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At least 55 records · Page 3Linked to original sources

PubMed1999

Rheological behaviour of red blood cells suspended in hemoglobin solutions. In vitro study comparing dextran-benzene-tetra-carboxylate hemoglobin, stroma free hemoglobin and plasma expanders.

Circulating volume expansion for intentional hemodilution and/or resuscitation of hemorrhagic shock can be performed with hemoglobin-based oxygen carriers (HBOC) which, in addition to oxygen transport, have vasoactive effects through poorly documented mechanisms. Among these, the effects of HBOC on red blood cell (RBC) rheology are relatively unknown. The aim of the present in vitro study was to measure the rheological effects of human hemoglobin bound to benzene-tetracarboxylate substituted dextran (Dex-BTC-Hb) as an example of chemically modified hemoglobin. The viscosity was assessed with a capillary and a rotational viscometer for shear rates of 0.5-128 s-1. Erythrocyte aggregation was determined by analysis of the red light backscattered in a RBC suspension and with a rheoscope. The deformability was determined by the pressure-flow relationship of the RBC suspensions passed through polycarbonate filters. At hematocrit of 0.35 l/l and at low shear rates, the viscosity of RBC was higher in the presence of Dex-BTC-Hb as compared to free Hb, Dex-BTC, Dextran 40 (Plasmacair), modified fluid gelatin (MFG-Plasmion) or hydroxyethyl starch (HEA-Elohes). The effect on erythrocyte aggregation of Dex-BTC-Hb was greater than that of standard solutions, but close to that of MFG or HEA. There was no apparent change in RBC deformability. Dex-BTC-Hb, unlike free Hb, has a hyperaggregating effect on RBC, similar to that of some clinically used volume expanders. This hyperaggregating effect could influence the in vivo rheological behavior of substituted Hb by increasing shear stress.

Blood Substitutes↗

PubMed1985

A new hemoglobin variant, hemoglobin Nunobiki [alpha 141 (HC3) Arg----Cys]. Notable influence of the carboxy-terminal cysteine upon various physico-chemical characteristics of hemoglobin.

A new hemoglobin variant, hemoglobin (Hb) Nunobiki, was detected in a Japanese male with marginal erythrocytosis. The Hb Nunobiki component amounted to 13.1% of the total hemoglobin. Structural analysis of this variant established the substitution of a cysteine for an arginine at the carboxy terminus of the alpha-chain (alpha 141). The oxygen equilibrium curves of Hb Nunobiki revealed extremely high oxygen affinity with a reduced Hill coefficient n, a decreased alkaline Bohr effect, and a decreased 2,3-diphosphoglyceric acid effect. The isoelectric point of the Hb Nunobiki changed during storage, although the oxyhemoglobin state was maintained. These findings could be accounted for by the specific characteristics of a newly introduced cysteinyl residue. Cysteinyl residue at alpha 141 in Hb Nunobiki did not seem to be involved in the formation of either intermolecular or intramolecular disulfide bonds under physiologic conditions. The low proportion of Hb Nunobiki (13.1%) in the propositus was also discussed after it was verified that he exhibited four alpha-globin genes per diploid cell.

Adult↗

PubMed1988

Hemoglobin hafnia: alpha 2 (beta 116 (G18) His----Gln)2; a new hemoglobin variant mistaken for glycated hemoglobin.

Isoelectric focusing of hemolysate from patients with diabetes mellitus is routinely performed to measure their level of HbA1c (glycated hemoglobin). For a 6 year old boy with diabetes mellitus this analysis showed an HbA1c fraction of approx. 50%, which is very unlikely to occur. The possibility of a hemoglobin variant was considered, and by HPLC-separation the presence of two different beta-chains was shown. One tryptic fragment was found to deviate from the normal, and amino-acid analysis and sequence determination revealed the following amino-acid substitution: beta 116 His----Gln. It is the first reported mutation at this position. Functional studies showed almost normal behaviour, consistent with the fact that the affected persons are without any symptoms. In a family survey we found five nondiabetic members with an abnormality similar to the proband. For the variant we chose the name Hafnia, which is Latin for Copenhagen.

