scholarly journals Intracellular Hemoglobin S Polymerization and the Clinical Severity of Sickle Cell Anemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1777-1783 ◽  
Author(s):  
William N. Poillon ◽  
Bak C. Kim ◽  
Oswaldo Castro
Keyword(s):  
Hemoglobin Concentration ◽  
Significant Negative Correlation ◽  
Clinical Severity ◽  
Homogeneous Distribution ◽  
Mean Corpuscular Hemoglobin ◽  
Heterogeneous Distribution ◽  
Sickle Erythrocytes ◽  
Hb S ◽  
2,3 Dpg

Abstract Recent work has enabled us to quantitate the four variables (2,3-DPG concentration, pHi, non-S hemoglobin composition, and O2 saturation) that modulate the equilibrium solubility (csat) of Hb S inside sickle erythrocytes (SS RBCs). Using measured values of mean corpuscular hemoglobin concentration (MCHC), 2,3-DPG concentration, and %Hb (F+A2), along with estimates of pHiand the Δcsat due to partial oxygenation of SS RBCs in the microcirculation, we calculated the mean polymer fraction (fp) in erythrocytes from 46 SS homozygotes. Values of fp derived from the conservation of mass equation ranged from 0.30 to 0.59. MCHC and %Hb F were major determinants of the magnitude of fp; 2,3-DPG concentration and pHialso contributed, but to a lesser extent. A clinical severity score (CSS) was assigned to each patient based on mean hospitalization rate. There was a weak, but statistically significant, negative correlation between fp and steady state hematocrit (P = .017), but none between fp and whole blood hemoglobin concentration (P = .218). Although there was no correlation between fp and mean number of hospitalization days per year, patients with the greatest number of admissions and hospitalization days were found only among those who had an fp > 0.45. All five patients who died during the follow-up period (median, 7 years; range, 3 to 10 years) had fp values ≥0.48. However, patients with few admissions, low hospitalization days, and long survivals occurred at all fp levels. These results suggest that the clinical course of homozygous SS disease cannot be predicted by mean fpcalculations, which assume a homogeneous distribution of the five variables that modulate intraerythrocytic polymerization. A heterogeneous distribution is more likely; so the amount of polymerized Hb S could vary considerably among cell populations. Factors such as membrane abnormalities and endothelial cell interactions may also contribute to clinical severity.

scholarly journals Intracellular Hemoglobin S Polymerization and the Clinical Severity of Sickle Cell Anemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1777-1783 ◽  
Author(s):  
William N. Poillon ◽  
Bak C. Kim ◽  
Oswaldo Castro
Keyword(s):  
Hemoglobin Concentration ◽  
Significant Negative Correlation ◽  
Clinical Severity ◽  
Homogeneous Distribution ◽  
Mean Corpuscular Hemoglobin ◽  
Heterogeneous Distribution ◽  
Sickle Erythrocytes ◽  
Hb S ◽  
2,3 Dpg

Recent work has enabled us to quantitate the four variables (2,3-DPG concentration, pHi, non-S hemoglobin composition, and O2 saturation) that modulate the equilibrium solubility (csat) of Hb S inside sickle erythrocytes (SS RBCs). Using measured values of mean corpuscular hemoglobin concentration (MCHC), 2,3-DPG concentration, and %Hb (F+A2), along with estimates of pHiand the Δcsat due to partial oxygenation of SS RBCs in the microcirculation, we calculated the mean polymer fraction (fp) in erythrocytes from 46 SS homozygotes. Values of fp derived from the conservation of mass equation ranged from 0.30 to 0.59. MCHC and %Hb F were major determinants of the magnitude of fp; 2,3-DPG concentration and pHialso contributed, but to a lesser extent. A clinical severity score (CSS) was assigned to each patient based on mean hospitalization rate. There was a weak, but statistically significant, negative correlation between fp and steady state hematocrit (P = .017), but none between fp and whole blood hemoglobin concentration (P = .218). Although there was no correlation between fp and mean number of hospitalization days per year, patients with the greatest number of admissions and hospitalization days were found only among those who had an fp > 0.45. All five patients who died during the follow-up period (median, 7 years; range, 3 to 10 years) had fp values ≥0.48. However, patients with few admissions, low hospitalization days, and long survivals occurred at all fp levels. These results suggest that the clinical course of homozygous SS disease cannot be predicted by mean fpcalculations, which assume a homogeneous distribution of the five variables that modulate intraerythrocytic polymerization. A heterogeneous distribution is more likely; so the amount of polymerized Hb S could vary considerably among cell populations. Factors such as membrane abnormalities and endothelial cell interactions may also contribute to clinical severity.

