HbF Concentration Research Articles

Plasma Levels of TNF- in Sickle Cell Patients Receiving Hydroxyurea

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-) from human macrophages in vitro and the concentration of TNF- is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF- and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF- and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF- was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF- in the StSt group was not significantly different than in the VOC group; however, the plasma TNF- tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF- (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-. These findings suggest that a HU-induced increase in TNF- does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF- does not counteract the beneficial effects of HU in SCD.

Hemoglobin F in primary myelofibrosis and in myelodysplasia.

Our study investigated two groups of adult patients with established diagnoses of primary myelofibrosis (21 patients) and myelodysplastic syndromes (MDS) (21 patients). The objective was to assess fetal hemoglobin (HbF) concentration and to investigate correlations with organomegaly and extramedullary hematopoiesis and with the level of anemia and blood transfusion requirement. In all patients, the diagnosis was confirmed by histopathological examination. Patients with myelofibrosis were investigated by ferrokinetics using 59Fe. The percentage of marrow sideroblasts was assessed in patients with refractory anemia with ringed sideroblasts. Increased values of HbF were found to occur both in patients with myelofibrosis and with MDS, although a higher incidence and higher concentrations were evident in patients with myelofibrosis. Statistically significant increases in HbF concentration were found when there was accompanying organomegaly, as compared to patients without this feature. The average HbF concentration in both groups of patients under study was twice as high in cases with as in those without marrow fibrosis. The difference was statistically significant. Increased HbF levels appear to correlate with extramedullary hematopoiesis. HbF concentration did not correlate with the level of anemia or with requirement for blood transfusion.

ßS-Haplotypes in sickle cell anemia patients from Salvador, Bahia, Northeastern Brazil

BetaS-Globin haplotypes were studied in 80 (160 betaS chromosomes) sickle cell disease patients from Salvador, Brazil, a city with a large population of African origin resulting from the slave trade from Western Africa, mainly from the Bay of Benin. Hematological and hemoglobin analyses were carried out by standard methods. The betaS-haplotypes were determined by PCR and dot-blot techniques. A total of 77 (48.1%) chromosomes were characterized as Central African Republic (CAR) haplotype, 73 (45.6%) as Benin (BEN), 1 (0.63%) as Senegal (SEN), and 9 (5.63%) as atypical (Atp). Genotype was CAR/CAR in 17 (21.3%) patients, BEN/BEN in 17 (21.3%), CAR/BEN in 37 (46.3%), BEN/SEN in 1 (1.25%), BEN/Atp in 1 (1.25%), CAR/Atp in 6 (7.5%), and Atp/Atp in 1 (1.25%). Hemoglobin concentrations and hematocrit values did not differ among genotype groups but were significantly higher in 25 patients presenting percent fetal hemoglobin (%HbF) > or = 10% (P = 0.002 and 0.003, respectively). The median HbF concentration was 7.54+/-4.342% for the CAR/CAR genotype, 9.88 3.558% for the BEN/BEN genotype, 8.146 4.631% for the CAR/BEN genotype, and 4.180+/-2.250% for the CAR/Atp genotype (P = 0.02), although 1 CAR/CAR individual presented an HbF concentration as high as 15%. In view of the ethnic and geographical origin of this population, we did not expect a Hardy-Weinberg equilibrium for CAR/CAR and BEN/BEN homozygous haplotypes and a high proportion of heterozygous CAR/BEN haplotypes since the State of Bahia historically received more slaves from Western Africa than from Central Africa.

Protein glycosylation in diabetes mellitus: biochemical and clinical considerations

Protein glycosylation in diabetes mellitus: biochemical and clinical considerations

Haemoglobin F and A2in Nigerian Children with Sickle Cell Anaemia

The concentration of haemoglobins F and A2 in 132 Hb SS children aged 6 months to 16 years and 50 age- and sex-matched controls has been determined. The mean HbF concentration in Hb SS patients and controls were 9.5 per cent (range 1.7-24.5 per cent) and 1.5 per cent (range 0.5-14.4 per cent) respectively while HbA2 concentrations were 2.7 per cent (range 1.6-3.7 per cent) and 2.4 per cent (range 1.3-3.9 per cent) respectively. For 18 Hb SS patients seen in the stable state and during vaso-occlusive crisis, there was no significant difference in HbF concentration between the two states.

Severity differences in beta-thalassaemia/haemoglobin E syndromes: implication of genetic factors.

Genetic factors determining the difference in severity of anaemia in beta-thalassaemia/HbE disease were studied in 90 patients who had haemoglobin levels, at steady state, ranging from 4.2 to 12.6 g/dl. Co-inheritance of alpha-thalassaemia 2 and haemoglobin Constant Spring could significantly decrease the severity of the disease. Inheritance of a beta-thalassaemia chromosome with Xmn I cleavage site at position -158 of the G gamma-globin gene which was linked to the haplotype -+-++ or ++-++, was associated with a milder anaemia. Two copies of these alleles were necessary to produce a significant clinical effect. Increased expression of the G gamma-globin gene and higher production of haemoglobin F, which could reduce the overall globin chain imbalance, were also associated with homozygosity for the Xmn I cleavage site and thus with less severe anaemia. However, this effect was not seen in Xmn I site heterozygotes. Whether the effects of the Xmn I polymorphism, HbF concentration and G gamma/A gamma ratio act separately or through common mechanisms in reducing anaemia remains to be ascertained.

