Articles de revues : « SS-thalassemia »

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Helley, Dominique, Amiram Eldor, Robert Girot, Rolande Ducrocq, Marie-Claude Guillin et Annie Bezeaud. « Increased Procoagulant Activity of Red Blood Cells from Patients with Homozygous Sickle Cell Disease and β-Thalassemia ». Thrombosis and Haemostasis 76, n^o 03 (1996) : 322–27. http://dx.doi.org/10.1055/s-0038-1650577.

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SummaryIt has recently been proved that, in vitro, red blood cells (RBCs) from patients with homozygous β-thalassemia behave as procoagulant cells. The procoagulant activity of β-thalassemia RBCs might be the result of an increased exposure of procoagulant phospholipids (i. e. phosphatidylserine) in the outer leaflet of the membrane. In order to test this hypothesis, we compared the catalytic properties of RBCs of patients with β-thalassemia and homozygous sickle cell disease (SS-RBCs) with that of controls. The catalytic parameters (Km, kcat) of prothrombin activation by factor Xa were determined both in the absence and in the presence of RBCs. The turn-over number (kcat) of the reaction was not modified by normal, SS- or (3-thalassemia RBCs. The Km was lower in the presence of normal RBCs (mean value: 9.1 µM) than in the absence of cells (26 µM). The Km measured in the presence of either SS-RBCs (mean value: 1.6 µM) or β-thalassemia RBCs (mean value: 1.5 pM) was significantly lower compared to normal RBCs (p <0.001). No significant difference was observed between SS-RBCs and p-thalassemia RBCs. Annexin V, a protein with high affinity and specificity for anionic phospholipids, inhibited the procoagulant activity of both SS-RBCs and (3-thalassemia RBCs, in a dose-dependent manner. More than 95% inhibition was achieved at nanomolar concentrations of annexin V. These results indicate that the procoagulant activity of both β-thalassemia RBCs and SS-RBCs may be fully ascribed to an abnormal exposure of phosphatidylserine at the outer surface of the red cells.

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Lai, Kristina, Sonia Anand, Maa-Ohui Quarmyne, Carlton Dampier, Peter A. Lane et Amenah Ibrahim. « Trends in Hospital Utilization for Acute Illness in a Large Population-Based Cohort of Children and Adolescents with Sickle Cell Disease (SCD) : 2010–2017 ». Blood 132, Supplement 1 (29 novembre 2018) : 3528. http://dx.doi.org/10.1182/blood-2018-99-120067.

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Abstract Disease severity and healthcare utilization varies widely among persons with sickle cell disease (SCD). Hydroxyurea (HU) has been demonstrated to reduce rates of pain and acute chest syndrome, the leading causes of inpatient utilization in patients with Hb SS and S β°-thalassemia in clinical trials. We recently reported that HU was clinically effective in reducing rates of pain and acute chest syndrome in patients who initiate treatment. Use of hydroxyurea in SS/S β°-thalassemia has increased markedly since 2010. Thus we sought to detemine trends of hospital utilization for acute illness during an 8 yr in which HU utilization increased markedly (2010-2017). Data from years 2010-201 were obtained from the SCD database and patient records at Children's Healthcare of Atlanta (CHOA). Utilization data were restricted to acute care admissions. Admissions for elective procedures, non-SCD related discharge diagnoses, rare SCD genotypes, and patients who had undergone bone marrow transplant were excluded. Patients were compared based on number of hospitalizations, age, sex, SCD genotype (SS/S β°-thalassemia vs Hb SC/S β+thalassemia), and discharge diagnosis. A total of 3,116 patients had at least one encounter between 2010 and 2017; 2,947 patients met inclusion criteria. From 2010-2017 the total number of active patients per year increased from 1,546 patients to 1,789 patients (+16%), while the total number acute care admissions increased from 1,295 admissions to 1,609 admissions (+24%). There were no significant differences in the proportion of patients with genotypes SS/S β° thalassemia genotypes (67.0% vs 63.9%, p=0.06). Overall patients with SS/S β° thalassemia had higher admission rates compared to SC/S β+ thalassemia patients (0.94 vs 0.57 admissions per patient per year). During the study period. overall admission rates in SCD (acute illness hospitalizations/patient/yr) increased from a low of 0.74 in 2011 to a high of 0.90 in 2017. The proportion of admissions attributed to SS/S β°-thalassemia patients decreased (79.2% in 2010 vs 72.3% in 2017, p<0.0001). However, admission rate in SC/S β+ thalassemia increased (0.53 to 0.69 admissions per patient per year). Overall, over 60% of patients were not admitted in any given year, and the proportion of patients with 0-1 admissions in a given year remained unchanged. However, the proportion of super high hospital utilizers (SHHU), patients with 8 or more admissions in a given year, increased by 185%. In 2001 this group made up 0.6% of all patients and accounted for 7.3% of admissions; in 2017 SHHU had increased 1.8% of patients and 24.3% of admissions. There was no difference in genotype or sex between SHHU and non-SHHU patients. SHHU were older (>90% of patients over age 8 years), and had greater percentages of admissions for pain and acute chest syndrome then non-SHHU. In conclusion, during a period in which HU utilization in SS/S β°-thalassemia increased significantly, hospital utilization for acute illness in SS/S β° thalassemia decreased as expected. However, during the same period there was an unexpected increase in overall hospital utilization for acute illness in SCD. This increase in hospital utilization was the result of 1) a marked increase in SHHU and 2) an overall increased utilization in SC/S β+ thalassemia. Disclosures Dampier: Pfizer: Research Funding.