scholarly journals 2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 1028-1036 ◽  
Author(s):  
WN Poillon ◽  
BC Kim
Keyword(s):  
Intracellular Ph ◽  
Ph Profile ◽  
Sickle Erythrocyte ◽  
System A ◽  
Sickle Erythrocytes ◽  
Hb S ◽  
Ph Range ◽  
Intrinsic Solubility ◽  
T State ◽  
2,3 Dpg

Abstract We have established that 2,3-diphosphoglycerate (2,3-DPG) content and intracellular pH exert separate, but interdependent, effects on the equilibrium solubility (csat) of deoxyhemoglobin S (deoxy-Hb S) that act in concert to modulate intraerythrocytic polymer formation. In a nonphysiologic csat assay system, a steep dependence of csat on pH in the physiologic range 7.0 to 7.6 was shown for both stripped (Hb) and DPG-saturated deoxy-Hb S (Hb-DPG). The solubility-pH profile for Hb under near-physiologic buffer conditions also showed that csat increased steeply in the same pH range (6.8 to 7.6). The effect of 2,3- DPG on csat under near-physiologic conditions was evaluated separately. At pH 7.20, the pH of the human red blood cell, csat values for Hb and Hb-DPG were 19.56 +/- 0.14 and 17.95 +/- 0.45 g/dL, respectively, indicating that the solubility of Hb-DPG is lower than that of Hb by 8.2% +/- 2.3%. Thus, binding of 2,3-DPG in the beta-cleft promotes the polymerization of deoxy-Hb S, the ultimate determinant of cell sickling. Furthermore, because of the abnormal Bohr effect of sickle blood (approximately double that of normal blood), the intracellular pH of deoxygenated sickle erythrocytes should be approximately 0.28 pH unit higher than that of oxygenated cells (ie, 7.41 v 7.13). At the higher pH, the corresponding csat for Hb-DPG is 20.22 g/dL, which is the best estimate of the intrinsic solubility of T-state Hb S under conditions that approximate closely those of pH, temperature, ionic strength, and 2,3-DPG saturation in the fully desaturated sickle erythrocyte.

scholarly journals Quantitative sensory testing in elderly: longitudinal study

2018 ◽  
Vol 76 (11) ◽  
pp. 743-750
Author(s):  
Luciana Alvarenga da Silva ◽  
Omar Jaluul ◽  
Manoel Jacobsen Teixeira ◽  
José Tadeu Tesseroli de Siqueira ◽  
Wilson Jacob Filho ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Quantitative Sensory Testing ◽  
Hemoglobin Concentration ◽  
Clinical Aspects ◽  
Mean Corpuscular Hemoglobin ◽  
Sensory Testing ◽  
Geriatric Service ◽  
Sensitivity Changes ◽  
Healthy Participants

ABSTRACT Objective: To evaluate elderly patients in a geriatric service, along with their sensory characteristics and their association with clinical aspects. Methods: This was a descriptive longitudinal study. We enrolled 36 healthy participants of both sexes in this study. The following instruments were used and evaluations performed: clinical evaluation, Mini-Mental State Exam, and quantitative sensory testing. Results: During the follow-up, there was reduction of mean corpuscular volume at each evaluation (p < 0.001) and significant increase in mean corpuscular hemoglobin concentration (p < 0.001). There was an increase of the olfactory (p < 0.001), salty (p = 0.024), sour (p = 0.020), bitter (p = 0.001), facial cold (p = 0.019), hand cold (p = 0.004), facial tactile (p < 0.001), hand tactile (p = 0.012) and facial vibration (p = 0.018) thresholds. Previous existing morbidities were associated with sensitivity changes in the individuals in this sample. Conclusion: This longitudinal study suggests that the loss of sensitivity with aging may be associated with the presence of morbidities in elders.

scholarly journals Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 183-189 ◽  
Author(s):  
GM Brittenham ◽  
AN Schechter ◽  
CT Noguchi
Keyword(s):  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Clinical Severity ◽  
Beta Thalassemia ◽  
Mean Corpuscular Hemoglobin ◽  
Mean Values ◽  
Polymer Formation ◽  
Primary Determinant ◽  
Hereditary Persistence ◽  
Polymer Fraction

We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.

scholarly journals 2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 1028-1036 ◽  
Author(s):  
WN Poillon ◽  
BC Kim
Keyword(s):  
Intracellular Ph ◽  
Ph Profile ◽  
Sickle Erythrocyte ◽  
System A ◽  
Sickle Erythrocytes ◽  
Hb S ◽  
Ph Range ◽  
Intrinsic Solubility ◽  
T State ◽  
2,3 Dpg