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia [see comments

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Hydroxyurea: Effects on Hemoglobin F Production in Patients With Sickle Cell Anemia

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Fetal haemoglobin and early manifestations of homozygous sickle cell disease.

The relevance of fetal haemoglobin (HbF) concentration to the development of early clinical manifestations of homozygous sickle (SS) disease has been investigated by examining the time to first occurrence and the proportional hazard of these complications in three groups of the HbF distribution at age 5 years. HbF was significantly related to dactylitis, painful crises, acute chest syndrome, and acute splenic sequestration. The relationship suggested that a critically low HbF concentration increased the risk, little difference in risk occurring between the medium and high HbF groups. The abdominal painful crisis and hypersplenism were not related to HbF concentration suggesting that the degree of sickling may not be important in their genesis. Parental education on acute splenic sequestration should be focused on children with HbF concentrations in the lowest part of the HbF distribution for age.

9-Hydroxybenfluron

The main purpose of the present investigation was to study the effect of 9-hydroxybenfluron (HBF) on aerobic glucose consumption, lactic acid formation, content of total (T-SH) and non-protein thiol groups (NP-SH), endogenous respiration and levels of ATP in both Ehrlich ascites and P388 murine leukemia cells. The lowest concentrations of HBF significantly stimulated both glucose consumption and lactate formation in Ehrlich ascites cells. HBF decreased the level of both T-SH and NP-SH in Ehrlich cells. However, the decrease in the level of NP-SH was significantly higher. Both respiration and ATP levels were inhibited more markedly in Ehrlich than in P388 cells. In P388 cells a significant decrease in ATP level (67%) was noted only at the highest concentration of HBF (100 mumol/l).

Fetal Hemoglobin Screening in Whole Blood and in Plasma of Cancer Patients

Fetal hemoglobin (HbF) screening was performed on 296 cancer patients. In almost 80% of the patients with active disease (n = 197) and 35-60% of those with inactive disease (n = 99), the concentration of HbF in the blood was above the normal range. Among patients with metastatic breast carcinoma (n = 27), 89% had a high HbF concentration. The HbF level was significantly higher (p less than 0.001) in patients with active disease than in those with inactive disease. There is evidence of an ectopic production of HbF into the plasma of patients, but it will be necessary to develop a method for the prevention of hemolysis in order to establish this claim.

Initial blood fetal hemoglobin concentration is elevated and is associated with prognosis in children with acute lymphoid or myeloid leukemia

We examined the relationship between initial blood fetal hemoglobin (HbF) concentration and prognosis in 100 children with leukemia. HbF concentration was usually elevated and ranged between 0 and 19.5 g/l. Multivariate analysis showed that, in patients with acute lymphoblastic leukemia (ALL), each increment of 1 g/l in initial HbF concentration resulted in a 1.13-fold rise in the risk of death or relapse (95% confidence limits 1.01-1.25, P less than 0.05). In patients with myeloid leukemias, each increment of 1 g/l in HbF was associated with a 1.20-fold (1.05-1.37, P less than 0.02) rise in the risk of death or relapse. In the patients with myeloid leukemias the mean initial HbF concentration was also higher (3.4 g/l; 0.5-19.5 g/l) than in the patients with ALL (1.1 g/l; 0-18.7 g/l; P = 0.08). Our results indicate that the degree of increase in HbF synthesis is associated with the degree of malignancy: the more aggressive the disease, the more augmented is the synthesis of HbF.

Comparison of homozygous sickle cell disease in Northern Greece and Jamaica

The clinical and haematological features of homozygous sickle cell (SS) disease were compared in 30 Greek and 310 Jamaican patients. Deletional α-thalassaemia, which modifies SS disease, is rare among Greek patients, so only Jamaican patients with four α-globin genes were included in the control group. Greek patients had higher total haemoglobin concentration and red cell counts, and lower mean cell haemoglobin concentration (MCHC) and reticulocyte counts. They also had a more normal body build and more adults had persistent splenomegaly. Fewer had a history of leg ulceration or priapism but more reported acute chest syndrome. The comparatively mild disease in Greek patients is consistent with less haemolysis and sickling and therefore less bone marrow expansion. In the absence of amelioriating factors such as high HbF concentration or α-thalassaemia, these findings may be explained by the low MCHC.

