The haematology of homozygous sickle cell disease after the age of 40 years.

Haematological indices have been studied in 181 patients with homozygous sickle cell (SS) disease aged 40-73 years. Cross-sectional analyses in 5-year age bands indicated age-related decreases in HbF (males only), total haemoglobin and platelet counts. Longitudinal studies within individuals confirmed the downward age-related trend in haemoglobin and platelets and also revealed a falling reticulocyte count, most significant when expressed as absolute values. Total nucleated cells also fell although the decline was significant only in females. These observations are consistent with a progressive bone marrow failure which is not explained by the commonly occurring renal impairment in older SS patients since the changes persisted in analyses confined to patients with normal creatinine levels. The mechanism of this bone marrow failure is currently unknown.

The red cell distribution width in sickle cell disease--is it of clinical value?

The red cell distribution width (RDW) has been studied during the clinical steady state in 1121 patients with homozygous sickle cell (SS) disease, 344 with sickle cell-haemoglobin C (SC) disease, 68 with sickle cell-beta+ thalassaemia, 49 with sickle cell beta 0 thalassaemia and in 130 control subjects with a normal (AA) genotype. The mean RDW was moderately increased in S beta + thalassaemia and SC disease and markedly increased in S beta 0 thalassaemia and SS disease. In SS, SC and S beta 0 thalassaemia genotypes, lower RDW values occurred in females and with alpha thalassaemia. The RDW correlated negatively with total haemoglobin, mean cell haemoglobin concentration, mean cell volume, and fetal haemoglobin (HbF) and positively with reticulocyte count in SS disease. A low RDW was associated with higher weight and less frequent dactylitis, painful crisis, acute chest syndrome, acute splenic sequestration, and hospital admissions. A low RDW in SS disease is consistent with a high total haemoglobin, high HbF, low reticulocyte count, alpha thalassaemia, and a more mild clinical course.

Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood.

alpha Thalassemia modifies the hematologic expression of homozygous sickle cell (SS) disease, resulting in increased total hemoglobin and HbA2 and decreased HbF, mean cell volume, reticulocytes, irreversibly sickled cells, and bilirubin levels. The age at which these changes develop in children with SS disease is unknown. Ascertainment of globin gene status in a large representative sample of children with SS disease has afforded an opportunity to study the hematologic indices in nine children homozygous for alpha thalassemia 2 (two-gene group), 90 children heterozygous for alpha thalassemia 2 (three-gene group), and 167 children with a normal alpha globin gene complement (four-gene group). The two-gene group had significantly lower mean cell volumes from birth, higher red cell counts from one month, lower reticulocytes from three months, and higher HbA2 levels from one year, as compared with the four-gene group. Children with three genes had intermediate indices but resembled more closely the four-gene group. Differences in total hemoglobin or in fetal hemoglobin between the groups were not apparent by eight years of age. The most characteristic differences of the two-gene group were the raised proportional HbA2 level and low mean cell volume, the latter having some predictive value for alpha thalassemia status at birth.

Haematological change in sickle cell-haemoglobin C disease and in sickle cell-beta thalassaemia: a cohort study from birth.

The haematological changes in early years following neonatal diagnosis have been observed in representative groups of children with sickle cell-haemoglobin C (SC) disease, sickle cell-beta(+) thalassaemia, and in sickle cell-beta(0) thalassaemia. Most haematological indices in SC disease were intermediate between previously published values in SS disease and in AA controls, generally being closer to values in normal children. Exceptions were microcytosis which may be genetically determined and a striking elevation of mean cell haemoglobin concentration from age 2 months to 4 years. The combination of a raised MCHC and a lowered MCV is unusual and may be characteristic of SC disease. Features in sickle cell-beta thalassaemia generally differed according to the type of beta thalassaemia gene. Sickle cell-beta(0) thalassaemia had lower levels of haemoglobin, MCHC, red cell count, MCV, and higher reticulocytes, most differences being significant before 1 year. No differences between S beta(0) thalassaemia and S beta(+) thalassaemia were apparent in HbF levels (which resembled those in SS disease) or in HbA2 levels (which exceeded those in SS disease by 1 year of age).