Amino Acid Sequence↗

PubMed1980

Unstable hemoglobins, hemoglobins with altered oxygen affinity, and m-hemoglobins.

Most patients with chronic Heinz body anemia do not require treatment. Dietary folic acid supplementation is recommended when hemolysis is chronic and severe. During infection, patients should be observed carefully because of the possibility of aplastic or hemolytic crises. Individuals with hemoglobins with altered oxygen affinity or M-hemoglobins do not require treatment, and should be counseled about the benign nature of their condition. Unnecessary procedures to exclude cardiac or pulmonary disease should be avoided.

Anemia, Hemolytic, Congenital↗

PubMed1983

Fetal hemoglobin production in cultures of primitive and mature human erythroid progenitors: differentiation affects the quantity of fetal hemoglobin produced per fetal-hemoglobin-containing cell.

Single-cell microscopic immunodiffusion assays were used to determine the cellular mechanisms that regulate fetal hemoglobin (HbF) levels in cultures of primitive and late erythroid precursors obtained from human adult bone marrow. Two variables--the percentage of cells containing HbF (F cells) and the picograms (pg) of HbF/F cell--were assayed in cells derived from erythroid colony-forming units (CFU-E) and from erythroid burst-forming units (BFU-E) at 7 and 14 days in culture, respectively. The percentage of F cells among all nucleated cells from CFU-E-derived colonies (29.4% +/- 12.5%, mean +/- SD) was not significantly different (p = 0.2) from the percentage of F cells from BFU-E-derived bursts (37.3% +/- 10.1%). Serial daily assays of all cells in cultures on days 3 through 7 and on day 14 revealed a marked increase in F cells between days 4 and 6 in culture. The average amount of HbF/F cell was less in CFU-E-derived F cells than in BFU-E-derived cells (3.5 +/- 0.3 pg versus 6.2 +/- 3.3 pg; p less than 0.01), while adult hemoglobin (HbA) levels in CFU-E-and BFU-E-derived cells remained comparable (19.9 +/- 2.2 pg versus 21.9 +/- 5.3 pg, p = 0.3). These findings indicate that F cell number in culture is not significantly influenced by the relative maturity of the erythroid precursors from which the cells are derived. Differences in the levels of HbF between CFU-E-and BFU-E-derived cells are due to differences in the amount of HbF per F cell, not F cell number.

Bone Marrow Cells↗

PubMed1984

Polymerization of AS hybrid hemoglobin. Potent inhibitory effect of hemoglobin A on the polymerization of AS hybrid hemoglobin.

Asymmetrically cross-linked AS hybrid hemoglobin (Hb AS-fumarate) was prepared by reacting a mixture of oxy-Hb A and oxy-Hb S with a cross-linking agent, bis(3,5-dibromosalicyl)fumarate. Kinetics of the polymerization of Hb AS-fumarate in 1.8 M phosphate buffer showed that Hb AS-fumarate polymerized similarly to Hb S-fumarate despite the presence of a beta A chain. The kinetics of the polymerization of a mixture of Hb AS-fumarate and Hb S-fumarate was similar to that of Hb S-fumarate or Hb AS-fumarate alone. However, when Hb AS-fumarate was mixed with Hb A, the delay time prior to polymerization of the mixture was markedly prolonged. Although the solubility of Hb AS-fumarate was similar to that of Hb S-fumarate, it nearly doubled upon the addition of Hb A. Analysis of Hb A in the polymer phase showed that a significant amount (35-40%) of Hb A copolymerized with Hb AS-fumarate. No such effect was observed when Hb A was mixed with Hb S-fumarate, where the delay time prior to polymerization and the solubility of the mixture were regulated by the concentration of Hb S-fumarate in the mixture. The strong inhibitory effect of Hb A on the polymerization of Hb AS hybrid hemoglobin may help explain the benign clinical course in sickle cell trait.

Chromatography, High Pressure Liquid↗

PubMed1979

Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S.

