Red cell survival studies in hereditary spherocytosis

Wiley, James S.

doi:10.1172/jci106278

Cited by 37 publications

(14 citation statements)

References 23 publications

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“…These observations on normal subjects arc consistent with the studies of Wiley [11], who reported recently that there was no correlation between sodium influx (presumably measuring permeability) and erythrocyte survival in patients with HS. These findings are inconsistent with the thesis that the increased sodium permeability of erythrocytes of patients with HS plays a central role in the pathogenesis of the hemolytic anemia in this disease [6].…”

Section: Discussionsupporting

confidence: 92%

Significance of Erythrocyte Sodium Flux in the Pathophysiology and Genetic Expression of Hereditary Spherocytosis

Zipursky

Israels

1971

Pediatr Res

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ExtractErythrocyte sodium transport was studied in five families of patients with hereditary spheroeytosis (HS). Values for ouabain-insensitive sodium efilux in the group with HS (mean = 19.9% of cellular sodium-22/hr, so = ±2.7) were significantly greater (P < 0.001) than those found in the normal group (mean = 13.8%, SD = ±2.7). No clinical evidence of HS was found in the parents; however, 4 of the 10 parents had ouabain-insensitive erythrocyte sodium-22 efilux rates in the HS range in comparison to 3 of 30 control subjects, a statistically significant difference (x ! = 4.67; P < 0.05). Speculation

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Section: Discussionsupporting

confidence: 92%

Significance of Erythrocyte Sodium Flux in the Pathophysiology and Genetic Expression of Hereditary Spherocytosis

Zipursky

Israels

1971

Pediatr Res

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“…The only indirect evidence comes from early studies documenting reduced survival of Cr 51 -labeled spherocytes infused into healthy recipients, whereas the survival of normal RBCs in HS subjects was normal. [17][18][19] This implied that the reduced life span and splenic entrapment was an intrinsic feature of HS RBCs. Unfortunately, because neither the surface area nor the S/V ratio of infused spherocytes was measured in these studies, the extent of membrane surface area loss (or reduced S/V ratio) that leads to splenic retention of altered RBCs remains undefined.…”

Section: Introductionmentioning

confidence: 99%

Quantitative assessment of sensing and sequestration of spherocytic erythrocytes by the human spleen

Safeukui

Buffet

Deplaine

et al. 2012

Blood

118

139

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IntroductionDuring their 120-day life span, human RBCs repeatedly traverse capillaries of the vascular bed and interendothelial slits of the venous sinus of spleen red pulp, both of which are narrower than their smallest dimension. 1 This necessitates maintenance of the ability of RBCs to undergo repeated, extensive, and reversible deformations. Repeated major membrane deformations induce ion and water permeability changes in the RBCs. [2][3][4][5] The biconcave discoid shape endows the human RBC with an advantageous surface area-to-volume (S/V) ratio, allowing the cell to undergo marked deformations while maintaining a constant surface area. [6][7][8] A reduced RBC S/V ratio has long been recognized to contribute to pathogenesis of several RBC disorders, 9-11 including hereditary spherocytosis (HS), the most common cause of inherited chronic hemolytic anemia in Northern Europe and North America, with an estimated incidence of 1 in 2000. 11 The clinical presentation of HS can range from mild to severe hemolytic anemia. 12,13 The molecular basis of HS is heterogeneous, the common denominator being the loss of HS RBC membrane surface area due to specific molecular defects in several membrane proteins (␣ or ␤ spectrin, ankyrin, protein 4.2, and protein band 3), which result in the loss of cohesion between the lipid bilayer and the membrane skeleton. 10,11,14,15 The loss of membrane surface area results in the transformation of the biconcave discoid shape, first to a stomatocyte and finally to a spherocyte, with a progressive reduction in cellular deformability.Although a major role for the spleen in pathogenesis of HS is well established, 16 there are currently no data on the quantitative relationship between the extent of surface area loss and the extent of splenic entrapment. The only indirect evidence comes from early studies documenting reduced survival of Cr 51 -labeled spherocytes infused into healthy recipients, whereas the survival of normal RBCs in HS subjects was normal. [17][18][19] This implied that the reduced life span and splenic entrapment was an intrinsic feature of HS RBCs. Unfortunately, because neither the surface area nor the S/V ratio of infused spherocytes was measured in these studies, the extent of membrane surface area loss (or reduced S/V ratio) that leads to splenic retention of altered RBCs remains undefined. As a result, there is no predictive biologic parameter with which to estimate the risk of splenic entrapment of spherocytic cells and the ensuing anemia. Previously, we addressed this important issue using the isolated human spleen system 20 perfused with human RBCs with defined extents of surface area loss.RBCs with defined loss in membrane surface area can be generated experimentally by treatment with lysophosphatidylcholine (LPC). 6,7 By initially accumulating exclusively in the external leaflet of the RBC lipid bilayer, LPC induces in a dose-dependent manner echinocytosis There is an Inside Blood commentary on this article in this issue.The online version of this article contai...

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“…Several studies have shown that the erythrocyte "permeability" to sodium and potassium is increased in HS and that the increased sodium permeability is associated with increased activity of the Na-K ATPase. [7][8][9][10][11][12] It has been postulated that the associated increase in adenosine triphosphate (ATP) consumption leads to ATP depletion during erythrostasis, followed by increased calcium entry, activation of the Gardos channel, and dehydration. 8,13 A more recent study found no changes in the transport activity of Na-K-2Cl cotransport and Na/Li exchange in human HS erythrocytes, whereas sodium potassium pump activity was increased and potassium chloride cotransport activity was decreased.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a protective role of the Gardos channel against hemolysis in murine spherocytosis

Franceschi

Rivera

Fleming

et al. 2005

Blood

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It has been shown that mice with complete deficiency of all 4.1R protein isoforms (4.1-/-) exhibit moderate hemolytic anemia, with abnormal erythrocyte morphology (spherocytosis) and decreased membrane stability. Here, we characterized the Gardos channel function in vitro and in vivo in erythrocytes of 4.1-/- mice. Compared with wild-type, the Gardos channel of 4.1-/- erythrocytes showed an increase in Vmax (9.75 +/- 1.06 vs 6.08 +/- 0.09 mM cell x minute; P < .04) and a decrease in Km (1.01 +/- 0.06 vs 1.47 +/- 1.02 microM; P < .03), indicating an increased sensitivity to activation by intracellular calcium. In vivo function of the Gardos channel was assessed by the oral administration of clotrimazole, a well-characterized Gardos channel blocker. Clotrimazole treatment resulted in worsening of anemia and hemolysis, with decreased red cell survival and increased numbers of circulating hyperchromic spherocytes and microspherocytes. Clotrimazole induced similar changes in 4.2-/- and band 3+/- mice, indicating that these effects of the Gardos channel are shared in different models of murine spherocytosis. Thus, potassium and water loss through the Gardos channel may play an important protective role in compensating for the reduced surface-membrane area of hereditary spherocytosis (HS) erythrocytes and reducing hemolysis in erythrocytes with cytoskeletal impairments.

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Red cell survival studies in hereditary spherocytosis

Cited by 37 publications

References 23 publications

Significance of Erythrocyte Sodium Flux in the Pathophysiology and Genetic Expression of Hereditary Spherocytosis

Significance of Erythrocyte Sodium Flux in the Pathophysiology and Genetic Expression of Hereditary Spherocytosis

Quantitative assessment of sensing and sequestration of spherocytic erythrocytes by the human spleen

Evidence for a protective role of the Gardos channel against hemolysis in murine spherocytosis

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