Malaria Infection in Patients with Sickle Cell Disease in Nigeria: Association with Markers of Hyposplenism.

Malaria is considered an important cause of morbidity and mortality among people living with sickle cell disease (SCD). This has partly been attributed to the loss of splenic function that occurs early in the disease process. We conducted a cross-sectional study and determined the frequency of malaria infection among SCD patients and explored the association with spleen's presence on ultrasonography and spleen function assessed using the frequency of Howell-Jolly bodies (HJBs). A total of 395 participants consisting of 119 acutely-ill SCD patients, 168 steady-state SCD controls, and 108 healthy non-SCD controls were studied. The prevalence of Plasmodium falciparum parasitemia was 51.3% in acutely-ill SCD patients, 31.7% in steady-state SCD controls, and 11.0% in the healthy non-SCD controls; however, the mean parasite density was significantly higher in the non-SCD controls compared to both SCD groups (p = 0.0001). Among the acutely-ill SCD patients, the prevalence of clinical malaria and severe malaria anemia were highest in children <5 years of age. The prevalence of parasitemia (p = 0.540) and parasite density (p = 0.975) showed no association with spleen presence or absence on ultrasonography. Similarly, the frequency of HJB red cells was not associated with the presence of parasitemia (p = 0.183). Our study highlights the frequency and role of malaria infection in acutely-ill SCD patients, especially in those younger than five years. Although we have found no evidence of an increased risk of malaria parasitemia or parasite density with markers of hyposplenism, the role played by an underlying immunity to malaria among SCD patients in malaria-endemic region is not clear and needs further studies.

Determinants of splenic preservation among patients with sickle cell disease in North-Eastern Nigeria.

OBJECTIVE: In patients with sickle cell disease (SCD), the spleen commonly enlarges during early childhood, but undergoes reduction in size and fibrosis from repeated episodes of vaso-occlusion and infarction. The rate of progression of this process varies markedly among these patients. The aim of current study was to explore clinical and laboratory factors associated with the preservation of the spleen among these patients. METHODS: Two hundred four patients with SCD (103 females; age 1-45 years) underwent abdominal ultrasonography at the University of Maiduguri Teaching Hospital, Nigeria between October 2020 and November 2021 to assess for splenic visualisation and echotexture. Steady-state clinical parameters and blood samples for full blood count, serum chemistry, high-performance liquid chromatography and malaria parasitemia were obtained from all the patients. RESULTS: The spleen was visualised in 107 (52.4%; 95% confidence interval [CI], 46%-59%) patients with SCD on ultrasonography. While the spleen was visualised in all children less than 5 years of age, it was visualised in only 23.5% of those aged 15 years and older. Visualisation of the spleen was significantly associated with low mean corpuscular haemoglobin concentration and high haemoglobin F (HbF) in those younger than 10 years. The odds of visualisation of the spleen on ultrasonography increased by a factor of 1.17% for every 1% increase in HbF level. Only 32 (15%) patients were on regular hydroxyurea therapy. The HbF level was significantly higher among patients on hydroxyurea (median 12.7 vs. 7.4; p < 0.0001). CONCLUSION: In patients with SCD, failure to visualise the spleen was not found in children less than 5 years old. Patients with visualised spleens had a higher level of HbF than those with non-visualised spleens. HbF was significantly associated with visualisation of the spleen before 10 years of age. Since early administration of hydroxyurea will increase HbF level, we expect that it would help to preserve the spleen.

Anti-inflammatory cytokines in sickle cell disease.

Sickle cell disease (SCD) is a well-studied monogenetic disease with an established chronic inflammatory component. The paradigm shift towards inflammation has made the pathophysiology of SCD even more complex. Studies have shown that an imbalance between the pro-inflammatory and anti-inflammatory cytokines in SCD exists; however, the reports are skewed toward the pro-inflammatory mediators. We enumerate recent in vitro and in vivo studies on anti-inflammatory cytokines in SCD patients, and discuss the biology of anti-inflammatory cytokines including the already reported IL-2, TGF-ß, and IL-10 as well as the recently discovered IL-27, IL-35 and IL-37. This review will improve the understanding of the pathophysiology of SCD and aid in the search of new therapeutic options for patients with SCD.