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Stevens, MC, GH Maude, M. Beckford, Y. Grandison, K. Mason, B. Taylor, BE Serjeant, DR Higgs, H. Teal et DJ Weatherall. « Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood ». Blood 67, n^o 2 (1 février 1986) : 411–14. http://dx.doi.org/10.1182/blood.v67.2.411.411.

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Abstract alpha Thalassemia modifies the hematologic 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 bilirubin 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 children with SS disease has afforded an opportunity to study the hematologic 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.

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Stevens, MC, GH Maude, M. Beckford, Y. Grandison, K. Mason, B. Taylor, BE Serjeant, DR Higgs, H. Teal et DJ Weatherall. « Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood ». Blood 67, n^o 2 (1 février 1986) : 411–14. http://dx.doi.org/10.1182/blood.v67.2.411.bloodjournal672411.

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alpha Thalassemia modifies the hematologic 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 bilirubin 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 children with SS disease has afforded an opportunity to study the hematologic 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.

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Vasavda, Nisha, Stephan Menzel, Sheila Kondaveeti, Emma Maytham, Moji Awogbade, Sybil Bannister, Juliette Cunningham et al. « The Interaction of UGT1A, HO1 and α-Thalassemia Variants with Bilirubin Levels and Gallstones in Sickle Cell Disease. » Blood 108, n^o 11 (16 novembre 2006) : 1202. http://dx.doi.org/10.1182/blood.v108.11.1202.1202.

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Abstract Chronic hyperbilirubinemia is common in patients with sickle cell disease (SCD), frequently resulting in the formation of gallstones. This hyperbilirubinemia (predominantly unconjugated) is attributed to hemolysis that exceeds the conjugating capacity of the hepatic UDP-glucuronosyltransferase (UGT1A) enzyme. Previous studies have shown that genetic variants ([TA]n repeats) in the promoter region of the UGT1A gene have a major influence on the levels of bilirubin and gallstones. Alpha-thalassemia, which is associated with reduced hemolysis, has also been shown to affect bilirubin levels. Another potential modulating factor is heme-oxygenase, a rate-limiting enzyme in the heme catabolic pathway that results in the production of bilirubin. While the severity of jaundice and cholelithiasis in patients with SCD is predisposed by the inheritance of certain variants of the UGT1A gene, inconsistencies have been observed. We propose that some of these inconsistencies may be explained by the modulating effects of genetic variants of HO1 and α-thalassemia. A total of 263 patients with SCD attending specialist clinics in two hospitals were studied: King’s 116 SS, 5 Sβ0 and 59 SC; St Thomas’ 83 SS. 81 ethnically matched subjects were recruited as controls (HbAA). Groups were age and sex matched. Cholelithiasis data, ascertained by liver ultrasound, was available for a subset of SCD patients (76 SS, 4 SC). Samples were genotyped for variants of UGT1A, HO1 and α-thalassemia. The different genetic allele distributions were statistically similar between groups. Data was analysed according to the sum of [TA] repeats on both alleles of UGT1A. A range of 10–15 [TA] repeats was observed. For HO1, the median sum of repeats on both alleles was 63, so samples were grouped as <63 or ≥ 63. α-thalassemia genotypes were as follows: SS, 127 αα/αα, 55 αα/α-, 11 α-/α-; SC, 37 αα/αα, 20 αα/α-; controls 51 αα/αα, 22 αα/α-, 4 α-/α-. Median bilirubin levels varied as expected between groups according to β-globin genotype and were as follows: King’s SS 42 (15–269.5); St Thomas’ SS 52.5 (15.5–696.5); King’s SC 22 (10–81.8); AA Controls 10 (5–24), median (range) mmol/L. Regression analysis showed that serum bilirubin levels were strongly associated with UGT1A repeat length in all subjects (p<0.0001). Furthermore, the increase in serum bilirubin (21.3% mean for SS/Sβ0, 20.5% for SC) and cholelithiasis risk odds (86.5% mean for SS/Sβ0, 67.6% for SC) could be quantified per [TA] repeat. HO1 genotype did not affect serum bilirubin in SCD patients or the control cohort. The presence of α- thalassemia correlated (negatively) with serum bilirubin in SCD patients (p<0.0001) but not controls. This is the first time the relationship between UGT1A [TA] repeat length, serum bilirubin and cholelithiasis has been shown quantitatively. Additionally, co-existing α-thalassemia appears to moderate bilirubin levels but HO1 variants do not.

