Homozygous sickle cell disease and priapism in the eastern province of Saudi Arabia

Two adult sickle cell homozygotes from the eastern oases of the Kingdom of Saudi Arabia presented with severe persistent priapism. Each patient had a high Hb F of 24%, and their red cells were neither hypochromic nor microcytic. Priapism probably occurs more frequently in homozygous sickle cell disease than reported previously from this region. It would appear that a high fetal haemoglobin alone without hypochromia and microcytosis--features suggestive of co-existing alpha-thalassaemia--does not protect against this agonizing vaso-occlusive event.     

Glycosylated hemoglobin levels in a benign form of sickle cell anemia in Saudi Arabia

Glycosylated hemoglobin was determined by the thiobarbituric acid method in sickle cell anemia patients from the Eastern Province of Saudi Arabia. The level of glycosylated hemoglobin in a Saudi SS sample (4.36%, SD 0.83) is 90% of that of the sample of normals (4.85%, SD 0.51). This is in contrast with the reported value of glycosylated hemoglobin in an American Black SS sample (3.9%, SD 0.6), which is only 60% of that of the sample of normals (6.6%, SD 0.7). The fetal hemoglobin level in Saudi sickle cell patients was 12.03% (SD 4.84), which is significantly different from that of Americans of African origin at p = 0.001. There was no significant correlation (r = 0.236) between the percentages of glycosylated Hb and Hb F at the 10% confidence level. The reported positive relationship between the percentages of glycosylated Hb and Hb F in American Blacks seems to be valid in the Saudi population only up to the level of 10-12% of fetal hemoglobin. Above this threshold of Hb F no further alleviating effect is seen. The 2,3-diphosphoglycerate value in Saudi Hb SS adults was 21.7 mumol/g (SD 7.4) and accordingly only twice as high as that of normal individuals. The benign clinical course exhibited by Saudi sickle cell patients is reflected by the survival of the RBC as indexed by its content of glycosylated Hb and 2,3-diphosphoglycerate. Moreover 10-12% of fetal hemoglobin in the RBC seems sufficient to ameliorate the severity of this disease in patients from the Eastern Province of Saudi Arabia.     

Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5' to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.     

Modulation of fetal hemoglobin in sickle cell anemia

A partial understanding of the pathophysiology of sickle cell disease has suggested one means of treatment-increasing the distribution and concentration of fetal hemoglobin in sickle erythrocytes. Although this can be accomplished clinically with drugs like hydroxyurea, a complete understanding of the molecular and cellular basis of fetal hemoglobin regulation may suggest new and better ways of attaining this goal.     

Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long- term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.     

Priapism in association with sickle cell anemia in Saudi Arabia

A questionnaire study of 42 Saudi patients with sickle cell anemia revealed that none of them had ever suffered from priapism. A comparison of hematological parameters between Jamaican priapism patients and Saudi non-priapism patients suggested that high Hb F levels and hypochromic microcytosis in Saudi patients might play an important role in preventing this complication.     

Splenic function in sickle cell anemia patients in Qatif, Saudi Arabia

A prospective study was conducted to study the splenic function among sickle cell anemia (SCA) patients in Qatif (Eastern Province of Saudi Arabia). Seventy-seven patients (30 children and 47 adults aged 2-57 years) were included. (99m)Tc stannous colloid liver-spleen scan was done for each patient during steady state. The splenic function was graded from 0 to 4 in relation to liver uptake. Seventy percent of our patients showed evidence of splenic hypofunction, and most of them (83%) had severe hyposplenism. Up to the age of 4 years, only 17% of the children showed evidence of functional hyposplenism, but by the age of 10 years >50% were hyposplenic. Most of the hyposplenic children had functional hyposplenism, whereas only one-third of hyposplenic adults had autosplenectomy. There was no effect of level of HbF on the frequency of hyposplenism, but on the other hand low MCV seems to be protective against hyposplenism. A significant number of adult SCA patients have clinically enlarged spleens, and almost a third have normally functioning spleens. Because of the low prevalence of hyposplenism in children younger than 4 years of age, routine penicillin prophylaxis is probably not indicated in this population, an issue which needs further evaluation.     

Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate

Intravenous arginine butyrate has been shown to increase fetal hemoglobin (HbF) in sickle cell and thalassemia patients. Recently, we observed that sodium 4-phenylbutyrate, a drug administered orally to treat urea cycle disorders, increases HbF production in nonanemic children and adults. We treated six subjects with sickle cell disease over a period of 14 to 179 days. All subjects received their initial therapy of 9 to 13 g/m2/day as 0.5-g tablets of sodium 4-phenylbutyrate as inpatients. All subjects showed a rapid increase in the percentage of F-reticulocytes (pretreatment, 1% to 20%; posttreatment, 10% to 44%). Four subjects were treated only 11 to 25 days as inpatients. Two of these four subjects failed to respond to the outpatient component because of their inability to maintain an intake of 30 to 40 tablets per day. One subject (C) developed a rash at day 10 and discontinued treatment at day 14. Another subject (B) was transfused for a painful crisis on day 25. Subject A, treated for 179 days, has an increased percentage of F cells, from 54% to 77%, and increased HbF levels, from 10.6% to 18%. Subject F, treated for 154 days, has an increased percentage of F cells, from 59% to 73%, and an increased percentage of HbF, from 10.4% to 16%. All subjects showed some increase in weight. Subject A developed mild transient ankle edema. Myelotoxicity was not seen in any treated patient. Oral administration of sodium 4- phenylbutyrate rapidly increases F-cell production in sickle cell disease.     

On the nature of sickle cell disease in the south-western province of Saudi Arabia

Sickle cell disease (SCD) occurs at a high prevalence in different parts of Saudi Arabia. Several reports indicate that the disease follows a mild clinical course in the Saudi population of the eastern province of Saudi Arabia, while little is known about the disease in other parts of the country. This study was conducted on 53 children from the Saudi Arabian south-western province with sickle cell disease and 53 age- and sex-matched normal controls (haemoglobin AA phenotype). A statistically significant difference was encountered in the haematological parameters investigated in the two groups. The SCD patients were divided into subgroups with high and low Hb F levels, alpha- and beta-thalassaemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. The haematological parameters were then compared in the different sub-groups. No significant difference could be demonstrated in the haematological parameters in patients with a high or low Hb F level. In patients without thalassaemia, the red cell count, total haemoglobin and haematocrit were significantly lower, while MCV, MCH and MCHC were higher. G-6 PD deficiency existed in association with thalassaemias, and apart from a reduction in MCV and MCH, no other statistically significant difference could be demonstrated. Clinical examination revealed a severe disease with several cases suffering from the hand and foot syndrome.     

Fetal hemoglobin in sickle cell anemia

Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.     

2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, gamma-globin synthesis ratio, complete blood count, and chemistry were measured. The average gamma-globin synthesis relative to non-alpha-globin synthesis prior to therapy was 3.19% +/- 1.43% and increased to 13.66% +/- 4.35% after treatment. HbF increased from 3.55% +/- 2.47% to 13.45% +/- 3.69%. F cells increased from 21% +/- 14.8% to 55% +/- 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% +/- 1.61% to 2.6% +/- 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% +/- 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.     

Non-benign sickle cell anaemia in western Saudi Arabia

Seventy-one Saudi and Yemeni Arabs with sickle cell anaemia from western Saudi Arabia aged between 1 1/2 and 42 years were studied. The mean steady state haemoglobin concentration of 8.1 g/dl was lower than that of 10.7 g/dl reported previously for sickle cell anaemia in eastern Saudi Arabia. The patients were divided into an SSLF group with fetal haemoglobin (HbF) of 10.0% or below (44 patients) and an SSHF group having HbF above 10.0% (27 patients). No significant differences were found in the haemoglobin concentrations, haematological indices and incidences of bone changes of the two groups. SSLF patients were significantly more prone to infections (P less than 0.01), however. Also, there was an overall high incidence of hepatomegaly (69.0%) and splenomegaly (54.9%) and hepatomegaly was significantly more common in the SSLF group (P less than 0.02). Many of the patients, even with HbF levels over 10.0%, did not follow a benign course and suffered from severe anaemia, infections of the respiratory and urinary tracts, bone pains and infarcts, or bossing of the skull. Rarer complications included hepatic crisis, chest syndrome, retinal haemorrhage, epistaxis and hemiplegia. It is therefore apparent that Saudi Arabian sickle cell anaemia, even in patients with raised haemoglobin F levels, may be as clinically severe as in African patients.     

Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia

Fetal hemoglobin (HbF, α(2)γ(2)) is a major contributor to the remarkable phenotypic heterogeneity of sickle cell anemia (SCA). Genetic variation at 3 principal loci (HBB cluster on chromosome 11p, HBS1L-MYB region on chromosome 6q, and BCL11A on chromosome 2p) have been shown to influence HbF levels and disease severity in β-thalassemia and SCA. Previous studies in SCA, however, have been restricted to populations from the African diaspora, which include multiple genealogies. We have investigated the influence of these 3 loci on HbF levels in sickle cell patients from Tanzania and in a small group of African British sickle patients. All 3 loci have a significant impact on the trait in both patient groups. The results suggest the presence of HBS1L-MYB variants affecting HbF in patients who are not tracked well by European-derived markers, such as rs9399137. Additional loci may be identified through independent genome-wide association studies in African populations.     

Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia

Patients with sickle cell anemia are at risk for organ damage including kidney disease. Microalbuminuria may be an early marker of disease progression. This retrospective review analyzed laboratory and clinical findings in children with sickle cell anemia according to the presence or absence of MA during well clinic sickle cell visits. Results were analyzed in sum as well as by therapeutic intervention (not on therapy,hydroxyurea therapy, or chronic transfusion therapy). Thirty two of 144(22%) children had MA, including 20 of 82 (24%) children not on a therapeutic intervention (chronic transfusion or hydroxyurea). In children not on therapy, low hemoglobin, low fetal hemoglobin and high lactate dehydrogenase were associated with MA. Frequency of positive screens for MA for the different treatment groups were: Hydroxyurea 13%; chronic transfusion 26% and children on no treatment 24%. However,the difference between the hydroxyurea group and the chronic transfusion or no treatment groups did not reach statistical significance.Increased hemoglobin and fetal hemoglobin may provide protection against kidney disease in sickle cell anemia and should be evaluated in a randomized, prospective clinical trial.     

Fibrocongestive splenomegaly in sickle cell disease: a distinct clinicopathological entity in the Eastern province of Saudi Arabia

Sickle cell disease displays a unique progression in the Eastern province of Saudi Arabia, where splenomegaly with hypersplenism is noted with high frequency in the adolescent and adult patients. The late persistence of splenomegaly although likely reflects the milder progression of sickle cell disease in this region; nevertheless, it predisposes the patients to increased morbidity. The present study documents the characteristic clinicopathological features of splenomegaly associated with sickle cell disease in the Al-Hassa region of Eastern province Saudi Arabia. Forty-four cases of sickle cell disease patients in whom splenectomy was performed during 1999-2003 were studied. The hemoglobinopathy profiles of the patients (age range 5-42 years) comprised sickle cell anemia (8 cases), sickle cell anemia with high fetal hemoglobin (23 cases), and sickle cell-beta degrees thalassemia (13 cases). All patients had manifestations of hypersplenism and 39 patients experienced episodes of minor-type sequestration crisis. Splenectomy was effective in ameliorating the hematological abnormalities in all cases, without any major complications in the follow-up period. The splenectomy specimens showed moderate-to-marked enlargement in most cases, with histological features of fibrocongestive splenomegaly and prominent Gandy-gamma body formations. Micro-infarcts in 27 cases and gross infarctions in 9 cases were evident. The relationship of persistent splenomegaly with higher fetal hemoglobin levels and splenic hypofunction is examined along with the significance of splenectomy in these cases.