Spleen size in homozygous sickle cell disease: trends in a birth cohort using ultrasound.

OBJECTIVES: To provide ultrasound baselines for spleen length in homozygous sickle cell disease (HbSS) and in normal controls with a HbAA genotype. METHODS: The Jamaican cohort study identified 311 babies with HbSS and 246 matched HbAA controls during the screening of 100,000 consecutive deliveries in Kingston, Jamaica from 1973 to 1981. Ultrasonography commenced in 1988 when the youngest patients were aged 6 years at which time deaths, emigrations and default had reduced the numbers to 206 HbSS and 89 controls. It continued annually until 2000. RESULTS: The spleen was visualized in all HbAA controls but in only 1103/2138 (52%) scans in HbSS. Where available, mean splenic lengths were significantly lower in HbSS (77-103 mm in males, 70-83 mm in females) compared to normal controls (89-101 mm in males, 86-95 mm in females). Assessed by statistical modelling after adjusting for body height, the splenic ratio (splenic length/body height) declined over the age range 12-20 years in HbSS, consistent with progressive splenic fibrosis. Genetic factors known to inhibit sickling, α thalassemia and fetal hemoglobin level (HbF) significantly reduced the decline in splenic ratio. Clinical splenomegaly was an insensitive measure of splenic enlargement as only 50% of patients aged 18 years and above with spleens measuring ≥150 mm on ultrasonography had palpable spleens. CONCLUSIONS: An age-related decline in splenic length occurred in HbSS and occurred more slowly with genetic factors known to inhibit sickling. The standards provided may be of value in assessing minor degrees of subclinical acute splenic sequestration. ADVANCES IN KNOWLEDGE: These are the first standards available for splenic length in HbSS. They may be useful in detecting red cell sequestration, not apparent from clinical splenomegaly and also provide a model for identifying factors inhibiting vaso-occlusion.

Newborn screening for abnormal haemoglobins in Jamaica: Practical issues in an island programme.

OBJECTIVE: To report the diagnostic challenges of newborn screening for abnormal haemoglobins. SETTING: Cord blood samples from 13 hospitals in southwest Jamaica taken in 2008-2019. METHODS: Blood spots, collected from the umbilical cord, were analysed by high pressure liquid chromatography (HPLC) to reveal phenotypes for HbSS and HbCC, but genotype confirmation may require parental studies or gene sequencing. Such cases that were successfully traced were analysed in this follow-up study. RESULTS: HPLC screening of 121,306 samples detected HbAS in 11,846 (9.8%), HbAC in 4508 (3.7%) and other electrophoretic abnormalities in 1090 babies. Among 101 previously unconfirmed cases, 34/90 (38%) with HPLC evidence of a HbSS phenotype had other genotypes, and 7/11 (64%) with a HbCC phenotype had other genotypes. Syndromes from the interaction of ß thalassaemia occurred in 112 babies (85 with HbS, 27 with HbC) and of genes for hereditary persistence of fetal haemoglobin (HPFH) in 18 (12 with HbS, 6 with HbC). Variants other than HbS and HbC occurred in 270 babies, 16 in combination with either HbS or HbC, and 254 as traits. Most variants are benign even when inherited with HbS, although HbO Arab, HbD Punjab, or Hb Lepore Washington, which occurred in 6 cases, may cause sickle cell disease. CONCLUSIONS: Genes for ß thalassaemia and HPFH are common in western Jamaica and when associated with HbS may present diagnostic challenges in newborns, as HbF and HbA2 have not reached diagnostic levels. Family and DNA studies may be necessary for genotype confirmation.

Causes of death and early life determinants of survival in homozygous sickle cell disease: The Jamaican cohort study from birth.

Globally, the majority of persons born with sickle cell disease do not have access to hydroxyurea or more expensive interventions. The objectives were to estimate the survival in homozygous sickle cell disease, unbiased by symptomatic selection and to ascertain the causes of death in a pre-hydroxyurea population. The utility of early life biomarkers and genetically determined phenotypes to predict survival was assessed. A cohort study based on neonatal diagnosis was undertaken at the Sickle Cell Unit, a specialist clinic delivering care to persons with sickle cell disease in Jamaica. Screening of 100,000 deliveries detected 315 babies with homozygous sickle cell disease of whom 311 have been followed from birth for periods up to 43 years. Pneumococcal prophylaxis and teaching mothers splenic palpation were important, inexpensive interventions. Anticipatory guidance, routine care and out-patient acute care were provided. Each participant was classified as alive, dead, or defaulted (usually emigration). Causes of death were ascertained from clinical records and/or post-mortem reports. Survival was assessed using the Kaplan-Meier function. Sex-adjusted Cox semi-parametric proportional hazards and Weibull modelling were used to assess the effects on survival of biomarkers. Survival to 40 years was 55.5% (95% CI 48.7% to 61.7%). Acute Chest Syndrome (n = 31) and septicemia (n = 14) were significant causes of death at all ages. Acute splenic sequestration (n = 12) was the most common cause of early deaths. Survival was significantly shorter in those with lower hemoglobin at 1 year, high total nucleated count at 1 year, and a history of dactylitis ever. In these hydroxyurea naïve patients, survival into midlife was common. Causes of death were often age specific and some may be preventable. Early life biomarkers predictive of decreased survival in SS disease identify a patient group likely to benefit from close clinical supervision and potentially high risk therapies.