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Voskaridou, Ersi, Dimitrios Christoulas, Thodoris Pantelaros, Konstantinos Varvagiannis, Charoula Xirakia, Athanasios Papatheodorou, Kleio Sinopoulou, Aggeliki Mpalasopoulou, Antonios Bilalis et Evangelos Terpos. « Serum Dickkopf-1 Is Increased and Correlates with Bone Mineral Density in Patients with Thalassemia-Induced Osteoporosis. Reduction Post Zoledronic Acid Administration ». Blood 112, n^o 11 (16 novembre 2008) : 3889. http://dx.doi.org/10.1182/blood.v112.11.3889.3889.

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Abstract Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Its pathogenesis is multifactorial, and includes mainly bone marrow expansion, endocrine dysfunction and iron overload. Bone metabolism is altered in thalassemia. Osteoclast function is elevated, while osteoblast activity seems to be reduced and thus the balance of bone remodeling is in favor of bone loss. The exact mechanisms of osteoblast dysfunction have not been fully clarified to-date. Wingless-type (Wnt) signaling is an important pathway for osteoblast differentiation. Dickkopf-1 (Dkk-1) protein is an inhibitor of Wnt pathway and is implicated in the pathogenesis of several bone disorders. Collagen type-I is the main structural protein of the bone. The collagen type-I alpha (COLIA)-1 specific protein (Sp)-1 polymorphism has been related to osteoporosis in thalassemia. The aim of this study was to evaluate the serum levels of Dkk-1 in patients with thalassemia-induced osteoporosis who receive therapy with zoledronic acid (ZOL) and evaluate possible correlations with clinical and laboratory data, including the COLIA-1 Sp1 polymorphism. Sixty-six patients (21M/45F; median age 35.5 years) with thalassemia and osteoporosis were studied. Patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. All patients received oral calcium (500 mg) during the treatment period. Dkk-1 was measured at baseline and after 12 months of therapy using ELISA methodology (Biomedica Medizinprodukte, Wien, Austria) along with a series of serum bone remodeling indices: bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], bone formation markers [bone-specific alkaline phosphatase (bALP), osteocalcin, and C-terminal propeptide of collagen type-I (CICP)], and osteoclast regulators [receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), and osteopontin]. The above bone markers were also evaluated in 30, age- and gender-matched, healthy controls. The G-->T mutation at base 1 of intron 1 at the binding site of the Sp1 transcription factor of the COLIA-1 gene was detected by polymerase chain reaction using mutagenesis primers followed by restriction enzyme analysis in all patients. BMD of the lumbar spine (L1-L4), femoral neck (FN) and wrist (W) was determined using DEXA, before and 12 months after treatment. At baseline, all patients had increased serum levels of Dkk-1 (mean±SD: 39±17.1 pmol/L) compared to controls (27.4±9.7 pmol/L; p<0.0001). Furthermore, thalassemia patients had increased values of CTX (p<0.0001), bALP (p<0.001), CICP (p=0.003), sRANKL (p=0.02), and OPG (p=0.001) compared to controls. Results for the COLIA-1 Sp1 polymorphism were available for 53 patients. Seventeen patients (32%) were G/T heterozygotes at the polymorphic Sp1 site (Ss), while 3 (5.6%) were T/T homozygotes (ss). Dkk-1 serum levels correlated with L1-L4 BMD (r=−0.290, p=0.022) and W-BMD (r=−0.415. p=0.001), but also with TRACP-5b (r=0.310, p=0.011) and bALP levels (r=−0.289, p=0.018). Ss and ss patients tended to have lower L1-L4 BMD compared with SS patients (p=0.09). No significant correlations were observed between Ss and ss patients with the measured bone markers or the response to ZOL. As reported previously, patients of group B experienced an increase of L1-L4 BMD, while no other alterations in BMD were observed in the 3 studied groups after 12 months of ZOL administration. Interestingly, patients of groups A+B showed a strong reduction of Dkk-1 after 12 months of ZOL (from 39.6±16.6 to 28.9±16.3 pmol/L; p=0.004); indeed they almost normalized Dkk-1 levels (no difference from control values). In contrast, patients of group C showed a borderline increase of Dkk-1 (from 33.1±16.8 to 40.1±23.2 pmol/L, p=0.08). These results show for the first time in the literature that Dkk-1 is increased in the serum of patients with thalassemia and osteoporosis, correlates with their BMD and is reduced post-ZOL therapy. This Dkk-1 elevation may be at least partially responsible for osteoblast dysfunction in thalassemia and reveal a novel possible target for the development of new agents for the management of bone loss in thalassemia patients.

