Iheanyi Okpala

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

Deferasirox is a once‐daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open‐label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (nu2003=u2003132) or deferoxamine (nu2003=u200363). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1u2003year, similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine. Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

The intriguing contribution of white blood cells to sickle cell disease – a red cell disorder

Sickle cell disease (SCD) is characterized by a point mutation that replaces adenine with thymidine in the sixth codon of the beta-globin gene, a unique morphological abnormality of red blood cells, vaso-occlusion with ischaemic tissue injury, and susceptibility to infections. Vascular lumen obstruction in SCD results from interaction of erythrocytes, leukocytes, platelets, plasma proteins, and the vessel wall. The disease phenotype is a product of various genes and environmental factors acting in concert with the protein lesion underlying the red cell anomaly. The severity of SCD increases with leukocyte count. The biological basis and therapeutic implications of this relationship are discussed. Leukocytes contribute to SCD by adhering to blood vessel walls and obstructing the lumen, aggregating with other blood cells with more effective blockage of the lumen, stimulating the vascular endothelium to increase its expression of ligands for adhesion molecules on blood cells, and causing tissue damage and inflammatory reaction which predispose to vaso-occlusion. Patients with impaired ability of leukocytes to kill microbes are more prone to infections; which precipitate sickle cell crisis. Reduction of leukocyte count ameliorates SCD. Similarly, targeted blockade or reduced synthesis of specific leukocyte adhesion molecules and their ligands might confer clinical benefit in SCD.

The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease

Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)‐glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate‐limiting enzyme upstream of UGT1A in the haem catabolic pathway, and α‐thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA]n and HMOX1 [GT]n promoter polymorphisms and α globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/β0, 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (Pu2003<u20030·0001 and Pu2003<u20030·01, respectively). While HMOX1 genotype had no effect, co‐inheritance of α‐thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.

The comprehensive care of sickle cell disease

Abstract: Millions of people across the world have sickle cell disease (SCD). Although the true prevalence of SCD in Europe is not certain, London (UK) alone had an estimated 9000 people with the disorder in 1997. People affected by SCD are best managed by a multidisciplinary team of professionals who deliver comprehensive care: a model of healthcare based on interaction of medical and non‐medical services with the affected persons. The components of comprehensive care include patient/parent information, genetic counselling, social services, prevention of infections, dietary advice and supplementation, psychotherapy, renal and other specialist medical care, maternal and child health, orthopaedic and general surgery, pain control, physiotherapy, dental and eye care, drug dependency services and specialist sickle cell nursing. The traditional role of haematologists remains to co‐ordinate overall management and liase with other specialities as necessary. Co‐operation from the affected persons is indispensable to the delivery of comprehensive care. Working in partnership with the hospital or community health service administration and voluntary agencies enhances the success of the multidisciplinary team. Holistic care improves the quality of life of people affected by SCD, and reduces the number as well as length of hospital admissions. Disease‐related morbidity is reduced by early detection and treatment of chronic complications. Comprehensive care promotes awareness of SCD among affected persons who are encouraged to take greater control of their own lives, and achieves better patient management than the solo efforts of any single group of professionals. This cost‐effective model of care is an option for taking haemoglobinopathy services forward in the new millennium.

Etilefrine for the prevention of priapism in adult sickle cell disease

Summary. Priapism is a common complication of sickle cell disease (SCD) that could lead to erectile dysfunction and psychosocial problems. Treatment of established fulminant priapism is usually not satisfactory. It is therefore important to prevent this complication of SCD. The alpha‐adrenergic agonist etilefrine (50–100u2003mg/d) produced a good clinical response in 13 of 18 (72%) adults who have recurrent priapism; 17 had SCD and one sickle cell trait. After a follow‐up of 1–48u2003months, none of the 18 people on etilefrine developed hypertension or sexual dysfunction. Similar efficacy and safety profiles of the drug have been reported previously.

The measurement of urinary hydroxyurea in sickle cell anaemia

Hydroxyurea is increasingly used in the treatment of sickle cell disease (SCD) although there is little evidence on how best to monitor treatment and compliance. It is also not known why 10–50% patients do not benefit from the drug and whether some of this resistance is because of pharmacokinetic factors. We have developed an assay using mass spectrometry (MS) to measure urinary concentrations of hydroxyurea. We have used this assay to study 12 children and six adults with SCD taking hydroxyurea and found that urinary hydroxyurea was present for at least 12u2003h following tablet ingestion. Thirty‐five urine samples were analysed that were expected to contain hydroxyurea, based on the reported timing of the last dose and hydroxyurea was detected in 29 (83%) of these. There were also marked differences in urinary hydroxyurea concentrations, suggesting pharmacokinetic variability may explain some of the differences in response to hydroxyurea. Urine samples were also analysed by MS for penicillin metabolites and 43 of the 57 (75%) contained phenoxyacetate, suggesting the ingestion of penicillin within the last 12u2003h. These assays are potentially useful to study hydroxyurea metabolism further, develop optimal dosing regimes and monitor compliance with treatment.