The spectrum of splenic complications in patients with sickle cell disease in Africa: a systematic review.

The majority of the global population of sickle cell disease (SCD) patients resides in Africa. Individuals with this condition are at great risk of serious infections and early mortality secondary to splenic dysfunction without preventative measures. This review investigated the spectrum of splenic complications encountered in SCD among populations in Africa. We systematically searched several databases for all articles published through March 3, 2020. We included 55 studies from 14 African countries. This review reveals the difference in frequency of splenic complications in SCD in Africa when compared with their counterparts in the United State and Europe. While several studies (n = 45) described splenomegaly with a prevalence of 12% to 73% among children, and 4% to 50% among adults with HbSS, the reported prevalence for acute splenic sequestration crisis (n = 6 studies) and hypersplenism (n = 4 studies) was <10% and <5% respectively. A total of 30 surgical splenectomy was reported across eight studies. Only two (3.7%) studies provided data on spleen function. A conflicting pattern was observed amongst studies that evaluated the relationship between splenomegaly and the presence of bacterial and malaria infections. This review reveals the paucity of studies describing the role of SCD-induced splenic dysfunction in morbidity and infection related mortality in Africa.

Neutrophil gelatinase-associated lipocalin as a biomarker of nephropathy in sickle cell disease.

Sickle cell nephropathy (SCN) develops via altered hemodynamics and acute kidney injury, but conventional screening tests remain normal until advanced stages. Early diagnostic biomarkers are needed so that preventive measures can be taken. This study evaluates the role of neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of SCN in steady state and vaso-occlusive crisis (VOC). In this case-control study, 74 sickle cell disease (SCD) patients (37 in steady state and 37 in VOC) and 53 control subjects had hematological and biochemical measurements including plasma and urine NGAL. Univariate and logistic regression analyses were used to find the associations between variables. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance characteristics of plasma and urine NGAL for detection of VOC. Plasma and urine NGAL, urine microalbumin:creatinine ratio, and urine protein:creatinine ratio were significantly higher in VOC. Microalbuminuria was present in 17.1% steady state and 32.0% VOC patients. Microalbuminuria showed significant correlations with age, plasma NGAL, WBC, and hemolytic parameters. Area under the ROC curve for plasma NGAL was 0.69 (95%CI = 0.567-0.813; p = 0.006) and 0.86 (95%CI = 0.756-0.954; p < 0.001) for urine NGAL. Urine NGAL cut-off value of 12.0 ng/mL had 95% sensitivity and 65% specificity. These results confirm the presence of nephropathy during VOC and suggest that plasma and urine NGAL would be useful in the identification of SCN. Urine NGAL should be used as the screening biomarker, and patients with VOC and urine NGAL > 12.0 ng/mL should be selected for aggressive management to prevent progression of renal damage.

Hydroxyurea in children with sickle cell disease in a resource-poor setting: Monitoring and effects of therapy. A practical perspective.

BACKGROUND: Although effectiveness of hydroxyurea (HU) in sickle cell disease is well established, unanswered questions persist about its use in African children. We determined real-life issues of acceptability, availability, and monitoring of HU use in Nigeria. METHODS: A retrospective longitudinal review of laboratory data of patients on HU was done from case files, followed by a cross-sectional survey that captured families' perception of medication and clinic adherence, laboratory tests, benefits, side effects, and acceptability. RESULTS: One hundred sixteen patients (1.2-17 years) received HU (mean ± SD = 18.5 ± 4.3 mg/kg/day) in 33 months. Eighty-nine had laboratory analysis. Dose escalation was the initial goal, but only 80% of patients had some form of it. Parents reported improvement in general well-being and reduction in bone pain episodes, hospital admissions, and blood transfusion. While most parents (89.5%) reported satisfaction with HU, 61% reported dissatisfaction with daily drug use, and the frequency and cost of monitoring. Sixteen percent voluntarily stopped therapy. Adherence to daily HU was 88.8%, doctor's appointments 24.5%, hematology tests 18.9%, and organ function tests 37.4%. There were no significant toxicities. Significant increases in hemoglobin, hemoglobin F and mean corpuscular volume, and reduction in absolute neutrophil count occurred despite inconsistent dose escalation. CONCLUSION: HU (10-15 mg/kg/day starting dose) is safe and seems effective and acceptable to parents. Parental commitment to therapy, pre-HU education (that continues during therapy), provision of affordable HU, and subsidized laboratory tests are important considerations for initiating therapy. Special HU clinics may facilitate dose escalation and reduce frequency of monitoring. Studies are needed on feasibility of maximum tolerable dose HU protocols in sub-Saharan Africa without compromising safety.