We have previously found that the inhibitory effect of hemoglobin F (Hb F) on the polymerization of Hb S proceeds via the formation of asymmetrical hybrid tetramers of the type alpha2betasgamma. Examination of the gelling properties of binary mixtures of Hb S and several Hb variants now shows that, among the gamma chain amino acid residues that differ from those of the beta chain, residues gamma80 (EF4) and gamma87 (F3) are at least partly responsible for this inhibition. Furthermore, we find that mixing Hb A2(alpha2delta2) with Hb S strongly inhibits gelling to an extent similar to that seen with Hb S/Hb F mixtures; this inhibition is attributable to amino acid differences between the delta and beta chain sequences at positions delta22 (B4) and delta87 (F3). Therefore, residues 22, 80, and 87 of the beta chain appear to be involved in intermolecular contact sites that stabilize the deoxy Hb S polymers.

Amino Acid Sequence↗

PubMed1984

Hemoglobin Shelby [beta 131(H9) Gln----Lys] a correction to the structure of hemoglobin Deaconess and hemoglobin Leslie.

Hemoglobin Shelby, detected in two unrelated black families, has an electrophoretic mobility like Hb F on cellulose acetate (pH 8.4) and a mobility between Hbs S and C on citrate agar (pH 6.2). Globin chain analysis in acid and alkaline buffers revealed an abnormal chain migrating between beta A and beta S. Tests for unstable hemoglobins were positive. Hematologic data on both families indicated carriers have mild anemia. The variant showed a slightly lower affinity for oxygen with normal cooperativity and Bohr effect, and its reactions with 2,3-diphosphoglycerate and inositol hexaphosphate were similar to those of Hb A. Sequence analysis indicated the substitution of lysine for glutamine at position 131 in the beta-chain. In a previous report (1) we described a variant, Hb Deaconess, in which this residue was deleted. On reexamination of the data, we find that Hb Deaconess is identical to Hb Shelby.

Adolescent↗

PubMed1994

Influence of the chemical nature of side chain at beta 108 of hemoglobin A on the modulation of the oxygen affinity by chloride ions. Low oxygen affinity variants of human hemoglobin expressed in transgenic pigs: hemoglobins Presbyterian and Yoshizuka.

Hemoglobin A (HbA) and two low oxygen affinity variants of HbA, HbPresbyterian and HbYoshizuka, were produced in transgenic pigs and purified to homogeneity by ion-exchange chromatography. These two variants contain either lysine (HbPresbyterian) or aspartic acid (HbYoshizuka) instead of the normal asparagine residue at position beta 108 in HbA. Transgenic pigs expressed these variants at a level up to 11% and were healthy. Both HbPresbyterian and HbYoshizuka exhibited low O2 affinity (P50 of 21.2 and 18.9, respectively, compared with control HbA value of 11.8 in 0.1 M NaCl, pH 7.5) and retained normal cooperativity with Hill coefficients of 2.9 and 2.5, respectively. HbPresbyterian exhibited Bohr effect comparable with HbA. In contrast, HbYoshizuka had a diminished response to changes in pH. Thus the structural basis of reduced O2 affinity of these variants appears to be distinct: the consequence of mutation at beta 108 is a function of the chemical nature of the side chain. This is further confirmed by the sensitivity of the O2 affinity of the variants to the presence of Cl-. The O2 affinity of HbYoshizuka is insensitive to changes in Cl- concentration, whereas the O2 affinity of HbPresbyterian exhibited a pronounced and dramatic chloride effect. In fact, P50 of HbPresbyterian was identical to that of HbA at very low Cl- concentrations, and the P50 increased to >40 at 0.5 M Cl-. The chloride effect was completely abolished when HbPresbyterian was stabilized at the 2,3-diphosphoglycerate pocket by interdimeric cross-linking. Molecular modeling studies demonstrate that in HbPresbyterian, Cl- can bridge the epsilon-amino group of Lys beta 108 with either the guanidino group of Arg beta 104 or the epsilon-amino group of Lys alpha 99, resulting in the stabilization of the "T" structure. The utility of these low O2 affinity hemoglobins as cell-free oxygen carriers is discussed.

