Sickle-cell disease in a British urban community.

Seventy cases of sickle-cell disease were identified in the London Borough of Brent from records dating back to 1962. All but three were still alive and, with one exception, were recalled for confirmation of the diagnosis and to provide personal and family histories. The group consisted of 22 individuals with homozygous sickle-cell anaemia (Hb SS), 12 with sickle-cell/beta-thalassaemia double heterozygosity, 34 with sickle-cell/haemoglobin C disease (Hb SC), and two with the combination of haemoglobin S and hereditary persistence of fetal haemoglobin. They were predominantly of West Indian origin, more than half had been born in Britain, and most were aged under 25. The records for 304 patient admissions between 1962 and 1979 were analysed. There were 199 sickle-cell-disease-related admissions, 61 unrelated to sickle-cell disease, and 44 for pregnancy or its complications. Admissions per patient-year averaged less than one, except for children with Hb SS under the age of 5 years, who were admitted more frequently. The commonest reasons for admission were painful crises (74% of all admissions) and the "chest syndrome" (21%). There were four pneumococcal infections, all in children with Hb SS under the age of 8 years; all recovered. Three patients, aged 10, 15, and 50 years, died. The two children with Hb SS died in their sleep without gross evidence of sickling at necropsy. Multiple brain infarcts were found at necropsy in the 50-year-old woman with Hb SC who, having survived nine uneventful pregnancies, succumbed to an infection after cryosurgery to the cervix. Obstetric records were available for 18 term pregnancies in 11 women. Three antenatal sickling crises and three postpartum thromboembolic complications were encountered. There were no maternal or perinatal deaths. Fifteen asymptomatic individuals with sickle-cell disease were diagnosed as a result of routine screening procedures. There are likely to be many such individuals currently undiagnosed in the community. They urgently need identification because of their increased risks from pregnancy, surgery, and infection.     

The Sickle-cell and Altitude

High altitude seemed to be responsible for seven recent cases of sickling crisis. People with sickle-cell trait are at risk if they fly in unpressurized aircraft, which are used for many local air services. Those with sickle-cell haemoglobin C disease should avoid air travel even in pressurized aircraft. Possibly as a result of “autosplenectomy,” patients with sickle-cell anaemia seem to be able to fly in pressurized aircraft with little risk. All passengers and aircrew who might have some form of sickle-cell disease should be screened before flight.     

Anaesthesia in Sickle-cell States: A Plea for Simplicity

505 patients with various haemoglobinopathies were given a general anaesthetic between January 1970 and February 1972. One patient with haemoglobin SC disease and one patient with sickle-cell trait (HbAS) died postoperatively. Four other patients who were sickling positive, but whose genotypes were unknown, died, one from sickle-cell crisis precipitated by haemorrhage.A simple anaesthetic technique together with good postoperative care can provide safe general anaesthesia for patients with sickle-cell states. A plea is made for simplicity in the anaesthetic management of these patients.     

Thalassaemia in the British

Different forms of thalassaemia or related disorders were found in 116 people of apparently pure British stock. Among them were one family with a child homozygous for β-thalassaemia and eight heterozygous relatives, 16 families with 83 persons heterozygous for β-thalassaemia, two families with three persons with Hb H disease and three heterozygous for α-thalassaemia 1, one family with a child apparently homozygous for the “silent β-thalassaemia gene,” one family with six members heterozygous for a form of β-thalassaemia intermedia, and three families with 11 members heterozygous for different types of hereditary persistence of fetal haemoglobin. The clinical, haematological, and haemoglobin biosynthetic findings in these persons were similar to those of patients with thalassaemia from other racial groups. The heterozygous state for β-thalassaemia is overlooked in British patients, particularly during pregnancy, because it is not considered in the differential diagnosis of refractory anaemia. In many cases this leads to much unnecessary investigation and potentially harmful treatment.There seem to be several varieties of hereditary persistence of fetal haemoglobin production among British people. These conditions, while not causing anaemia, may cause difficulties during examination of maternal blood for fetal cells and may, if inherited with a β-thalassaemia gene, produce an unusually high level of Hb F in a person heterozygous for β-thalassaemia.     

