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Biomedical subjects

M E Fabry

Publications and source records attributed to M E Fabry.

At least 73 records · Page 4Linked to original sources
PubMed1989

Pentoxifylline (Trental) has no significant effect on laboratory parameters in sickle cell disease.

The possible effect of pentoxifylline (Trental) in sickle celle disease was tested in 2 clinical trials: a controlled double-blinded intravenous study involving patients hospitalized with painful crises and an ublinded 5-month oral study in steady state patients. In the intravenous trial 29 painful episodes were treated in 16 patients. Complete blood counts, serum chemistries, red cell density gradients, intracellular pH, p50, whole blood viscosity, plasma viscosity and red cell distribution widths were monitored daily during the hospital admission. We confirmed the decrease of dense red cells during crisis and found, in addition, the related significant decrease in whole blood p50. There were no major differences in any of these parameters when pentoxifylline was compared to placebo for each individual day. When the data was examined over time, minor differences emerged. The red cell distribution width, the number of cells in density fraction SS2 (discocytes) and the plasma viscosity were all slightly higher over time in the pentoxifylline group than in the control group. In the oral group 23 patients were monitored for the same parameters on seven visits during a five month period. Administration of oral pentoxifylline produced no changes from baseline for all parameters examined except for a statistically significant, but minor, increase in plasma viscosity demonstrable for these patients during one visit only. We conclude that pentoxifylline has little effect on laboratory parameters in sickle cell disease.

Administration, Oral↗
PubMed1988

Atypical haplotypes linked to the beta S gene in Africa are likely to be the product of recombination.

We report here the haplotypes of 10 MstII-defined SS patients and a S/beta o thalassemia from the Central African Republic, exhibiting 7 different atypical haplotypes that are different from the typical Bantu haplotype that characterize over 93% of the beta s bearing chromosomes in that region of Africa. Of the seven atypical haplotypes, six can be easily interpreted as the result of recombination around the "hot spot" 5' of the beta gene, between a typical Bantu haplotype and other haplotypes available in the normal population. Except for one case that requires further study, this result demonstrates that the main mutational event leading to sickle hemoglobin in Bantu-speaking Africa was the mutation of the beta gene in a Bantu haplotype background.

Africa↗
PubMed1988

Evolution of laboratory parameters during sickle cell painful crisis: evidence compatible with dense red cell sequestration without thrombosis.

We find that during 51 episodes of sickle cell painful crisis indirect bilirubin fell 52% from its steady state value of 2.3 +/- 1.9 mg% to a value of 1.1 +/- 0.37 mg% at the end of crisis (p less than .00000085). The indirect bilirubin decline correlates with a decrease in the dense sickle cells during crisis (r = .31, p less than .0009). During steady state, both indirect bilirubin and lactic acid dehydrogenase correlate significantly with number of dense red cells (r = .62, p less than .000002 and r = .32, p less than .02 respectively). Platelet counts, beta-thromboglobulin, Platelet Factor 4, and Fibrinopeptide A levels all were elevated during steady state and did not change during the evolution of crisis. These data demonstrate that elevated indices usually associated with platelet activation are a feature of the steady state of sickle cell disease but argue against thrombosis as a factor in the progression of a sickle cell painful crisis episode. The parallel decline of both dense cells and bilirubin during painful crises indicates that the disappearance of dense cells during crisis is not caused by hemolysis and supports the hypothesis that dense red cell sequestration, in the absence of evidence of thrombosis, is an intrinsic component of the evolution of sickle cell painful crisis.

Adult↗
PubMed1988

Red cell density is sex and race dependent in the adult.

Using a highly sensitive method for the determination of red cell densities (Percoll-Stractan continuous isopyknic gradients), we find that, in adults, this parameter varies with sex and race. Whites have red cell densities (expressed as mean corpuscular hemoglobin concentration [MCHC]) that are, on the average, 0.7 gm/dl higher than those in blacks (the difference of the means has p less than 2 x 10(-7]. White men have, on the average, 0.6 gm/dl higher MCHC than white women (the difference of the means has p less than 6 x 10(-5]. We find a strong correlation between all red cell densities and intracellular K+ and a slightly weaker correlation between red cell density and intracellular Na+ + K+. Men have an average intraerythrocytic K+ that is approximately 4.5 mmol/L of red cells less than that of women among whites as well as blacks (p less than 10(-5) and p less than 9 x 10(-4), respectively). Blacks have significantly higher plasma ferritin levels than do whites (in addition to the sex difference). Future work will have to dissect the possible causes of these differences, which include the high incidence of deletional alpha-thalassemia (-a/aa) among blacks, menstruation, hormonal effects, and the red cell transport and volume regulation differences between sexes and races. Whatever the cause of the sex and racial differences reported here, they are bound to affect the pathophysiologic expression of genetic red cell diseases that are particularly sensitive to the MCHC, such as the sickle cell syndromes.

Black People↗
PubMed1988

Hemoglobin distribution width: a rapid assessment of dense red cells in the steady state and during painful crisis in sickle cell anemia.