ß-Thalassemia Mutations in Jamaica: Geographic Variation in Small Communities.

Over the last 43 years, surveys of over 200,000 subjects in Jamaica have identified ß-thalassemia (ß-thal) mutations. In most, these genes were detected at birth in patients with sickle cell-ß-thal and so the prevalence and distribution would not be influenced by subsequent clinical course. There were two newborn populations, 100,000 deliveries in the corporate area between 1973-1981 and 84,940 in south and western Jamaica between 2008-2016. A third population, which derived from the Manchester Project in central Jamaica, screened 16,612 secondary school children, aged predominantly 15-19 years, and identified 150 students with the ß-thal trait and 11 with sickle cell [Hb S (HBB: c.20A>T)]- or Hb C (HBB: c.19G>A)-ß-thal. The latter patients may have been subject to symptomatic selection, but this should not have affected those with ß-thal trait. Of the 24 different molecular mutations, ß0-thal genes accounted for 10.0-27.0% of these groups and most common was IVS-II-849 (A>G) (HBB: c.316-2A>G). Of the ß+ mutations, seven subjects had severe genes with low levels of ß chain synthesis but the majority were benign mutations in the promoter region. The -29 (A>G) (HBB: c.-79A>G) mutation dominated in the newborn study in Kingston, similar to experiences in Guadeloupe and African Americans but the -88 (C>T) (HBB: c.-138C>T) mutation was more common among school students in central Jamaica. Caribbean populations are genetically heterogeneous but variations within different parts of Jamaica is of potential importance for prenatal diagnosis and genetic counseling. This information may also be useful among the large Jamaican diaspora.

The haematology of homozygous sickle-cell disease - abstract

The purpose of the study was to investigate age- and sex-related variations in the haematology of older patients with SS disease, in order to determine haematological characteristics possibly favouring survival. Steady state haematology was available in 181 patients aged 40-73 years. There appeared to be no consistent sex differences in any of the indices examined. Longitudinal analyses were performed for the 133 patients with at least two observations, using analysis of covariance (ANCOVA) methods. Highly significant declines in total haemoglobin (Hb), platelet counts and absolute reticulocyte count were displayed in both sexes. Overall, Hb levels decreased by approximately 0.076 gm/dl/year in females and 0.113 gm/dl/year in males. Significant increases occurred in HbA, HbF and MCV in females only. The total nucleated count (NBC) fell with age, although the decline was only significant 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 the 84 patients with normal creatinine levels (C=120 æmol/l). The mechanism for this bone marrow failure is currently unknown. The prevalence of homozygous alpha thalassaemia in the study group (4.4 percent) was similar to that in the overall SS population, providing no evidence that this may lead to improved survival, as has been suggested (AU)

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 cell beta§ thalassaemia and in 130 control subjects with a normal (AA) genotype. The mean RDW was moderately increased in Sbeta+ thalassaemia and SC disease and markedly increased in Sbeta§ thalassaemia and SS disease. In SS, SC and Sbeta§ 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. (AU)

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

Alpha thalassemia modifies the gematolic 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 biliru-bin 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 study the gematologic 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.(AU)

The haematology of steady state homozygous sickle cell disease: frequency distibutions, 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 (Summary)

Effect of alpha thalassaemia on the rheology of homozygous sickle cell disease

A study of rheological determinants (plasma viscosity, whole-blood viscosity, and erythrocyte deformability) was made in 24 matched pairs of patients with homozygous sickle cell disease, with and without homozygous x-thalassaemia. Patients with coexisting x-thalassaemia showed a significant increase in erythrocyte deformability measured as filtration of washed erythrocytes through 5 um diameter pores and also as viscosity of whole blood at high shear rate (230s-1) and standard haematocrit (0.45). This rheological advantage may explain the beneficial effect of x-thalassaemia 2 on haematological parameters and clinical events in homozygous sickle cell disease (AU)

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 groups showed a significantly lower mean cell volume and the placebo group contained a significant excess of children experiencing multiple episodes of datylitis. 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 (AU)

Post-natal decline of fetal haemoglobin in homozygous sickle cell disease: relationship to parental 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 cell (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 onwards but, unlike the normal controls, no sex differences 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 á-like globin gene complex and be in linkage disequilibrium with the áý allele (Summary)

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

Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (O-/O-), may be heterozygous for alpha-thalessemia 2 (O-/OO), or may have a normal alpha-globin-gene complement (OO/OO). 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 Aý, 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 billirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (O-/OO) 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 the other two subgroups. These data confirmed 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.