Benign Obstetric History in Women with Sickle-cell Anaemia Associated with α-Thalassaemia

Two Ghanaian women with sickle-cell anaemia and α-thalassaemia were found to have an unusually benign obstetric history. In addition to two factors present which are known to moderate the clinical course of sickle-cell anaemia, good socioeconomic status and a relatively high Hb F level, it is suggested that α-thalassaemia may act among other things by lowering the haemoglobin concentration in the red cells and thereby lowering their tendency to sickle in vivo.     

Estimation of relative fitnesses from relative risk data and the predicted future of haemoglobin alleles S and C

Epidemiological studies of genetic differences in disease susceptibility often estimate the relative risks (RR) of different genotypes. Here I provide an approach to calculate the relative fitnesses of different genotypes based on RR data so that population genetic approaches may be utilized with these data. Using recent RR data on human haemoglobin beta genotypes from Burkina Faso, this approach is used to predict changes in the frequency of the haemoglobin sickle-cell S and C alleles. Overall, it generally appears that allele C will quickly replace the S allele in malarial environments. Explicit population genetic predictions suggest that this replacement may occur within the next 50 generations in Burkina Faso.     

Association of red cell glucose-6-phosphate dehydrogenase with haemoglobinopathies

A total of 1,112 randomly selected Saudi Arabs, of both sexes, living in Jeddah and the surrounding areas were screened for the phenotypic distribution of red cell glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). They were also investigated for haemoglobin and for thalassaemia. Phenotyping of the haemoglobins and the red cell enzymes was carried out by starch gel electrophoresis and the dye-decolouration screening test, while the investigation for thalassaemia was carried out by globin-chain biosynthesis, followed by column chromatography. The red cell Gd- alleles were significantly associated with the sickle-cell gene in both the males (chi 2(1): AS-28.80; SS-4.89) and females (chi 2(1): AS-10.99; SS-13.16). A similar association was also observed between G6PD deficiency and thalassaemias in males (chi 2(1): alpha-thalassaemia - 3.13; beta-thalassaemia - 11.06) and females (chi 2(1): alpha-thalassaemia - 6.63). However, no such association was detected between red cell 6PGD types and haemoglobin genes. The results suggest that the red cell G6PD deficiency, sickle-cell and thalassaemia genes might have evolved as a result of the same ecological factor, probably malaria.     

Effect of Maternal Sickle-cell Trait on Perinatal Mortality

Possession of the sickle-cell trait (Hb AS) by the African mother has been shown to be associated with a significant increase in perinatal mortality when there is anoxic stress. This observation should be taken into consideration in the management of labour of both the indigenous and immigrant mothers at risk. The findings do not influence the proposed explanations for the maintenance of high frequencies of the haemoglobin S gene in areas of endemic malaria.     

Growth,behaviour, and educational achievement of Jamaican children with sickle-cell trait.

A longitudinal study of the mental and physical development of 200 children with normal haemoglobin and 21 with the sickle-cell trait was carried out in a small rural community in Jamaica. At about 2 and 10 years of age heights and weights showed no significant differences. At about 10 years of age classroom behaviour, sociability, and educational achievement were similar. The results suggest that the sickle-cell trait does not affect growth and mental development.     

Relatively Benign Sickle-cell Anaemia in 60 Patients Aged Over 30 in the West Indies

A study in Jamaica of 60 patients with sickle-cell anaemia over the age of 30 years showed that most of them were in full-time employment. Pains in the bones or joints, leg ulceration, and jaundice were the most frequent types of presentation, but only two patients had a haemoglobin level consistently below 6 g./ 100 ml. Most of the patients were well developed and of average height, and, though the development of secondary sexual characteristics was delayed, there was an average of 2.6 pregnancies per patient. These findings suggest that the course is more benign than has been realized.     

Admissions to hospital of children with sickle-cell anaemia: a study in south London.