We have established that 2,3-diphosphoglycerate (2,3-DPG) content and intracellular pH exert separate, but interdependent, effects on the equilibrium solubility (csat) of deoxyhemoglobin S (deoxy-Hb S) that act in concert to modulate intraerythrocytic polymer formation. In a nonphysiologic csat assay system, a steep dependence of csat on pH in the physiologic range 7.0 to 7.6 was shown for both stripped (Hb) and DPG-saturated deoxy-Hb S (Hb-DPG). The solubility-pH profile for Hb under near-physiologic buffer conditions also showed that csat increased steeply in the same pH range (6.8 to 7.6). The effect of 2,3- DPG on csat under near-physiologic conditions was evaluated separately. At pH 7.20, the pH of the human red blood cell, csat values for Hb and Hb-DPG were 19.56 +/- 0.14 and 17.95 +/- 0.45 g/dL, respectively, indicating that the solubility of Hb-DPG is lower than that of Hb by 8.2% +/- 2.3%. Thus, binding of 2,3-DPG in the beta-cleft promotes the polymerization of deoxy-Hb S, the ultimate determinant of cell sickling. Furthermore, because of the abnormal Bohr effect of sickle blood (approximately double that of normal blood), the intracellular pH of deoxygenated sickle erythrocytes should be approximately 0.28 pH unit higher than that of oxygenated cells (ie, 7.41 v 7.13). At the higher pH, the corresponding csat for Hb-DPG is 20.22 g/dL, which is the best estimate of the intrinsic solubility of T-state Hb S under conditions that approximate closely those of pH, temperature, ionic strength, and 2,3-DPG saturation in the fully desaturated sickle erythrocyte.

scholarly journals Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 183-189 ◽  
Author(s):  
GM Brittenham ◽  
AN Schechter ◽  
CT Noguchi
Keyword(s):  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Clinical Severity ◽  
Beta Thalassemia ◽  
Mean Corpuscular Hemoglobin ◽  
Mean Values ◽  
Polymer Formation ◽  
Primary Determinant ◽  
Hereditary Persistence ◽  
Polymer Fraction

Abstract We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.

Abstract 12550: Persistent Relative Hypochromia is Associated With Adverse Outcomes in Non-anemic Patients With Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Muhammad Hammadah ◽  
Yuping Wu ◽  
Lin Li ◽  
Stanley Hazen ◽  
W.H.Wilson Tang
Keyword(s):  
Mortality Risk ◽  
Hemoglobin Concentration ◽  
Adverse Outcomes ◽  
Mean Corpuscular Hemoglobin ◽  
Good Representation ◽  
Functional Iron Deficiency ◽  
Blood Indices ◽  
Patients With Heart Failure ◽  
Mean Time

Background: We previously reported that functional iron deficiency, assessed by low mean corpuscular hemoglobin concentration (MCHC), has been associated with adverse outcomes in non-anemic patients with HF. Yet, the effect of change in MCHC levels on outcomes has not been studied before. Methods: We prospectively enrolled 1,579 subjects with HF undergoing coronary angiography, with 5-year follow-up. Blood indices [hemoglobin (Hb), MCHC, MCV, RDW] were assessed on enrollment and after 6 months of follow up by reviewing medical records. Anemia was defined as Hb levels <12 g/dL in males, and <11 g/dL in females. Results: In our population (age 66 ± 10 years, male 65%, CAD 75%), most patients were non-anemic (n=1,161, 73.5%). In non-anemic patients, mean Hb and median (IQR) MCHC were 13.3±1.2 g/dL and 34.2 (33.43-34.9) g/dL, respectively. Non-anemic HF patients with lower MCHC had higher mortality risk [Q1 vs Q4 Hazard ratio (HR) (95%CI) of 2.5(1.9-3.2), p<0.001]. Total of 552 (35%) had follow up Hb levels with a mean time between baseline and follow up levels of 169.3 ± 41.6 days. HF severity (EF, BNP), outcomes and blood indices were similar in patients with and without follow up levels, suggesting good representation of the total population. Changes in MCHC levels was studied in non-anemic patients on baseline and follow up (n=318). Most patient with low MCHC at baseline (<Q1, n=79) continued to have low MCHC on follow up (n=61), while half of the patients with high baseline MCHC (≥Q1, n=239) developed low MCHC on follow up (n=120). In comparison to patient with persistently high MCHC, patients with persistently low MCHC had a significantly increased mortality risk [HR(95%CI) of 3.5(2.1-6.1), p<0.001]. All models remained significant even after adjusting for traditional CAD risk factors, EF and baseline blood indices. Conclusion: Relative hypochromia is an independent predictor of increase mortality in patients with HF, even in the setting of normal hemoglobin levels.

