Clinical Manifestations Of Sickle Cell Disease Research Articles

β‐Globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon

Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the beta-globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the beta-globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the epsilon-Ggamma-Agamma-psibeta-delta-beta-globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF < 5%, Group B: HbF between 5 and 15%, and Group C: HbF > 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon.

Relationship between the clinical manifestations of sickle cell disease and the expression of adhesion molecules on white blood cells.

The severity of sickle cell disease (SCD) increases with leukocyte count. The biological basis could be that leukocyte adherence to vascular endothelium mediated by adhesion molecules (AMs) facilitates vaso-occlusion, the basic pathological process in SCD. To find out if there is a relationship between expression of AMs by leukocytes and the clinical manifestations of SCD. Flow cytometry was used to study the relationship between leukocyte AM expression and disease manifestations in 100 patients with homozygous (HbSS) sickle cell disease and 34 genotype HbAA controls. The effect of hydroxyurea therapy on AM expression was also examined. We excluded HbSS patients with any other disease, pregnancy in the previous 3 months, or Haemogloben F (HbF) > or = 10%. Patients with complications of SCD showed high expression of alphaMbeta integrin by the neutrophils; and l-selectin by lymphocytes and neutrophils (P < 0.03). CD18 was highly expressed by neutrophils in patients with sickle nephropathy (P = 0.018), and l-selectin by lymphocytes in those with stroke (P = 0.03). Monocyte l-selectin increased in sickle cell crisis relative to steady state (P = 0.04). Expression of alphaLbeta2 integrin by neutrophils, monocytes, and lymphocytes decreased within a month of hydroxyurea therapy (P < 0.05), with symptomatic improvement in the patients and no more than 3.3% rise in HbF level. The findings suggest that in SCD (1): High steady-state expression of alphaMbeta2 integrin and l-selectin by leukocytes predisposes to severe manifestations. (2) Increased leukocyte AM expression above steady-state levels could be important in the genesis of crisis. (3) The early symptomatic improvement that follows hydroxyurea therapy is mediated via mechanisms independent of increased HbF, and may involve reduced AM expression in leukocytes. (4) Other treatment modalities that reduce leukocyte AM expression might also confer clinical benefit.

Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease

Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

Variation in Fetal Hemoglobin Parameters and Predicted Hemoglobin S Polymerization in Sickle Cell Children in the First Two Years of Life: Parisian Prospective Study on Sickle Cell Disease

Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

Relationship of plasma alpha tocopherol to index of clinical severity in individuals with sickle cell anemia.

Several parameters of micronutrition related to antioxidant activity are reduced in individuals with sickle cell anemia (SCA). The data presented here suggest that vitamin E, specifically alpha tocopherol, has a significant correlation (r = -0.38, P < 0.04) with a retrospective survey of clinical events and a significant correlation with a prospective survey of clinical events (r = -0.42, P < 0.03). The survey of clinical events score takes into account important vaso-occlusive manifestations in SCA. Differences in plasma vitamin E levels explained about 15% of the variability in the clinical manifestations of SCA in the population studied. Previously reported data from our lab suggests that the differences in alpha tocopherol levels are not related to dietary intake. Vitamin E may play an important role in modulating the ability of sickle hemoglobin containing erythrocytes to produce vaso-occlusion. Alternatively, it may simply be a marker of disease activity. Studies are ongoing at our center to determine if the relationship of alpha tocopherol to clinical events is causal.

Studies in sickle-cell anemia: II. Clinical manifestations of sickle-cell anemia in children (an analysis of thirty-seven cases with observation on the use of ACTH and cortisone in two additional cases)

Summary Thirty-seven cases of sickle-cell anemia have been reviewed. The disease occurred in twenty-seven males and ten females. The average age of onset of symptoms was 3.5 years while the average age of first admission to the hospital was 4.5 years. Abdominal and joint pains and anorexia were the most frequent symptoms observed in these cases. Respiratory infections, pallor, icterus, splenomegaly, and cardiac murmurs were the most outstanding physical findings. Some of the clinical difficulties encountered in the diagnosis of sickle-cell anemia are discussed. The parameter test of Winsor and Burch has been useful in the differential diagnosis of this disease. The therapy in these cases was essentially supportive, consisting chiefly of blood transfusions and measures to combat respiratory infections. There were five deaths in this series, representing a mortality of 13.5 per cent. The prognosis in sickle-cell anemia has improved since the advent of modern chemotherapy and antibiotics. Two cases in which ACTH and cortisone were successful in relieving joint pains have been reported. ACTH and cortisone give promise of value in the management of hemolytic crises by controlling severe joint and abdominal pains. Should future clinical observations confirm our preliminary impression regarding the value of ACTH and cortisone in the control of hemolytic crises, the questionable use of splenectomy with its attendant mortality may be discontinued in the management of this disease.