OXYHEMOGLOBIN AFFINITY MODULATES CEREBRAL BLOOD FLOW (CBF) IN PREMATURE BABIES

Low CBF is thought to cause periventricular leukomalacia in premature babies, but a normal outcome has also been observed. Low CBF found after exchange transfusion in lambs was explained by the lower oxygen affinity of adult as compared to fetal hemoglobin (HbF). We studied the influence of relative HbF concentration [HbF] and thus the oxygen affinity on CBF in 41 small premature infants: GA 29.1 ±2.0 wks, BW 1064 ±153 g (mean ±ISD). In cerebral ultrasonography 12 were found normal, 14 had subependymal or intraventricular hemorrhage (SEH/IVH), and 15 had intra-parenchymal anomalies (IPE). CBF was measured with the i.v. Xe-133 method at day 1,3 and 7, and [HbF] was obtained chromatographically. In normal babies a positive correlation between [HbF] and CBF was found: day 1 r= 0.62*, day 3 r=0.64*, day 7 r=0.63* (*=p<0.05). In those with SEH/IVH this correlation was significant only on day 3, in those with IPE only on day 7. Multiple regression analysis including all babies exept IPE showed a significant influence of [HbF] on CBF, independent of BP, pCO2 and Hct. We conclude that normal babies and to a lesser extent those with SEH/IVH or IPE can adapt their CBF to the actual oxygen affinity of blood.

Measurement of α‐Fetoprotein and Fetal Erythrocyte Levels for Detecting Fetomaternal Hemorrhage

This study was designed to measure changes in AFP levels and increases in fetal red cells in maternal blood before and after delivery to detect fetomaternal hemorrhaging in 41 full-term singleton deliveries. Discrepancy was noted between the increase in fetal red cells and the elevation of AFP levels. Six cases (14.6%) showed both elevation of AFP levels and an increase in fetal red cells. Six showed elevation of HbF concentration with stable AFP levels, and another 6 showed an increase in maternal serum AFP levels with stable HbF concentration. The measurements of maternal serum AFP levels seem highly useful for detecting FMH in the presence of fetomaternal blood incompatibility.

Evaluation of Fetal Hemoglobin in Various Malignancies with Reference to the Patients&amp;rsquo; Age

Concentration of fetal hemoglobin (HbF) was measured in the blood of 172 cancer patients with solid tumors. The patients' age groups were compared with matched age groups of normal controls. Above the age of 50, a significant difference was found between patients and normal controls. In 70% of the patients with active disease, the concentration of HbF was above the normal range. There were indications that by reducing HbF concentrations irradiation of patients interferes with the evaluation of the results. In addition to whole blood, HbF was also measured in the plasma of 35 patients; the average HbF concentration in this group was found to be twice as high as that of the controls.

Directly measured arterial oxygen saturation in the newborn infant

An understanding of oxygen transport is fundamental to the management of the critically ill neonate, because at no other time in life is the oxyhemoglobin dissociation curve in such a state of flux? Current practice relies almost exclusively on oxygen tension as an index of oxygenation, but oxygen content and saturation and the affinity of hemoglobin for oxygen are also important in tissue oxygen delivery.' We directly measure arterial oxygen hemoglobin saturation with a co-oximeter and calculate P503 (the Po2 at which the blood is 50% saturated) as a guide in the management of oxygen therapy. With this information we establish daily limits for the transcutaneous Po2 monitors in order to maintain HbO2% between 80% and 90%. We were impressed with the high carboxyhemoglobin levels recorded by the co-oximeter, but found that this is a feature of the instrument in the presence of fetal hemoglobin. +,5 This study was undertaken to test the hypothesis that the measured HbCO% is related to the HbF%; we postulated that it could provide an indirect but simple method of determining HbF concentration.

Graded hemagglutination inhibition for quantification of human fetal hemoglobin.

We describe a hemagglutination system for quantification of fetal hemoglobin (HbF), especially at low concentrations. This system consists of three components: (a) sheep erythrocytes coated with purified HbF, (b) sheep antiserum of human HbF made specific for the gamma-chain, and (c) human blood lysate with a known concentration of HbF as the standard. We can measure the whole range of HbF proportions in human blood, from 100% down to 0.01%. Statistical analysis showed that our measurements agreed with those made by the methods of alkali denaturation and radial immunodiffusion. Reproducibility of the method is shown by the low CVs for six repeated measurements. Low concentrations of HbF not measurable by other methods are easily assayed. We offer examples of the clinical utility of data on low concentrations of HbF.

Foetal Haemoglobin in Patients with Thyroid Disorders

The concentration of HbF and the number of HbF containing cells as measured by the sensitive fluorescent antiHbF antibody technique have been evaluated in 65 patients with treated and untreated thyroid dysfunction. The mean HbF concentration and mean percentage of F‐cells were both found to be significantly greater in untreated thyrotoxic patients than in those with treated thyrotoxicosis and treated or untreated hypothyroidism. The clinical relevance of these observations and their explanation by the modulating influence of thyroid hormones on erythropoiesis and Hb synthesis are briefly discussed.

Fetal hemoglobin and alpha-fetoprotein in various malignancies.

Fetal hemoglobin (HbF) concentrations were measured by a radial immunodiffusion assay in 233 patients with various malignancies. In 96 of these, alpha-fetoprotein (AFP) was also measured by radioimmunoassay. The concentration of HbF exceeded 2 SDs above the normal mean in 39 of 233 patients, most notably in patients with leukemia, lymphomas, multiple myeloma and testicular tumors. The proportion of HbF was not correlated with the total hemoglobin concentration or with serum AFP concentration.