Relationship of Thrombospondin 1 to von Willebrand Factor and ADAMTS-13 in Sickle Cell Disease Patients of Arab Ethnicity.

BACKGROUND: Thrombospondin 1 (TSP-1) is a multifunctional glycoprotein secreted by platelets. In sickle cell disease (SCD), TSP-1 promotes red cell adhesion to the endothelium by binding to von Willebrand factor (vWF) and inhibiting its degradation by the protease ADAMTS-13. We investigated a possible correlation between TSP-1, vWF and ADAMTS-13 in adult and pediatric SCD patients. METHODS: Using commercially available ELISA kits, TSP-1, vWF and ADAMTS-13 levels were measured in 59 SCD patients (20 children and 39 adults) and compared with 59 age- and sex-matched controls. Associations between TSP-1 and parameters of interest were analyzed using Pearson's correlation coefficient. RESULTS: Although TSP-1 levels were higher in adult and pediatric SCD patients than in controls, the increase was not statistically significant (p > 0.05). We found a significant positive correlation between TSP-1 and platelet count in both adult (r = 0.402, p = 0.01) and pediatric (r = 0.589, p = 0.01) patients, which is expected due to increased platelet activation in SCD. There was a positive correlation between TSP-1 and vWF in normal adults (r = 0.305, p = 0.049) and children (r = 0.633, p = 0.005) but not in patients (p > 0.05). A significant negative correlation between TSP-1 and ADAMTS-13 activity (r = -0.41, p = 0.01) was found in adult patients. Also, a significant negative correlation between TSP-1 and ADAMTS-13/vWF antigen ratio in both normal controls (r = -0.595, p = 0.009) and patients (r = -0.493, p = 0.032) is reported for the pediatric group. CONCLUSIONS: Our findings confirm the inhibitory effects of TSP-1 on ADAMTS-13 activity in adult SCD patients. The negative correlation reported between TSP-1 and ADAMTS-13/vWF antigen ratio in pediatric subjects suggests a possible protective mechanism in younger individuals, although this is not related to the presence of SCD. This work emphasizes the impact of age on interpreting results related to the regulation of vWF expression and interaction with TSP-1 and ADAMTS-13 in SCD.

Perforated Duodenal Ulcer Associated with Deferasirox in a Child with ß-Thalassemia Major.

The oral iron chelator, deferasirox (DFX), is commonly associated with mild gastrointestinal (GI) complaints, but GI hemorrhage and ulcers have occasionally been reported. However, perforated duodenal ulcer (PDU) has been previously reported in only one patient with ß-thalassemia major (ß-TM) on Exjade (DFXE). We hereby report the second case of a 5-year-old Syrian patient, who recently presented with PDU while on DFXE. She was not on any other ulcerogenic medication and was negative for H. pylori and Celiac disease. She had a surgical repair and has done well. She is back on DFX, but with the film-coated tablet, Jadenu or DFXJ. Perforated duodenal ulcer should be suspected in patients with severe GI symptoms, abdominal distension and tenderness while on DFXE, especially at high doses (30+ mg/kg).

Utilization of Pneumococcal Vaccine and Penicillin Prophylaxis in Sickle Cell Disease in Three African Countries: Assessment among Healthcare Providers in SickleInAfrica.