The haematology of steady state homozygous sickle cell disease: frequency distributions, variation with age and sex, longitudinal observations.

The steady state haematological characteristics observed in 1071 patients with homozygous sickle cell (SS) disease aged 5-66 years are presented. Cross sectional studies indicated that HbA2 levels were consistently higher in males but no age related change was apparent. Fetal haemoglobin levels were consistently higher in females and fell significantly in males between the 5-9 and 10-14 year age groups. Total haemoglobin was significantly higher in females before age 15 and higher in males after 20 years, a dramatic age related rise occurring in males between the 10-14 and 25-29 year age groups, and a fall in patients aged 40 years and over. The mean cell volume was consistently greater in females after 15 years and a marked age related rise occurred in both sexes between the 5-9 and 25-29 year age groups. Counts of irreversibly sickled cells were consistently higher in males. Reticulocytes fell significantly with age, while platelets and total bilirubin fell significantly after the age of 15 years. Longitudinal studies confirmed the increase in total haemoglobin levels in males over the ages 10-14 years, and a significant fall in males after the age of 30 years. Such studies also confirmed the fall in HbF in males aged 5-14 years, the increase in MCV in both sexes aged 5-29 years, and the fall in platelet counts in both sexes over the age of 20 years. These observations provide 'normal' values for patients seen elsewhere and also contribute to an understanding of factors determining the haemoglobin indices in SS disease.

Alpha thalassaemia and the haematology of normal Jamaican children.

Haematological indices were studied from birth to 9 years in a representative sample of 195 children with a normal haemoglobin (AA) genotype subdivided according to the number of alpha globin genes. These were 5 homozygotes for alpha-thalassaemia 2 (two-gene group), 60 heterozygotes for alpha-thalassaemia 2 (three-gene group), and 130 with a normal alpha globin gene complement (four-gene group). HbF and HbA2 showed no differences between the groups. Compared to the four-gene group, the three-gene group tended to have significantly lower levels of total haemoglobin, MCHC, MCV, and MCH, and higher levels of red cell count. These differences became apparent with increasing age in the order of MCV, RBC, MCHC, and total haemoglobin. The data suggested that haematological differences were more marked in the two-gene group but with the small numbers available, the differences were not significant.

A trial of folate supplementation in children with homozygous sickle cell disease.

A double blind controlled trial of supplementation with folic acid has been performed in 117 children with homozygous sickle cell (SS) disease aged 6 months to 4 years over a 1 year period. No megaloblastic change was observed in either group. At the end of the study period the folate supplemented group showed no significant differences in haemoglobin, growth characteristics, or in the proportion of children affected by major or minor infections, acute splenic sequestration, dactylitis or episodes of bone or abdominal pain. However, the folate supplemented group showed a significantly lower mean cell volume and the placebo group contained a significant excess of children experiencing multiple episodes of dactylitis. The results are compatible with mild folate deficiency in some patients in the placebo group but the absence of striking effects on haematology or growth suggest that the policy of regular folate supplementation in children with SS disease should be critically reviewed.

Post-natal decline of fetal haemoglobin in homozygous sickle cell disease: relationship to parenteral Hb F levels.

The decline of fetal haemoglobin (Hb F) from birth to 6 years has been compared in a cohort of 266 Jamaican children with homozygous sickle cel (SS) disease and in 243 matched controls with a normal haemoglobin (AA) genotype. Hb F levels were significantly higher in the SS cases from 1 month onward but, unlike the normal controls, no sex difference was apparent. The Hb F levels in SS disease were significantly correlated with parental Hb F levels, suggesting that genetic factors regulating adult Hb F levels are active at earlier stages in development. Furthermore, some of these genetic determinants of Hb F production may be linked to the beta-like globin gene complex and be in linkage disequilibrium with the beta s allele.