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Shimauti, Eliana Litsuko Tomimatsu, Paula Juliana Antoniato Zamaro et Claudia Regina Bonini-Domingos. « Interaction between Hb SS and alpha thalassemia (3.7 kb deletion) ». Revista Brasileira de Hematologia e Hemoterapia 33, n^o 3 (2011) : 244–45. http://dx.doi.org/10.5581/1516-8484.20110063.

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Ulug, Pinar, Nisha Vasavda, Stephan Menzel, Karthik Ramasamy, Taku Sugai, Gordon Cheung, Sheila Kondaveeti et al. « Circulating DNA as a Prognostic Marker in Sickle Cell Disease. » Blood 108, n^o 11 (16 novembre 2006) : 1218. http://dx.doi.org/10.1182/blood.v108.11.1218.1218.

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Abstract Free circulating DNA has been shown to be present in the plasma of healthy subjects and elevated in conditions characterised by increased cell death, such as cancer and physical trauma. In sickle cell disease (SCD) an increased cell turnover can be expected through hemolysis and recurrent episodes of vaso-occlusion and inflammation, leading to cell death and organ damage. We propose that circulating DNA levels would be higher in patients with SCD, that these elevations would increase with acute crises and that the extent of increase may serve as a prognostic marker of disease severity. Plasma samples were collected from patients with SCD attending the specialist clinic at King’s College Hospital (KCH). Over a 2 year period (April 2003 - May 2005) a total of 442 samples from 154 patients (105 HbSS, 46 HbSC, 3 HbS/β0 thalassemia) in steady state at each visit to the KCH outpatient sickle clinic was collected. Samples were also obtained from 21 of these 154 patients during an acute crisis, as defined by hospital admission for sickle-related pain. Control subjects consisted of 55 healthy Afro-Caribbean and West African individuals (53 HbAA, 2 HbAS). Plasma DNA concentration was measured by real-time quantitative PCR using a probe specific for the β-globin gene. As the distribution of plasma DNA levels was not gaussian, data was normalised by log-transformation. The median plasma DNA levels in genome equivalents (GE)/ml were as follows: 933 (range 144 to 19370) in controls; 841 (range 60.1 to 16070) in all sickle patients (SS, HbSC and S/β0 thalassemia) during steady state; 970 (range 92 to 16070) in SS and S/β0 thalassemia during steady state; 719 (range 60.1 to 14650) in SC during steady state. Median DNA levels for crisis samples were 10070 (range 444 to 57910) in all SCD and 12000 (range 444–57910) in the SS and S/β0 thalassemia group. There was no significant difference in plasma DNA levels between controls and SCD patients during steady state. Differences between steady state and crisis did not reach significance in the SC group due to the small number of crisis samples (n=3). However, mean plasma DNA levels for sickle patients during steady state, and those in crisis were highly significantly different (by Student’s t test) for all sickle patients (p<0.0001) and for the SS and S/β0 thalassemia group (p<0.0001). Circulating DNA levels correlated with CRP levels in the SS/Sβ0 (r = 0.24, p<0.005) and SC groups (r = 0.31, p <0.05) but not in the controls. DNA levels correlated with WBC in the SS/Sβ0 group only (r = 0.25, p<0.05). However, plasma DNA showed no correlations with hemoglobin, reticulocyte count, red blood cell count or LDH levels. Our preliminary studies show that, unexpectedly, circulating DNA levels are not elevated in steady state SCD despite ongoing organ damage and hemolysis. However, DNA concentration may be a reliable biomarker in SCD crisis. We are currently carrying out longitudinal studies to explore the value of serial measurement of plasma DNA levels and their association with organ damage in SCD.