Sickle cell disease is a genetic disease with a predisposition to infections caused by encapsulated organisms, especially Streptococcus pneumoniae. Pneumococcal vaccines and prophylactic penicillin have reduced the rate of this infection and mortality in sickle cell disease. However, implementation of these interventions is limited in Africa. The objectives of the study were to assess health care providers' behaviors with the implementation of pneumococcal vaccination and penicillin prophylaxis and to identify barriers to their use. A 25-item online questionnaire was administered through SickleinAfrica: a network of researchers, and healthcare providers, in Ghana, Nigeria, and Tanzania, working to improve health outcomes of sickle cell disease in Africa. Data was collected and managed using the Research Electronic Data Capture (REDCap), tools and data analysis was done using STATA version 13 and R statistical software. Eighty-two medical practitioners responded to the questionnaire. Only 54.0 and 48.7% of respondents indicated the availability of published guidelines on sickle cell disease management and pneumococcal vaccine use, respectively, at their facilities. The majority (54.0%) perceived that the vaccines are effective but over 20.0% were uncertain of their usefulness. All respondents from Ghana and Tanzania affirmed the availability of guidelines for penicillin prophylaxis in contrast to 44.1% in Nigeria. Eighty-five percent of respondents affirmed the need for penicillin prophylaxis but 15.0% had a contrary opinion for reasons including the rarity of isolation of Streptococcus pneumoniae in African studies, and therefore, the uncertainty of its benefit. Lack of published guidelines on the management of sickle cell disease and doubts about the necessity of prophylactic measures are potential barriers to the implementation of effective interventions.

The Genetic and Clinical Significance of Fetal Hemoglobin Expression in Sickle Cell Disease.

Sickle cell disease (SCD) is phenotypically heterogeneous. One major genetic modifying factor is the patient's fetal hemoglobin (HbF) level. The latter is determined by the patient's ß-globin gene cluster haplotype and cis- and trans-acting single nucleotide polymorphisms (SNPs) at other distant quantitative trait loci (QTL). The Arab/India haplotype is associated with persistently high HbF levels and also a relatively mild phenotype. This haplotype carries the Xmn1 (C/T) SNP, rs7482144, in the HBG2 locus. The major identified trans-acting QTL contain SNPs residing in the BCL11A on chromosome 2 and the HMIP locus on chromosome 6. These collectively account for 15-30% of HbF expression in different world populations and in patients with SCD or ß-thalassemia. Patients with SCD in Kuwait and Eastern Saudi Arabia uniformly carry the Arab/India haplotype, but despite this, the HbF and clinical phenotypes show considerable heterogeneity. Pain episodes and avascular necrosis of the femoral head are particularly common, but severe bacterial infections, stroke, priapism, and leg ulcers are uncommon. Moreover, the HbF modifiers appear to be different; the reported BCL11A and HMIP SNPs appear to play insignificant roles. There are probably novel modifiers to be discovered in this population. This review examines the common clinical phenotypes in Kuwaiti patients with elevated HbF and the available information on HbF modifiers. The response of the patients to hydroxyurea is discussed. The presentation of patients with other sickle compound heterozygotes (Sßthal and HbSD), vis-à-vis their HbF levels, is also addressed critically.

Sickle cell disease clinical phenotypes in Nigeria: A preliminary analysis of the Sickle Pan Africa Research Consortium Nigeria database.

BACKGROUND/OBJECTIVE: Sickle cell disease (SCD) is a monogenic disease with multiple phenotypic expressions. Previous studies describing SCD clinical phenotypes in Nigeria were localized, with limited data, hence the need to understand how SCD varies across Nigeria. METHOD: The Sickle Pan African Research Consortium (SPARCO) with a hub in Tanzania and collaborative sites in Tanzania, Ghana and Nigeria, is establishing a single patient-consented electronic database with a target of 13,000 SCD patients. In collaboration with the Sickle Cell Support Society of Nigeria, 20 hospitals, with paediatric and adult SCD clinics, are participating in patient recruitment. Demographic and clinical information, collected with uniform case report forms, were entered into Excel spreadsheets and uploaded into Research Electronic Data Capture software by trained data clerks and frequency tables generated. RESULT: Data were available on 3622 patients enrolled in the database, comprising 1889 (52.9%) females and 1434 (39.6%) children ≤15 years. The frequencies of Hb SS, Hb SC and Hb Sß thalassemia in this data set were 97.5%, 2.5% and 0% respectively. Sixty percent, 23.8%, 5.9%, 4.8% and 2.5% have had bone pain crisis, dactylitis, acute chest syndrome, priapism and stroke respectively. The most frequent chronic complications were: leg ulcers (6.5%), avascular necrosis of bone (6.0%), renal (6.3%) and pulmonary hypertension (1.1%). Only 13.2% had been hospitalized while 67.5% had received blood transfusion. CONCLUSION: These data on the spectrum of clinical phenotypes of SCD are useful for planning, improving the management of SCD across Nigeria and provide a foundation for genomic research on SCD.