The interaction of alpha-thalassemia and homozygous sickle-cell disease.

Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (alpha-/alpha-), may be heterozygous for alpha-thalassemia 2 (alpha-/alpha alpha), or may have a normal alpha-globin-gene complement (alpha alpha/alpha alpha). We compared the clinical and hematologic features of 44 patients who had sickle-cell disease and homozygous alpha-thalassemia 2 with those of controls with the two hematologic conditions. The patients with homozygous alpha-thalassemia 2 had significantly higher red-cell counts and levels of hemoglobin and hemoglobin A2, as well as significantly lower hemoglobin F, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte counts, irreversibly-sickled cell counts, and serum total bilirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (alpha-/alpha alpha) had intermediate values. In the group with homozygous alpha-thalassemia 2, fewer patients had episodes of acute chest syndrome and chronic leg ulceration and more patients had splenomegaly, as compared with patients in other two subgroups. These data confirm previous suggestions that alpha-thalassemia inhibits in vivo sickling in homozygous sickle-cell disease and may be an important genetic determinant of its hematologic severity.

The development of haematological changes in homozygous sickle cell disease: a cohort study from birth to 6 years.

A cohort study of sickle cell disease from birth has allowed observations on the disease without the symptomatic selection inherent in previous series. The development of haematological indices from birth to 6 years in male and female infants with homozygous sickle cell (SS) disease is presented and compared with values in age and sex matched controls with a normal haemoglobin (AA) genotype previously presented elsewhere. In SS disease total haemoglobin levels fell rapidly from birth to a plateau at 3-6 months before falling again to 15 months after which no age related change occurred. Mean cell haemoglobin concentration fell from birth to lowest values at 15-18 months before increasing to reach the level present at birth by the age of 5 years. Red cell counts fell rapidly after birth to a plateau at 2 months, increased slightly to 6 months and then fell steadily throughout the remaining period of the study. The men cell volume and mean cell haemoglobin also fell rapidly after birth reaching the lowest values by 6 months and then increased progressively. Female patients showed significantly higher MCV from 4 to 8 months and significantly higher haemoglobin levels from 15 months to 4 1/2 years. Compared to AA controls, SS patients manifested significantly lower levels of haemoglobin from 2 weeks, and red cell counts from 1 month, and significantly higher levels of MCHC from 4 months to 3 years, MCV from 8 months to 5 years, and serum iron levels from 1 to 4 years. Children with SS disease were partially protected from iron deficiency in early childhood, perhaps by increased intestinal absorption of iron, and the associated increase in intracellular haemoglobin concentration might be disadvantageous during this high risk period.

Haematological indices in normal negro children: a Jamaican cohort from birth to five years.

Haematological indices, including total haemoglobin, mean cell haemoglobin concentration, red cell count, mean cell volume, mean cell haemoglobin, reticulocytes, and serum iron values, in a cohort of 243 randomly selected Negro children with normal haemoglobin genotype, followed from birth to 5 years, are reported. Total haemoglobin fell rapidly from high levels at birth to a plateau at 2-6 months; a secondary fall occurred after 6 months and a gradual increase after 18 months. The red cell count also fell rapidly, but increased after 2 months to a plateau and then slowly declined from age 1-5. Mean cell volume and mean cell haemoglobin fell continuously from birth to the lowest values at 15 months and then progressively increased to the age of 5 years. Serum iron levels were low at one year of age (mean 9.7 mumol/l) increasing slowly by age 4 and sharply by age 5. Mean cell haemoglobin concentration fell gradually to 1-1 1/2 years and then increased progressively to age 5. Values for Hb, MCHC, MCV, and MCH were consistently and often significantly lower in males before the age of 2 years, compatible with greater depletion of iron stores. Serum iron values were generally lower in males but there was no sex difference at one year when highly significant differences in Hb, MCHC, MCV, and MCH occurred. The cause of sex differences in early haematological development is currently unclear.