Sickle cell-Hb Lepore Boston syndrome: uncommon differential diagnosis to homozygous sickle cell disease

Two siblings assumed on the basis of clinical and hematological evidence to have homozygous sickle cell (SS) disease were found to have a mother without sickle hemoglobin. Subsequent investigation and hemoglobin structural studies indicated the diagnosis to be sickle cell-Hb Lepore Boston syndrome. This syndrome generally manifests clinically significant sickle cell disease, and this genotype should be borne in mind in apparent SS disease where a parent without sickle hemoglobin is discovered.(AU)

Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent

Since 1952, 112 childen with sickle cell anaemia (SCA) in Jamaica have had an aplastic crisis. Outbreaks occurred in 1956, 1960, 1965-67, 1971-73, and 1979-80. Most cases occurred in children under 10 years of age, and an aplastic crisis in a patient over the age of 15 years is rare. There were 38 cases in 1970-80 and stored serum specimens from 28 of these were available for virus studies. Evidence for infection with a parvovirus-like agent was found in 24 of these 28 cases. Viral antigen was detected in 2 patients, both of whom demonstated seroconversion. Serconversion during 1980 was detected in a further 7, increasing amounts of antibody during the convalescent period were found in 5, antibody was found in 2 of 4 patients from whom only an acute phase specimen was available and the remaining 10 were antibody positive in the only convalescent phase sample available for testing. Antibody was found in 4 of 94 controls with the SS genotype (in retrospect 2 of these may have had an aplastic crisis) and in 17 percent of 48 controls with a normal haemoglobin (AA) genotype. The results accord with the possibility that the parvovirus-like agent is the principal cause of aplastic crisis in SCA (Summary)

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 occured. 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 2 months and then fell steadily throughout the remaining period of study. The mean cell voloume 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 haemoglobin levels from 15 months to 4« 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 MCHA 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 (Summary)

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 continously 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/1) 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 (AU)

Comparison of sickle cell-beta§ thalassaemia with homozygous sickle cell disease

Clinical and haematological features in 41 patients with sickle cell-᧠thalassaemia (S᧠thalassaemia) and in 123 age-sex matched controls with homozygous sickle cell (SS) disease were compared. Persistence of splenomegaly was more common and fetal loss less common in S᧠thalassaemia but other clinical features were similar in the two genotypes. Total haemoglobin, Hb A2, PCV, CCV, and red cell count were significantly higher and MCV, MCH, MCHC,and ISC counts significantly lower in Sá§thalassaemia. Proportional reticulocyte counts were significantly lower in S᧠thalassaemia but there was a difference in absolute reticulocyte counts. Persistence of splenomegaly and low ISC counts are compatible with decreased intravascular sickling which may result from the lower mean cell haemoglobin S concentration in S᧠thalassaemia. If beneficial effects of a low MCHC can be confirmed then a carefully monitored trial of iron deficiency in SS disease may be a logical experimental procedure.(AU)

The determinants of irreversible sickled cells in homozygous sickle cell disease

The relationship between the irreversible sickled cell (ISC) count and other haematological parameters has been investigated. Positive correlations occurred with MCH, MCHC, and with two expressions of intracellular Hb S content. Since the ISC has a high MCHC, the positive correlations with MCHC and with factors derived from the MCHC may be difficult to evaluate. Negative correlations occurred with total haemoglobin and Hb F. The MCHC was found to affect the relationship between HbF and ISC count, a low MCHC being associated with, and probably determining, lower ISC counts at any level of Hb F. It is proposed that a low MCHC may inhibit ISC formation and the practical implications of this are discussed (AU)

The development of haemoglobin A2 in normal negro infants and in sickle cell disease

The development of haemoglobin A2 levels from birth to 3 years has been compared in normal, á-thalassaemia trait, sickle cell (SS) disease, and S-á-thalassaemia genotypes. Hb A2 levels were almost identical in normals and in children with SS disease at 1, 2 and 3 years. The most rapid increases in Hb A2 levels occurred before 6 months but levels were still rising at the end of the third year. Sickle cell-á+ thalassaemia could be differentiated from SS disease by the higher Hb A2 levels between 6 months and 1 year. Insufficient data were available on S-᧠thalassaemia but since Hb A2 levels in this condition are generally higher than those in S-á+ thalassaemia, differentiation from SS disease may also be possible from the age of 6 months (AU)