Alpha thalassemia genotypes in Kuwait.

BACKGROUND: The frequency of the alpha thalassemia trait is approximately 40% in the Kuwaiti population, but there has been no comprehensive study of the prevalent alleles. This is a report of patients who were referred for molecular diagnosis over a 20-year period. METHODS: This is a retrospective study of the α-globin genotypes obtained in the Hemoglobin Research Laboratory of the Department of Pediatrics, Kuwait University from 1994 to 2015. Genotyping was performed by a combination of PCR, allele-specific oligonucleotide hybridization and reverse dot blot hybridization (Vienna Lab Strip Assay). RESULTS: Four hundred samples were characterized and analyzed from individuals aged < 1 month to 80 years, with a median of 6 years from 283 unrelated families. Most (90.8%) were Kuwaiti nationals. The commonest genotype was homozygosity for the polyadenylation-1 mutation (αPA-1α/α PA-1α) in 33.3% of the samples, followed by heterozygosity (αα/α PA-1α) for the same mutation in 32.3%. PA-1 was therefore the most frequent allele (0.59). The frequency of the α0 (--MED) allele was 0.017. Rare alleles that were found in very low frequencies included α0 (--FIL) in a Filipino child, Hb Constant Spring, Hb Adana, and Hb Icaria. CONCLUSION: There is a wide variety of alpha thalassemia alleles among Kuwaitis, but nondeletional PA-1 is by far the most common cause of the moderate to severe HbH (ß4 tetramer) disease phenotype. The α0 (-MED) allele is also encountered, which has implications for premarital counseling, especially for the possibility of having babies with alpha thalassemia major (Barts hydrops fetalis).

Pattern of Renal Blood Flow and Renovascular Parameters in Adult Patients With Sickle Cell Disease.

OBJECTIVES: To evaluate renal blood flow patterns and renovascular parameters in adult patients with sickle cell disease (SCD) without laboratory evidence of renal impairment. METHODS: Sixty-five steady-state adult patients with SCD (50 hemoglobin SS [HbSS], 12 HbSß0 , and 3 HbSD) and 30 age- and sex-matched healthy controls were studied. The kidney length, echo pattern, peak systolic velocity (PSV), end-diastolic velocity, renal-to-aortic ratio, resistive index (RI), acceleration time (AT), and renal vein velocity were acquired, recorded, and analyzed with a 1-5-MHz curvilinear transducer through the abdomen. RESULTS: The mean age ± SD of the patients with SCD was 32.89 ± 13.89 years. The highest means for the ultrasound-measured renal length and cortical thickness in the SCD and control groups were 11.78 ± 1.30 and 11.27 ± 0.77 cm and 1.86 ± 0.41 and 1.78 ± 0.28 cm, respectively. The figures were significantly higher in the SCD group than the control group (P < .05). Fifty-nine (90.8%) patients had a mild diffuse increase in cortical echogenicity with preserved renal cortical thickness. The highest mean extrarenal PSVs in the SCD and control groups were 138.46 ± 56.32 and 101.75 ± 31.48 cm/s (P < .05). However, the highest intrarenal RI and AT in SCD and control groups were 0.69 ± 0.07 and 0.06 ± 0.02 seconds and 0.63 ± 0.05 and 0.04 ± 0.01 seconds (P < .05). There was no significant correlation between the RI, AT, and PSV among the patients with SCD (P > .05). CONCLUSIONS: Increased renal length and cortical echogenicity with elevated PSV, RI, and AT values can serve as early ultrasound changes in adult patients with SCD without renal impairment.