scholarly journals A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy

Blood ◽  
1996 ◽  
Vol 88 (12) ◽  
pp. 4701-4710 ◽  
Author(s):  
KR Bridges ◽  
GD Barabino ◽  
C Brugnara ◽  
MR Cho ◽  
GW Christoph ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Umbilical Vein ◽  
Hemoglobin Concentration ◽  
Mean Corpuscular Hemoglobin ◽  
Cell Disease ◽  
Hydroxyurea Treatment ◽  
Sickle Erythrocytes ◽  
Delay Times ◽  
Umbilical Vein Endothelial Cells

During 24 weeks of hydroxyurea treatment, we monitored red blood cell (RBC) parameters in three patients with sickle cell disease, including F-cell and F-reticulocyte profiles, distributions of delay times for intracellular polymerization, sickle erythrocyte adherence to human umbilical vein endothelial cells in a laminar flow chamber, RBC phthalate density profiles, mean corpuscular hemoglobin concentration and cation content, reticulocyte mean corpuscular hemoglobin concentration, 1H-nuclear magnetic resonance transverse relaxation rates of packed RBCs, and plasma membrane lateral and rotational mobilities of band 3 and glycophorins. Hydroxyurea increases the fraction of cells with sufficiently long delay times to escape the microcirculation before polymerization begins. Furthermore, high pretreatment adherence to human umbilical vein endothelial cells of sickle RBCs decreased to normal after only 2 weeks of hydroxyurea treatment, preceding the increase in fetal hemoglobin levels. The lower adhesion of sickle RBCs to endothelium would facilitate escape from the microcirculation before polymerization begins. Hydroxyurea shifted several biochemical and biophysical parameters of sickle erythrocytes toward values observed with hemoglobin SC disease, suggesting that hydroxyurea moderates sickle cell disease toward the milder, but still clinically significant, hemoglobin SC disease. The 50% reduction in sickle crises documented in the Multicenter Study of Hydroxyurea in Sickle Cell Disease is consistent with this degree of erythrocyte improvement.

Genetic control of erythrocyte volume regulation: effect of a single gene (rol) on cation metabolism

1994 ◽  
Vol 267 (1) ◽  
pp. C211-C219 ◽  
Author(s):  
P. R. Fernandes ◽  
M. J. Dewey
Keyword(s):  
Single Gene ◽  
Fatty Acid Content ◽  
Strain Differences ◽  
Osmotic Fragility ◽  
Hemoglobin Concentration ◽  
Cytoskeletal Proteins ◽  
Mean Corpuscular Hemoglobin ◽  
Mean Cell Volume ◽  
Erythrocyte Volume ◽  
2,3 Dpg

In laboratory mice we previously defined a gene, rol (resistance to osmotic lysis), based on its effect on erythrocyte osmotic fragility. Here we report a physiological characterization of rol gene action utilizing congenic strains developed for the purpose; these two strains have a common genetic background and differ only by the two alleles of rol, susceptible (rols) or resistant (rolr). In comparison to rols/s erythrocytes, rolr/r cells have a reduced mean cell volume, a higher mean corpuscular hemoglobin concentration and hemolytic volume, and respond differently to swelling induced by ion influx. Rolr/r erythrocytes also have reduced cell water and K, which are associated with a threefold higher activity of the Na-K-Cl cotransporter (measured as ouabain-resistant, bumetanide-sensitive 86Rb influx) and 30% higher Na pump activity. Apart from differences in ion transport and water content, the content of 2,3-diphosphoglycerate (2,3-DPG) in rolr/r cells is 15% lower than in rols/s ones. Analyses of membrane structural components revealed no rol-associated differences in their phospholipid or fatty acid content, nor were strain differences evident among the membrane and cytoskeletal proteins and their posttranslational modifications (phosphorylation and fatty acylation). Rol is not the structural gene for either the alpha- or the beta-chain of hemoglobin and has no effect on erythrocyte production or destruction. The concerted effect of rol variation on erythrocyte volume, water and cation content, cation cotransport, and 2,3-DPG levels is similar in many ways to the variation observed among individual humans for the same characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2384-2390 ◽  
Author(s):  
Jose R. Romero ◽  
Sandra M. Suzuka ◽  
Ronald L. Nagel ◽  
Mary E. Fabry
Keyword(s):  
Transgenic Mice ◽  
Hemoglobin Concentration ◽  
Red Cells ◽  
Mean Corpuscular Hemoglobin ◽  
Red Cell ◽  
Knock Out ◽  
High K ◽  
Hb S ◽  
Knock Out Mice ◽  
Human Red Cells

Abstract Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3- and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3- are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+γ, replacement of isotonic Cl- media by hypotonic Cl- resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+γ, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.

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