Admissions to hospital of 171 children with sickle-cell anaemia, genotype Hb SS, were reviewed over a 20-year period. Altogether 887 admissions occurred in 797 patient-years. The commonest cause of admission was painful vaso-occlusive crisis. Appreciable morbidity also resulted from pulmonary disease, infection, and anaemic episodes. The complications resulting in the most severe illness were acute splenic sequestration, pneumococcal meningitis, and some episodes of erythroid hypoplasia resulting in very low haemoglobin concentrations. Most deaths occurred in children aged under 5. Mortality and morbidity could be reduced by measures including prophylaxis of pneumococcal infections and more active treatment of seemingly minor illness in children with sickle-cell anaemia.     

Classification of complete blood count and haemoglobin typing data by a C4.5 decision tree,a naïve Bayes classifier and a multilayer perceptron for thalassaemia screening

This article presents the classification of blood characteristics by a C4.5 decision tree, a naïve Bayes classifier and a multilayer perceptron for thalassaemia screening. The aim is to classify eighteen classes of thalassaemia abnormality, which have a high prevalence in Thailand, and one control class by inspecting data characterised by a complete blood count (CBC) and haemoglobin typing. Two indices namely a haemoglobin concentration (HB) and a mean corpuscular volume (MCV) are the chosen CBC attributes. On the other hand, known types of haemoglobin from six ranges of retention time identified via high performance liquid chromatography (HPLC) are the chosen haemoglobin typing attributes. The stratified 10-fold cross-validation results indicate that the best classification performance with average accuracy of 93.23% (standard deviation = 1.67%) and 92.60% (standard deviation = 1.75%) is achieved when the naïve Bayes classifier and the multilayer perceptron are respectively applied to samples which have been pre-processed by attribute discretisation. The results also suggest that the HB attribute is redundant. Moreover, the achieved classification performance is significantly higher than that obtained using only haemoglobin typing attributes as classifier inputs. Subsequently, the naïve Bayes classifier and the multilayer perceptron are applied to an additional data set in a clinical trial which respectively results in accuracy of 99.39% and 99.71%. These results suggest that a combination of CBC and haemoglobin typing analysis with a naïve Bayes classifier or a multilayer perceptron is highly suitable for automatic thalassaemia screening.     

Erythropoietin and renal function in sickle-cell disease.

The relation between haemoglobin concentration, creatinine clearance, and the serum concentration of erythropoiesis-stimulating factor were assessed in 31 patients with homozygous sickle-cell disease. Haemoglobin concentrations fell significantly with decreasing creatinine clearance (r = 0.58, p less than 0.001) and were positively correlated with the concentration of erythropoiesis-stimulating factor (r = 0.65, p less than 0.001). These observations suggest that erythropoietin concentration is the factor limiting production of red cells in sickle-cell disease with renal insufficiency and have implications for treatment.     

Relation between Serum Cholesterol and Triglyceride Concentration and Haemoglobin Values in Non-anaemic Healthy Persons

In a study of 2,458 healthy non-anaemic subjects a positive correlation was found between haemoglobin levels and serum cholesterol and triglyceride levels. This may be due to simple changes in plasma volume, which may increase when the haemoglobin concentration decreases. Such an association between plasma lipid levels and haemoglobin values might be of importance in the aetiology of coronary heart disease, as a high haemoglobin value is known to be a “risk factor” in myocardial infarction.     

Haemoglobin scavenger receptor: function in relation to disease

Highly efficient systems remove the toxic and proinflammatory haemoglobin from the circulation and local sites of tissue damage. Macrophages are major haemoglobin-clearing cells; CD163 was recently recognized as the specific haemoglobin scavenger receptor (HbSR). It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection and inflammation. Haemoglobin functions as a double-edged sword. In moderate quantities and bound to haptoglobin, it forms a ligand for haemoglobin scavenger receptor CD163/HbSR, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. CD163/HbSR plays a crucial role in the control of inflammatory processes, probably in part through its effects on both ferritin induction and subsequent induction of antiinflammatory pathways through interleukin-10 and haem oxygenase. Besides the observation that the haemoglobin scavenger receptor provides a promising target for new treatment possibilities, it offers a novel view on the aetiology of diverse physiological as well as pathophysiological processes. In addition, monocyte CD163/HbSR and soluble CD163/HbSR are potential diagnostic tools in a variety of disease states, such as inflammation, atherosclerosis, transplant rejection, and carcinoma.     