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Al Shueili, Fayiz, Murtadha K. Al-Khabori, Salam Al-Kindi, Yasser Wali et Shoaib Al-Zadjali. « The Optimal Cut-Off Level for Hemoglobin A2 to Differentiate between Sickle Cell Disease Genotypes ». Blood 132, Supplement 1 (29 novembre 2018) : 2391. http://dx.doi.org/10.1182/blood-2018-99-118697.

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Abstract Objectives: Hemoglobin A2 (HbA2) is elevated in the presence of beta thalassemia trait and it is used as an indicator of its presence. High-Performance Liquid Chromatography (HPLC) overestimates HbA2 in patients with Sickle Cell Disease (SCD) due to the co-elution of HbS in HbA2 column. The optimal cut-off level of HbA2 to indicate the presence of beta thalassemia trait has not been well established in patients with SCD. We aim to define the optimal cut-off level of HbA2 to differentiate between SS and S/Beta SCD genotype variants. Methods: In this cross-sectional study, we included 241 patients with SCD who have either SS or S/Beta genotype based on their HPLC and the Sickledex test®. The diagnoses were confirmed by the direct sequencing of PCR amplified products of all exons, exon-intron junctions and promoter region of the beta globin gene. We retrieved the following clinical and laboratory variables from the electronic health records: age, gender, Hemoglobin (Hb), Mean Corpuscular Volume (MCV), Red Blood Cell (RBC) count and HbA2. We used the receiver operating curve (ROC) analysis to obtain the optimal cut-off level of HbA2 using the maximum sensitivity and specificity (Youden criteria). All descriptive and analytical statistics were performed using R program. The ROC analysis was performed with the "OptimalCutpoints" package available in R program. Results: Among the 241 patients included in the analysis, SS and S/Bthal patients were 81% and 19% respectively. Male to female ratio was 126:115. Fifty-two percent were using hydroxyurea. The median HbA2 level was 4.5% (Range: 0.0-6.5) in the SS group and 6.5% (Range: 3.5-8.2) in the S/Bthal group. The median Hb, MCV and RBC count was 9.4 g/dL (Range: 5.3 - 15.0), 75 fL (55 - 111) and 3.8 *1012/L (1.9 - 6.3) respectively for the SS group; while it was 9.7 g/dL (6.6 - 12.3), 68 fL (57 - 86) and 4.2 *1012/L (2.5 - 5.4) respectively for the S/Bthal group. The optimal cut-off level for HbA2 was estimated to be 5.7% using a sensitivity of 91% and a specificity of 92%. The positive and negative predictive values were 75% and 98% respectively. The discrimination estimated using the Area Under the Curve (AUC) was 0.936 (95% Confidence Interval: 0.878-0.994). Conclusions: The optimal cut-off HbA2 level to differentiate SCD with the S/Bthal genotype from the SS genotype is 5.7% with a high sensitivity, specificity and discrimination. The unexpected overlap in the MCV and the RBC count is likely related to the high rate of Alpha thalassemia trait in the analyzed population. Incorporation of the presence of alpha thalassemia trait in the analysis may improve the discrimination of MCV and RBC count. Disclosures No relevant conflicts of interest to declare.

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Singh, Ashima, Javier Mora et Julie A. Panepinto. « Identification of patients with hemoglobin SS/Sβ0 thalassemia disease and pain crises within electronic health records ». Blood Advances 2, n^o 11 (23 mai 2018) : 1172–79. http://dx.doi.org/10.1182/bloodadvances.2018017541.

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Key Points The algorithms have high sensitivity and specificity to identify patients with hemoglobin SS/Sβ0 thalassemia and acute care pain encounters. Codes conforming to common data model are provided to facilitate adoption of algorithms and standardize definitions for EHR-based research.