Allosteric Regulation↗

PubMed1994

Effect of 2,3-diphosphoglycerate on O2-dissociation kinetics of hemoglobin and glycosylated hemoglobin using the stopped flow technique and an improved in vitro method for hemoglobin glycosylation.

Studies under equilibrium conditions have shown that the oxygen affinity of hemoglobin (Hb) is lowered by 2,3-diphosphoglycerate (2,3-DPG), the physiological allosteric effector in erythrocytes, and enhanced by glycosylation of Hb. The kinetics of oxygen release, as a function of 2,3-DPG and the degree of glycosylation have been determined using the stopped flow method and a new in vitro glycosylation procedure allowing adequate amounts of functionally intact hemoglobin to be obtained. The rate constant k of O2-dissociation in glycosylated Hb (8% HbA1c) was approximately 10% lower than in native Hb (4% HbA1c). The addition of 2,3-DPG in concentrations up to 20 mmol/l resulted in a progressive increase of k from 61.5 +/- 3.3 s-1 to 65.3 ae 4.1 s-1 for native Hb and from 56.8 +/- 5.2 s-1 to 59.4 +/- 4.1 s-1 for glycosylated Hb. We conclude that (a) the degree of glycosylation similar to that found in diabetic patients is responsible for a significant decrease of the oxygen dissociation velocity and (b) 2,3-DPG concentration similar to those occurring in vivo have only a weak effect on the oxygen dissociation velocity.

2,3-Diphosphoglycerate↗

PubMed1996

Polymerization of three hemoglobin A2 variants containing Val6 and inhibition of hemoglobin S polymerization by hemoglobin A2.

To understand determinants for hemoglobin (Hb) stability and Hb A2 inhibition of Hb S polymerization, three Valdelta6 Hb A2 variants (Hb A2 deltaE6V, Hb A2 deltaE6V,deltaQ87T, and Hb A2 deltaE6V, deltaA22E,deltaQ87T) were expressed in yeast, and stability to mechanical agitation and polymerization properties were assessed. Oxy forms of Hb A2 deltaE6V and Hb A2 deltaE6V,deltaQ87T were 2- and 1.6-fold, respectively, less stable than oxy-Hb S, while the stability of Hb A2 deltaE6V,deltaA22E,deltaQ87T was similar to that of Hb S, suggesting that Aladelta22 and Glndelta87 contribute to the surface hydrophobicity of Hb A2. Deoxy Hb A2 deltaE6V polymerized without a delay time, like deoxy Hb F gammaE6V, while deoxy Hb A2 deltaE6V,deltaQ87T and deoxy Hb A2 deltaE6V,deltaA22E,deltaQ87T polymerized after a delay time, like deoxy Hb S, suggesting that beta87 Thr is required for the formation of nuclei. Deoxy Hb F gammaE6V,gammaQ87T showed no delay time and required a 3.5-fold higher concentration than deoxy Hb S for polymerization, suggesting that Thr effects on Valdelta6 Hb A2 and Valgamma6 Hb F variants are different. Mixtures of deoxy Hb S/Hb A2 deltaE6V,deltaQ87T polymerized, like deoxy Hb S, while polymerization of Hb S/Hb A2 deltaE6V mixtures was inhibited, like Hb S/Hb F gammaE6V mixtures. These results suggest alpha2betaSdelta6 Val, 87 Thr hybrids and Hb A2 deltaE6V,deltaQ87T participate in Hb S nucleation, while only 50% of alpha2betaSdelta6 Val hybrids and none of the Hb A2 deltaE6V participate. These findings are in contrast to those of mixtures of Hb S with Hb F gammaE6V or Hb F gammaE6V,Q87T, which both inhibit Hb S polymerization. Our results also suggest participation in nucleation of some alpha2betaSdelta hybrids in A2S mixtures but not alpha2betaSgamma hybrids in FS mixtures.

Animals↗

PubMed1995

Chromatographic evaluation of minor hemoglobins: clinical significance of hemoglobin A1d, comparison with hemoglobin A1c, and possible interferences.