Hemoglobin distribution width (HDW) is a measurement of the heterogeneity of the red cell hemoglobin concentration as determined by the Technicon H1 automatic counter. The utility of this measurement for patients with sickle cell disease was assessed in 275 samples from 61 patients. We found that patients with sickle cell disease in steady state had an elevated HDW (3.89 +/- 0.82 gm/dl) compared with the normal range of 2.2 to 3.2 gm/dl, and that this value correlated strongly with the number of dense red cells (r = 0.72, p less than 1 x 10(-10]. When HDW was determined daily for patients with SS in painful crisis, the decline in dense cells observed during this event was paralleled by a decrease in HDW. The percent of dense cells fell from steady state levels of 10.0% +/- 9.5% to 5.7% +/- 4.9% at the beginning (days 1 through 3) to 3.1% +/- 2.0% at the end of painful crisis (days 6 through 9). HDW decreased from the steady state value of 3.89 +/- 0.82 gm/dl to 3.44 +/- 0.73 gm/dl at the beginning of crisis and fell further to 3.14 +/- 0.40 gm/dl at the end. We conclude that HDW is a rapid and reliable assessment of the percent of dense cells in sickle cell disease and is a useful objective parameter to follow in sickle cell crisis.

Acute Disease↗
PubMed1987

The structure and formation of the glucose 6-phosphate adduct of hemoglobin A: a 31P-NMR study.

The glucose 6-phosphate adduct of hemoglobin formed on deoxy incubation of the sugar with hemoglobin is primarily present in solution as the unstable aldimine compound; in contrast, the percent ketoamine is higher if the adduct is formed in the presence of carbon monoxide. The adduct has a 31P nuclear magnetic resonance peak with a chemical shift which is 0.7 ppm up-field from the shift of unreacted glucose 6-phosphate at pH 7.0 and is constant between pH 6 and 8, while the unreacted sugar phosphate shows the characteristic change of chemical shift due to ionization of one of the phosphate protons. This suggests that, in the adduct, phosphate is involved in a salt bridge, probably at the 2,3-diphosphoglyceric acid binding site.

2,3-Diphosphoglycerate↗
PubMed1987

Volume-stimulated, Cl(-)-dependent K+ efflux is highly expressed in young human red cells containing normal hemoglobin or HbS.

We report here that a Cl(-)-dependent K+ (K:Cl) efflux, which is stimulated by N-ethylmaleimide (NEM) and by increased red cell volume, exists in young red cells of individuals with normal hemoglobin A (AA) and in those homozygous for hemoglobin S (SS). We have investigated this K:Cl efflux in several density-defined red cell fractions obtained from Percoll-Stractan continuous density gradients. We found high activity of the NEM-stimulated K:Cl transport in reticulocytes and young red cells from nine sickle cell (SS) patients (43 +/- 27 mean +/- SD mmol K+/liter of cells/hr = flux units (FU)) and in the young cell fraction of three AA individuals with high reticulocytosis recuperating from nutritional anemias (41.7 +/- 10 FU). In addition, we observed significant interindividual variation of this K:Cl efflux in the discocyte fraction of SS blood. Cell swelling markedly stimulated the K:Cl efflux, in SS whole blood (9.8 +/- 7.4 FU, in SS young cells (13 +/- 13 FU), and in AA young cells (21.4 +/- 11 FU). The activity of the Na-K-Cl cotransport, as estimated by the bumetanide sensitive K+ efflux was not found to be cell-age dependent in either AA or SS cells. Measurements of red cell density by isopycnic gradients indicated that 27% of the young cells reduce their volume by a Cl(-)-dependent process in hypotonic or low pH-induced swelling. The large volume-stimulated K:Cl efflux in AA young cells raises the possibility that these fluxes may be involved in the maturation of erythropoietic precursors.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Separation↗
PubMed1987

The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between G gamma and HbF level.

Previous work has demonstrated that the HbS gene has appeared and expanded three times in Africa in three separate geographic locations and that these three distinct mutational events can be identified by linked DNA polymorphic sites (haplotypes) surrounding the abnormal gene. We have reported that the Senegalese and Beninian haplotypes differ in G gamma expression, mean percentage of HbF, and percentage of dense cells. We now report on the third haplotype, the Bantu, and find that it has intermediate features, namely, the high mean percentage of HbF and low percentage of dense cells associated with the Senegalese haplotype, but with a low percentage of G gamma expression similar to the Beninian haplotype. The distribution of percent HbF is quite different from Senegal haplotype-bearing sickle cell anemia patients since it covers a much wider range. The low G gamma expression is also different from the Beninians since it contains a significant and unique cluster of individuals with lower than 38% G gamma. Interestingly, among the Bantu there is a strong correlation between HbF levels and G gamma expression, which is not seen with the other haplotypes. These findings open the possibility that among the Bantu haplotype-bearing individuals two chromosomal types exist that define different levels of G gamma and HbF expression. Further structural exploration of these two potential subhaplotypes is needed.

