of sickle-cell-anemia patients. The therapeutic rationale is based on effects of zinc on the red cell membrane by which it decreases hemoglobin and calcium binding and improves deformability, which may result in decreased trapping of sickle cells in the capillaries where pain cycle is normally initiated. Undoubtedly more thorough evaluation of zinc therapy in sickle cell disease is needed in the future. 

Zinc is known to compete with cadmium, lead, copper, iron, and calcium for similar binding sites (109). In the future, a potential use of zinc may be to alleviate toxic effects of cadmium and lead in human subjects. Use of zinc as an antisickling agent is an example of its antagonistic effect on calcium, which is known to produce irreversible sickle cells by its action on red-cell membrane. 

The zinc content of human blood is 8.8 /Ug/mL, of which 80-90% is within erythrocytes, mostly in carbonic an-hydrase. Zinc binds to hemoglobin, increasing its oxygen affinity. By binding to erythrocyte membranes, it increases the flexibility of irreversibly sickled cells in vitro but plasma levels high enough to be therapeutic cannot be achieved. Leukocytes and platelets also contain an appreciable amount of zinc. 

Membrane defect Spherocytosis and elliptocytosis Hemoglobin defect Sickle cell anemia Thalassemia syndrome Metabol ic defect... 

Intravascular destruction of sickle cells may occur at an accelerated rate. The stresses of circulation, and repetitive sickle-unsickle cycles are likely to lead to cell fragmentation. Damage to the cell membrane promotes cell recognition by macrophages. Rigid ISCs are easily trapped, resulting in short circulatory survival and chronic hemolysis. The typical sickled cell survives for about 10 to 20 days, while life spans of normal RBCs are 100 to 120 days. 

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