HemoTypeSC, a low-cost point-of-care testing device for sickle cell disease: Promises and challenges.

BACKGROUND: Sickle cell disease (SCD) is a neglected burden of growing importance. >312,000 births are affected annually by sickle cell anaemia (SCA). Early interventions such as newborn screening, penicillin prophylaxis and hydroxyurea can substantially reduce the mortality and morbidity associated with SCD. Nevertheless, their implementation in African countries has been mostly limited to pilot projects. Recent development of low-cost point-of-care testing (POCT) devices for sickle haemoglobin (HbS) could greatly facilitate the diagnosis of those affected. METHODS: We conducted the first multi-centre, real-world assessment of a low-cost POCT device, HemoTypeSC, in a low-income country. Between September and November 2017, we screened 1121 babies using both HemoTypeSC and HPLC and confirmed discordant samples by molecular diagnosis. FINDINGS: We found that, in optimal field conditions, the sensitivity and specificity of the test for SCA were 93.4% and 99.9%, respectively. All 14 carriers of haemoglobin C were successfully identified. Our study reveals an overall accuracy of 99.1%, but also highlights the importance of rigorous data collection, staff training and accurate confirmatory testing. It suggests that HPLC results might not be as reliable in a resource-poor setting as usually considered. INTERPRETATION: The use of such a POCT device can be scaled up and routinely used across multiple healthcare centres in sub-Saharan Africa, which would offer great potential for the identification and management of vast numbers of individuals affected by SCD who are currently undiagnosed. FUNDING US: Imperial College London's Wellcome Trust Centre for Global Health Research (grant #WMNP P43370).

Uridine diphosphate glucuronosyl transferase 1A (UGT1A1) promoter polymorphism in young patients with sickle cell anaemia: report of the first cohort study from Nigeria.

BACKGROUND: (TA) n repeat sequence (rs8175347) of UGT1A1 gene promoter polymorphism is associated with serum bilirubin levels and gallstones among different sickle cell anaemia (SCA) populations. There are no data on UGT1A1 polymorphisms and their impact on Nigerian SCA patients. In this study, we determined the distribution of the UGT1A1 (TA) n genotypes among a group of young Nigerian SCA patients and healthy controls. In addition, the influence of UGT1A1 (TA) n genotypes on the laboratory and clinical events among the patients was determined. METHODS: The distribution of the UGT1A1 (TA) n genotypes among 101 young Nigerian SCA patients and 64 normal appropriate controls were determined and studied. The UGT1A1 (TA) n genotypes were further classified into subgroups and used to differentiate the clinical events and laboratory parameters of the patients. RESULTS: Four (TA) n alleles:(TA)5, 6, 7, and 8 were found. These were associated with 10 genotypes: TA5/5, 5/6, 5/7, 5/8, 6/6, 6/7, 6/8, 7/7, 7/8, 8/8. The normal (wild-type)-(TA) 6/6), low- (TA) 7/7, 7/8, 8/8), intermediate- (TA) 5/7, 5/8, 6/7, 6/8), and high-activity (TA) 5/5, 5/6,) genotypes were found in 24.8, 24.8, 41.5, and 8.9% patients and 20.3, 15.6, 61, and 3.1% controls respectively. The general genotype distribution of the patients and control group were not significantly different. There were significant differences in serum bilirubin and lactate dehydrogenase (LDH) of the patients when differentiated by the UGT1A1 (TA) n genotypes (p<0.05). Asymptomatic gallstones were found in 5.9% of patients and were significantly of the low-activity genotypes sub-group 5 (20%) vs 1(1.3%) p = 0.0033. Although, bilirubin and fetal hemoglobin (HbF) of patients with gallstones were significantly different from those without gallstone, only the serum bilirubin was associated with UGT1A1 (TA) n genotypes on multivariate analysis (p < 0.0001). CONCLUSION: This study highlights the contribution of UGT1A1 polymorphisms, a non-globin genetic factor, to the laboratory and clinical manifestations of young Nigerian SCA patients for the first time. It also shows that children with co-inheritance of low UGT1A1 (TA) n affinity genotypes may be at risk of gallstone, hence the need to follow them up.