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Quinn, Charles T., Zora R. Rogers et George R. Buchanan. « Survival of children with sickle cell disease ». Blood 103, n^o 11 (1 juin 2004) : 4023–27. http://dx.doi.org/10.1182/blood-2003-11-3758.

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Abstract Contemporary survival data are not available for children with sickle cell disease (SCD). The few previous childhood SCD cohort studies do not reflect the benefits of modern therapy. We defined an inception cohort of newborns with sickle cell anemia (SS), sickle-β°-thalassemia (S β°), sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were identified by newborn screening and followed for up to 18 years. The incidence of death and stroke were calculated. Overall survival, SCD-related survival (considering only SCD-related deaths), and strokefree survival were determined. The 711 subjects provided 5648 patient-years of observation. Twenty-five subjects died; mean age at death was 5.6 years. Five patients died from infection. Thirty had at least one stroke. Among SS and Sβ° subjects (n = 448), the overall rates of death and stroke were 0.59 and 0.85/100 patient-years. Survival analysis of SS and Sβ° subjects predicted the cumulative overall, SCD-related, and stroke-free survival to be 85.6%, 93.6%, and 88.5% by 18 years of age. No SCD-related deaths or strokes occurred in SC or Sβ+ subjects (n = 263). Childhood mortality from SCD is decreasing, the mean age at death is increasing, and a smaller proportion of deaths are from infection.

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El-Beshlawy, Amal M., Mona Mohamed Hamdy, Ibtesam Ramzy Hussein, Hala Fathy Sheba et Mona Abdel Gawad. « The Study of G/T Polymorphism in COLIA1 Gene and Osteoporosis in b-Thalassemia Patients. » Blood 114, n^o 22 (20 novembre 2009) : 4078. http://dx.doi.org/10.1182/blood.v114.22.4078.4078.

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Abstract Abstract 4078 Poster Board III-1013 Introduction Osteoporosis is an important cause of morbidity in patients with β thalassemia major. Several genes are thought to be involved in the pathogenesis of osteoporosis. Collagen type I alpha 1 (COLIA1) is one of the most prominent candidate genes, which has been consistently associated with osteoporosis in different populations. Polymorphism at the Sp1 binding site within a key regulatory region of COLIA 1 has been reported to be associated with susceptibility to osteoprotic fractures. Our objective was to detect the allelic distribution of COLIA1 gene in beta thalassemia patients and its relation to bone mineral density (BMD). Patients and methods The study included 25 beta thalassemia major patients (12-28 years, mean = 18.12±5.077 years) and 20 controls (mean age = 23.05±2.3 years) with no family history of thalassemia. Anthropometric measurements were done to all patients .Femoral and lumbar BMD was measured in all patients and control groups using dual energy absorbiometry (DXA). Assessment of the COLIA1 genotypes (SS, Ss, ss) and G/T polymorphism were done using PCR amplification and restriction enzyme digestion (Bal1) of DNA amplified products to thalassemic patients and control groups. Results High prevalence of growth retardation was observed in β thalassemia major patients in the form of short stature (36%), truncal shortening (48%) and under weight (8%). Osteopenia and osteoporosis were detected in 68% of the thalassemia patients with a highly significant lower lumbar and femoral BMD compared to controls (P<0.01) (Table 1). There was a non significant difference between genders regarding BMD, significant negative correlation was observed between long duration of desferroxamine (DFO) intake and low femoral and lumbar BMD (R=-0.571& P<0.01,R=-0.571&P<0.05) in β thalassemia patients. A negative correlation was observed between ferritin level and fat free mass% (FFM%) in thalassemic patients (R=-0.48& P<0.05) and low lumbar BMD in female patients (R=-0.55& P<0.05). There was a positive correlation between age of starting DFO and decreased sitting height in male patients (R=0.74&P<0.01). In the thalassemic group, frequency of COLIA1 alleles was S (94%), s (6%), 12% showed the G/T polymorphism while 88% had the G/G polymorphism (Table 2). Non significant difference was observed in most of the parameters between the 2 different groups of polymorphism. In the control group allele frequencies were S (87.5%) and s (12.5%), G/T polymorphism was present in 25%.and G/G in 75%. No association was detected between COLIA1 gene polymorphism and BMD in the lumbar spine or in femur bone in the thalassemia patients (P>0.05) while the s allele was associated with femoral and lumbar BMD in the control group (P<0.05, P<0.01) (Table 3). Conclusion High prevalence of growth impairment, osteopenia and osteoporosis in our β thalassemia major patients. Desferroxamine duration therapy was related to osteoporosis in our patients. The absence of association between BMD and COLIA 1 polymorphism and the low frequency of s allele in our thalassemic group may be due to the small sample size of the thalassemia patients together with the fact that BMD is determined by a variety of genetic and environmental factors. Further studies including larger number of patients are needed to evaluate these findings. Disclosures: No relevant conflicts of interest to declare.