Using an HPLC procedure, we evaluated > 10 minor hemoglobins (Hbs) in healthy adults, individuals on long-term aspirin therapy, diabetic subjects, and uremic patients. Hb A1c and Hb A1d3 were the most abundant and important minor Hb components, respectively, accounting for 4.10% +/- 0.50% and 3.46% +/- 0.43% of total Hb in 361 healthy subjects. Acetylated Hb A was a potential interferent in the measurement of Hb A1c. The amounts of both Hb A1d3 and Hb A1carb were significantly increased in uremic patients, indicating that these Hb adducts may be carbamylated. There was a significant correlation (r = 0.69, P < 0.0001) between the amounts of Hb A1d3 and plasma urea in uremic patients. Nonuremic subjects were clearly separated from uremic patients with regard to the Hb A1d3 content of their total Hb. Our data suggest that Hb A1d3 is useful for assessment of the uremic state and that the combination of Hb A1c and Hb A1d3 could be well-suited for simultaneous control of carbohydrate and urea metabolism.

Aspirin↗

PubMed1996

Polymerization of recombinant hemoglobin F gamma E6V and hemoglobin F gamma E6V, gamma Q87T alone, and in mixtures with hemoglobin S.

To further understand determinants for Hemoglobin (Hb) S polymerization, as well as the inhibitory mechanism of Hb F on Hb S polymerization, Hb F variants containing Val-gamma 6 (Hb F gamma E6V) or Val-gamma 6, Thr-gamma 87 (Hb F gamma E6V, gamma Q87T) were expressed in yeast. The oxy form of Hb F gamma E6V was about 10-fold less stable to mechanical agitation than native oxy Hb F, which is similar to stability differences comparing oxy Hb S and oxy Hb A. Deoxy Hb F gamma E6V showed approximately 20-fold decreased solubility compared with native deoxy Hb F in high phosphate buffer and formed gels like deoxy Hb S in low phosphate buffer, indicating that the Val-gamma 6 substitution decreases solubility of Hb F like Val-beta 6 in deoxy Hb S. Oversaturated deoxy Hb F gamma E6V polymerized without a delay time in low and high phosphate buffers, in contrast to deoxy Hb S, which is accompanied by a distinct delay time before polymerization. Deoxy Hb F gamma E6V, gamma Q87T also polymerized without a delay time like deoxy Hb F gamma E6V. These results suggest that deoxy Hb F gamma E6V gamma Q87T polymers are different from those of deoxy Hb S, and that contact sites differ from those of deoxy Hb S, even though both have the same primary donor (A3) and acceptor sites in the EF helix. These results also suggest that other amino acids in addition to beta 6 Val and amino acids in the F helix are critical for nucleation-controlled polymerization of deoxy Hb S. 1:1 mixtures of deoxy Hb S and either Hb F variant polymerized with a delay time when the concentrations for the Hb S/Hb F gamma E6V and Hb S/Hb F gamma E6V, gamma Q87T mixtures were about 2- and 1.5-fold, respectively, higher than that for Hb S. Logarithmic plots of delay time versus concentration for Hb S/Hb F gamma E6V mixtures showed the same straight line as the line for Hb S/Hb S beta T87Q mixtures, but values for Hb S/Hb F gamma E6V, gamma Q87T mixtures were intermediate between those for Hb S and Hb S/Hb F gamma E6V mixtures. A 1:1 mixture of deoxy Hb A and Hb F gamma E6V, gamma Q87T also polymerized, but exhibited biphasic kinetics, when the concentration was increased to more than 3.5-fold higher than that required for Hb S polymer formation. These results suggest that Gin-gamma 87 is a critical amino acid for exclusion of FS hybrids (alpha 2 beta S gamma) from nuclei formation with Hb S. Our findings also show that Val-gamma 6 in hybrids that form in mixtures of the Hb F variants with either Hb S or Hb A interacts with the hydrophobic acceptor pocket on the EF helix of an adjacent tetramer containing Thr-beta 87.

Base Sequence↗

PubMed1965