Haemoglobin S and C affect the motion of Maurer's clefts in Plasmodium falciparum‐infected erythrocytes

The haemoglobinopathies S and C protect carriers from severe Plasmodium falciparum malaria. We have recently shown that haemoglobin S and C interfere with host‐actin remodelling in parasitized erythrocytes and the generation of an actin network that seems to be required for vesicular protein trafficking from the Maurer's clefts (a parasite‐derived intermediary protein secretory organelle) to the erythrocyte surface. Here we show that the actin network exerts skeletal functions by anchoring the Maurer's clefts within the erythrocyte cytoplasm. Using a customized tracking tool to investigate the motion of single Maurer's clefts, we found that a functional actin network restrains Brownian motion of this organelle. Maurer's clefts moved significantly faster in wild‐type erythrocytes treated with the actin depolymerizing agent cytochalasin D and in erythrocytes containing the haemoglobin variants S and C. Our data support the model of an impaired actin network being an underpinning cause of cellular malfunctioning in parasitized erythrocytes containing haemoglobin S or C, and, possibly, for the protective role of these haemoglobin variants against severe malaria.     

Thalassaemia is paradoxically associated with a reduced risk of in‐hospital complications and mortality in COVID‐19: Data from an international registry

Although numerous patient‐specific co‐factors have been shown to be associated with worse outcomes in COVID‐19, the prognostic value of thalassaemic syndromes in COVID‐19 patients remains poorly understood. We studied the outcomes of 137 COVID‐19 patients with a history of transfusion‐dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID‐19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID‐19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age‐, sex‐ and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in‐hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all‐cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in‐hospital, all‐cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all‐cause mortality. The presence of thalassaemia in COVID‐19 patients was independently associated with lower in‐hospital, all‐cause mortality and few in‐hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.     

Acid–Base Status of Adults with Sickle-cell Anaemia

Determinations of the acid–base status of 10 adult Jamaican patients with sickle-cell anaemia during “painful crisis” and after recovery showed no evidence of metabolic acidosis in the former, in contrast to reports from elsewhere. These results could explain the failure of alkalis to abort or alter the acute painful episodes of most patients with sickle-cell anaemia.     

On the nature of sickle-cell disease in the Arabian Peninsula

Summary The sickle-cell gene contributes substantially to the presentation of anaemia in certain areas of the Arabian Peninsula. However, the clinical presentation of the homozygous state of Hb S is less severe than that observed in other ethnic groups, such as American negroes. In the present paper, biosynthesis studies performed on reticulocytes from heterozygotes and homozygotes for the Hb S give further indications of the mild nature of sickle-cell disease in Arabia. Comparison of two affected families, from Saudi Arabia and Jordan, showed that clinical manifestation of the disease is mirrored by the biochemical and haematological findings in affected individuals. The results are discussed in terms of the effect of co-existing thalassaemia and/or iron deficiency with Hb S. It is suggested that both genetic and acquired conditions play a role in the clinical features of the disease. The mechanisms responsible for regulation of -chain synthesis by iron (haem) deficiency are discussed.     

A highly cost effective method of mass screening for thalassaemia.

A simple, fast, and reliable two step procedure for the detection of non-alpha-thalassaemias in mass screening programmes is presented. Step 1 consists of a study of red cell morphology and a one tube red cell osmotic fragility tests. This step eliminates the non-thalassaemic samples; the rest are processed through step 2, consisting of determination of red cell indices and haemoglobin studies. Over the past seven years this procedure has been used at this centre in mass screening secondary school students in Latium. Blood samples from 289 763 students were examined, and 6838 cases of thalassaemia detected. It is estimated that 0.35 +/- 0.25% of subjects with thalassaemia escaped detection by this procedure.