Red blood cells microparticles are associated with hemolysis markers and may contribute to clinical events among sickle cell disease patients.

Microparticles are sub-micron vesicles possessing protein and other materials derived from the plasma membrane of their parent cells, and literature suggests that they may have a role in the pathophysiology and downstream manifestations of sickle cell disease (SCD). The contributions of red blood cells microparticles (RMP) to the pathogenic mechanisms and clinical phenotypes of SCD are largely unknown. There is a controversy as to whether the proportions of intravascular hemolysis (approximately ≤ 30% of total hemolysis) would be enough to explain some complications seen in patients with SCD. We investigated RMP among 138 SCD patients and 39 HbAA individuals. Plasma RMPs were quantified by flow cytometry, plasma hemoglobin and heme by colorimetric assays, and haptoglobin and hemopexin by ELISA. The patients had higher RMP, plasma hemoglobin, and heme compared to the controls. On the contrary, haptoglobin and hemopexin were depleted in the patients. The RMP correlated positively with heme, lactate dehydrogenase, plasma hemoglobin, serum bilirubin, reticulocyte counts, and tricuspid regurgitant jet velocity of the patients. Contrarily, it correlated negatively with HbF, hemopexin, red blood cells counts, hemoglobin concentration, and haptoglobin. Although patients treated with hydroxyurea had lower RMP, this did not attain statistical significance. Patients with sickle leg ulcer and elevated tricuspid regurgitant jet velocity had higher levels of RMP. In conclusion, these data suggest that RMPs are associated with hemolysis and may have important roles in the pathophysiology and downstream complications of SCD.

Risk of avascular necrosis of the femoral head in children with sickle cell disease on hydroxyurea: MRI evaluation.

BACKGROUND: There are conflicting reports on the role of hydroxyurea (HU) in the pathogenesis of avascular necrosis of the femoral head (AVNFH) in patients with sickle cell disease (SCD). PROCEDURE: The present study is a prospective cohort study of Kuwaiti children with SCD who were treated with HU. They had magnetic resonance imaging of the hips before starting HU and at regular intervals during a follow-up period, ranging from 1 to 15 years. RESULTS: There were 40 patients (18 SS, 19 Sß0-thalassemia, and three SD genotypes), aged 6-20 years. Pre-HU, 11 (27.5%) had varying grades of AVNFH, while post HU, the prevalence was 32.5%. Two patients developed new lesions during the study, while five (45.5%) that had lesions pre-HU remained static, another five (45.5%) progressed, and one (9%) improved radiologically. The older patients who had been on HU the longest were more likely to deteriorate. The only hematological parameter that was consistently associated with AVNFH was the reticulocyte count. CONCLUSIONS: The frequency and rate of progression of AVNFH in this study is much less than that previously reported for our patients not treated with HU. There is no evidence that HU therapy is a risk factor for AVNFH. It may, in fact, prevent new lesions and deter the progression of existing AVNFH.

Thrombospondin-1 and Vitamin D in Children With Sickle Cell Anemia.

BACKGROUND: Thrombospondin-1 (TSP-1) and 25-hydroxyvitamin D (25-OHD) play significant roles in the pathogenesis of sickle cell anemia (SCA). TSP-1 enhances cellular adhesion/inflammation, hence contributing to vaso-occlusive crisis (VOC); vitamin D, in contrast, retards inflammation and may lower rate of pain episodes. We determined serum levels of TSP-1 and 25-OHD in Nigerian children with SCA and their matched hemoglobin AA controls; and assess the relationship between the 2 biomarkers. METHODS: In total 90 children (32 SCA in steady state, 30 SCA in VOC, and 28 HbAA controls) were studied. Serum TSP-1 and 25-OHD levels were measured with ELISA and HPLC, respectively. RESULTS: The mean TSP-1 of children with VOC was significantly higher than those in steady state (P=0.022) and HbAA controls (P<0.001). Similarly, the mean TSP-1 of those in steady state was higher than the controls (P=0.007). However, mean serum 25-OHD of the children with VOC was significantly lower than those in steady state (28.9±8.2 ng/mL vs. 37.1±12.3 ng/mL, P =0.004). There was a significant inverse correlation between TSP-1 and 25-OHD among the VOC subgroup, r=-0.57, P=0.001. The mean TSP-1 of the 28 children with SCA who had suboptimal vitamin D (213.5±118.6 ng/mL) was higher than 144.2±58.7 ng/mL of the 34 SCA who had normal serum vitamin D, P=0.008. CONCLUSIONS: Children with SCA, especially those with VOC, had high serum TSP-1 and low 25-OHD. Also, an inverse relationship exist between serum 25-OHD and TSP-1 in children with VOC. These findings provide basis for further studies into the regulation of TSP-1 by vitamin D.