Anemia, Sickle Cell↗
PubMed1987

Deoxygenation inhibits the volume-stimulated, Cl(-)-dependent K+ efflux in SS and young AA cells: a cytosolic Mg2+ modulation.

We recently reported that the Cl(-)-dependent K+ (K:Cl) efflux, which can be stimulated by cell swelling in the presence of inhibitors of the Na+ pump (ouabain) and of the Na-K-Cl cotransport (bumetanide), is highly active in young AA and SS RBCs. We report here that deoxygenation inhibits volume-stimulated K:Cl efflux in SS and reticulocyte-enriched density-separated SS and AA RBCs. In SS whole blood, the K:Cl efflux stimulated by hypotonic (220 mOsm) swelling was reduced from 9.2 +/- 2 (mean +/- SE) in oxygen to 2.7 +/- 1.9 (mmol/L cell/h = flux units = FU) (n = 4) under deoxygenated conditions (P less than .005). Deoxygenation also decreased the acid pH-stimulated K:Cl efflux from 5.9 +/- 1.5 to 3.7 +/- 1.1 FU (n = 3) (P less than .025) but did not inhibit NEM-stimulated K:Cl transport. The effect of deoxygenation on density-separated SS cells is similar: When fraction SS2 (reversible discocytes) is deoxygenated under hypotonic conditions, the K:Cl efflux is reduced by 50%. In reticulocyte-enriched AA cells obtained from anemic patients, deoxygenation under hypotonic conditions also reduces K+ efflux by 50%. In SS cells only, deoxygenation under isotonic conditions results in an increased Cl(-)-independent K+ efflux. Because ionized Mg2+ in the cytosol increases during deoxygenation, we investigated the effect of external and internal Mg2+ on the volume-stimulated K:Cl efflux. Removal of external Mg2+ did not influence the rate of transport in oxygenated cells. When internal Mg2+ was clamped at 0.15 mmol/L with A23187 and EDTA at ionized cytosolic Ca2+ = O, however, the inhibitory effect of deoxygenation on the K:Cl efflux was eliminated. We conclude that deoxygenation inhibits the volume-stimulated, Cl(-)-dependent K+ efflux in AA and SS young red cells by concomitantly increasing ionized cytosolic Mg2+.

Anemia, Sickle Cell↗
PubMed1986

Erythrocyte sedimentation rate during steady state and painful crisis in sickle cell anemia.

To define its diagnostic utility in sickle crisis, the erythrocyte sedimentation rates of oxygenated blood were studied in patients with sickle cell anemia and healthy normal subjects using the Guest-Westergren method. A normal range for sedimentation rate as a function of hematocrit was established in 22 normal subjects. Twenty-seven asymptomatic patients with sickle cell anemia had abnormally low sedimentation rates in relation to their hematocrits. Those low sedimentation rates were not increased by substituting plasma from healthy control subjects, which suggests that the low sedimentation rate was a cell-related phenomenon. Sedimentation rates measured in 28 patients with sickle cell anemia at the end of uncomplicated painful crisis increased to levels appropriate for their degree of anemia. In patients with sickle crisis and medical complications, the sedimentation rates were even higher. At the end of an uncomplicated painful crisis, the mean plasma fibrinogen level was significantly higher than at the onset (p less than 0.005). When red cells from patients with sickle cell anemia at the end of crisis were suspended in normal plasma from control subjects, the sedimentation rates remained high. It is concluded that the erythrocyte sedimentation rate of asymptomatic patients with sickle cell anemia is abnormally low due to cellular factors, and the increase during painful crisis is due primarily to red cell changes, modified by plasma factors.

Adult↗
PubMed1986

The percentage of dense red cells does not predict incidence of sickle cell painful crisis.

To test the hypothesis that the tendency of hemoglobin S (HbS) to polymerize within cells is the major determinant of the incidence of vaso-occlusive episodes, we have examined the effect of the percentage of dense cells (as measured by Percoll-Stractan continuous density gradient centrifugation) on the frequency of painful crises in a group of 36 patients with sickle cell disease. No correlation was found between the percentage of dense cells and admissions for crisis. Among the patients with known alpha-gene status (n = 25), the strong correlation between decreased dense cells and alpha-thalassemia (-alpha/alpha alpha) reported previously was confirmed (P less than .001). In addition, in this small subset, patients with alpha-thalassemia (-alpha/alpha alpha) appeared to have a marginally increased number of admissions for sickle cell crisis (t = 2.1910, P less than .05), which was independent of the percentage of dense cells. We conclude that the percentage of dense sickle cells cannot predict the incidence of painful crisis, suggesting that other factors (microcirculatory regulation or other humoral and cellular factors) are more important in the generation maintenance of painful crises than the necessary, but not sufficient, tendency of HbS-containing red cells to sickle.

Adult↗
PubMed1986

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

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.

Anemia, Sickle Cell↗
PubMed1985

Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type.

Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa.

Adult↗