Hepcidin, haemoglobin and ferritin levels in sickle cell anaemia

To the Editor: The variant haemoglobin S (HbS) results from substitution of valine for glutamic acid as the sixth amino acid of b-globin (1). Homozygous HbSS disease or sickle cell anaemia (SCA) is characterised by reduced concentration of haemoglobin in the blood, susceptibility to infections, recurrent vasoocclusion, tissue infarction and complications such as stroke, avascular necrosis of joints or nephropathy (2). Tissue hypoxia from vessel obstruction facilitates deoxygenation of HbS, its crystallisation, erythrocyte sickling and chronic haemolysis (3). Recurrent tissue damage from vessel occlusion leads to chronic inflammation, as evidenced by increased levels of C-reactive protein and other inflammatory markers, even in steady-state SCA (4). A major public health problem on a global scale, SCA affects millions of people worldwide and about 300 000 newborns every year (5). Although the genetic mutation (GAG GTG) is identical in all HbSS patients studied to date, marked individual variation in disease severity occurs. Previous investigations have shown that differences in b-globin gene haplotype (6), the number of aglobin genes (7, 8), HbF levels (6, 9), neutrophil count (10) and leucocyte adhesion molecule expression (11) affect the severity of SCA. However, the biological basis of the individual variation in clinical severity is not completely understood. The novel iron-regulatory peptide hormone hepcidin is made in the liver, and inhibits intestinal absorption as well as macrophage recycling of iron (12). The gene for hepcidin is regulated by anaemia, hypoxia and inflammation, and its urinary excretion is greatly increased in patients with iron overload and infection (13). All these conditions occur in SCA. There is evidence that hepcidin has a role in the pathogenesis of anaemia of chronic inflammation (14, 15). Recent reports indicate that increased hepcidin production in inflammatory states is mediated via interleukin-6 (14, 16, 17); a cytokine known to be increased in SCA (18). From the perspective that chronic inflammation occurs in sickle cell disease, it is pertinent to find out if increased hepcidin production contributes to anaemia in the disorder. It has been suggested that blood levels of hepcidin and ferritin may correlate because they are regulated by similar pathological stimuli (14). In anaemia of chronic inflammation, hepcidin production is increased up to 100-fold and this may account for the sequestration of iron in macrophages (15). Hepcidin also has microbicidal activity (19, 20). People with SCA are prone to infection: a classical cause of inflammation, and the commonest precipitant of vaso-occlusive crisis (2). Repeated vasoocclusive infarction causes complications such as stroke or avascular necrosis of joints, and organ dysfunction such as nephropathy from cumulative loss of functional parenchyma tissue. Considering that hepcidin has antimicrobial properties and a role in the pathogenesis of anaemia in chronic inflammatory states, the specific objective of this study was to find out if plasma concentration of this peptide hormone affects steady-state haemoglobin and ferritin levels, number of disease complications or infections in SCA. Following informed consent, venous blood samples were obtained from 40 HbSS adults in steady state and 30 HbAA, healthy, racially-matched controls with similar age and sex-distribution. We excluded HbSS patients who had pregnancy in the previous 2 months, HbF ‡10%, any other disease apart from SCA or sickle crisis in the previous 2 months. Hb genotype was determined by highperformance liquid chromatography. In SCA patients steady-state Hb level was measured with the Beckman Coulter GEN-S analyser (Coulter Electronics, Luton, UK). Patients with complications of sickle cell disease (e.g. stroke, avascular necrosis or renal impairment), or who had infection during the period of 1 yr preceding the date of blood sampling were noted. Plasma hepcidin concentration was measured by enzyme-linked immunoassay using a commercially available kit (DRG Diagnostics, Marburg, Germany). Ferritin levels were determined by enzyme-linked immunoflourescence with the Beckman Coulter Access analyser. Eur J Haematol 2005: 74: 86–88 All rights reserved Copyright Blackwell Munksgaard 2005

Platelet count as a predictor of the severity of sickle cell disease during pregnancy

Summary Recent evidence implicates the immune system and the clotting mechanisms in the pathophysiology of sickle cell disease (SCD). This study investigates the association of steady state platelet count with the severity of SCD in pregnancy. A total of 40 SCD women who were asymptomatic early in pregnancy were studied retrospectively: 14 remained asymptomatic throughout pregnancy and 26 developed at least one SCD-related complication. The early pregnancy platelet count was compared between the two groups using t-test and its ability to predict SCD-related complications in pregnancy was investigated using Receiver-Operator Characteristics (ROC) curve. Compared with asymptomatic patients, women who developed SCD-related complications had significantly higher early-pregnancy platelet count [328×109/l (95% CI: 268–389) vs 210×109/l (146–275), p < 0.01]. The area under the ROC curve was 76.4% (95% CI 59.7–93.2). These indicate that the platelet count in early pregnancy is significantly higher in SCD patients who subsequently develop SCD-related complications and may be used for screening.