Influence of alpha thalassemia on clinical and laboratory parameters among nigerian children with sickle cell anemia.

BACKGROUND: There is paucity of data on the influence of alpha thalassemia on the clinical and laboratory parameters among Nigerian sickle cell anemia (SCA) patients. This study aimed to determine the prevalence of alpha thalassemia and the influence of alpha thalassemia on laboratory parameters and clinical manifestations in a group of young Nigerian SCA patients. METHODS: This was a cross-sectional retrospective study conducted on 100 patients with SCA and 63 controls. The diagnosis of SCA was confirmed by DNA studies. Alpha thalassemia genotyping was performed by multiplex gap-PCR method. Laboratory parameters including complete blood count, hemoglobin quantitation, serum lactate dehydrogenase (LDH), and bilirubin were determined with standard techniques. RESULTS: Alpha thalassemia was found in 41 (41.0%) patients compared to 24 (38.1%) controls (P = 0.744), and all were due to the 3.7 κb α-globin gene deletions. Alpha thalassemia was associated with more frequent bone pain crisis, higher hemoglobin concentration, red blood cell count, and HbA2 level among the patients. On the contrary, patients with alpha thalassemia had lower mean corpuscular volume, mean corpuscular hemoglobin, and white blood cell count (WBC) (P Ë‚ 0.05). There were 6 (6.0%) patients with leg ulcers, and none of them had alpha thalassemia, P = 0.04. CONCLUSION: This study confirms that coexistence of alpha thalassemia with SCA significantly influences both the clinical and laboratory manifestations of young Nigerian SCA patients. The coexistence of this genetic modifier is associated with increased bone pain crisis and protects against sickle leg ulcers among the patients.

Transcranial Doppler Ultrasound in Peninsular Arab Patients With Sickle Cell Disease.

OBJECTIVES: Transcranial Doppler ultrasound is used to identify patients with sickle cell disease (SCD) at risk for stroke. We performed transcranial Doppler studies in patients from 4 countries in the Arabian Peninsula (Kuwait, Oman, Iraq, and United Arab Emirates) to document the prevalence of abnormal transcranial Doppler findings. METHODS: The patients were recruited from outpatient clinics and studied in a steady state. Transcranial Doppler examinations were performed with standard equipment by experienced operators. The time-averaged maximum mean velocity (TAMMV) was documented in the arteries of the circle of Willis. The hemoglobin (Hb) genotype was confirmed, and the fetal Hb level and complete blood counts were determined. RESULTS: There were 415 patients in the study, aged 2 to 18 years (mean ± SD, 8.6 ± 3.5 years). None of the patients had an abnormal TAMMV (ie, > 200 cm/s), whereas only 13 (3.1%), all from Iraq, had conditional values (170-200 cm/s) in the right middle cerebral artery and 7 (1.7%) in the left middle cerebral artery. There were no consistent TAMMV differences among male and female patients or in patients with different Hb genotypes (sickle cell anemia, sickle cell ß0- thalassemia, and sickle D). The use of hydroxyurea was associated with a lower TAMMV, whereas a blood transfusion history had no influence. Total hemoglobin, reticulocyte count, serum bilirubin, and fetal Hb values showed varying degrees of association with the TAMMV in the different vessels. CONCLUSIONS: This study has demonstrated the rarity of abnormal transcranial Doppler findings among Peninsular Arab patients with SCD. The guidelines for transcranial Doppler screening in this population need further studies and recommendations.