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Dover, GJ, VT Chang, SH Boyer, GR Serjeant, S. Antonarakis et DR Higgs. « The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes ». Blood 69, n^o 1 (1 janvier 1987) : 341–44. http://dx.doi.org/10.1182/blood.v69.1.341.341.

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Abstract Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.

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Dover, GJ, VT Chang, SH Boyer, GR Serjeant, S. Antonarakis et DR Higgs. « The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes ». Blood 69, n^o 1 (1 janvier 1987) : 341–44. http://dx.doi.org/10.1182/blood.v69.1.341.bloodjournal691341.

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Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.

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De Castro, Laura M., Jude C. Jonassaint, Felicia L. Graham, Allison Ashley-koch et Marilyn J. Telen. « Pulmonary Hypertension in SS, SC and Sβ Thalassemia : Prevalence, Associated Clinical Syndromes, and Mortality. » Blood 104, n^o 11 (16 novembre 2004) : 1663. http://dx.doi.org/10.1182/blood.v104.11.1663.1663.

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Abstract The natural history and mechanisms associated with pulmonary hypertension (pHTN) in sickle cell disease (SCD) are incompletely characterized. We investigated the prevalence of pHTN, diagnosed by echocardiography and/or cardiac catheterization, in adults with all types of SCD, to determine whether the frequency of pHTN varied by Hgb diagnosis. We also analyzed which clinical conditions and laboratory findings were associated with pHTN. We screened 125 outpatients with Hgb SS, SC, Sβ0 or Sβ+ thalassemia who presented with symptoms including either shortness of breath, fatigue, or low or decreasing O2 saturation. PHTN was defined by tricuspid regurgitation jet velocity (TRjet) of ≥ 2.5 m/s by echo and was present in 36% (28/77) of SS & Sβ0 and in 25% (12/48) of SC & Sβ+ patients studied. Of patients with pHTN, 16 (57%) of the SS & Sβ0 patients had a peak TR jet >3.0 m/sec and 12 (43%) ≥2.5-<3.0m/sec, whereas 8(67%) of the SC & Sβ+ patients had a peak TR jet ≥3.0 m/sec (50% of these were ≥4.0) and 4 (33%) TR jet ≥2.5-<3.0m/sec. Two SS patients included in our analysis were diagnosed with pHTN by cardiac catheterization when echo failed to show pHTN. Other patients’ echos (83) were reported as either normal or abnormal but not consistent with pHTN. In SS & Sβ0, the mean age of patients whose echos were consistent with pHTN was significantly higher than of those without pHTN (43.3 vs. 34.4yrs, p=0.001). A similar trend was observed in SC & Sβ+(48.8 vs 42.6 yrs). No significant association was noted between the presence of pHTN and history of CVA, AVN, or renal failure. Patients with pHTN had higher mean systolic BP than patients without pHTN (SS & Sβ0126.3±19.4 vs 122.0±17.6 and SC & Sβ+130.7±15.0 vs 124.4±19.02 mmHg), but these differences were not statistically significant. SS & Sβ0 patients with pHTN had significantly lower Hgb values than patients without pHTN. Leukocyte, platelet and reticulocyte counts, creatinine, and O2 saturation were not significantly different for patients with and without pHTN. LDH and bilirubin values were slightly higher in patients with pHTN. Most interestingly, 18/29 SS & Sβ0 patients with pHTN had proteinuria ≥ 1+, while only 13/46 SS & Sβ0 patients without pHTN had proteinuria (p<0.05). The presence of proteinuria was found to have a high positive predictive value (0.60) for the presence of pHTN in patients with SS and Sβ0. Proteinuria overall was rarely present in SC & Sβ+. During the 2 yr study period, 6/42 (14%) patients with pHTN died; deaths were limited to patients with Hgb SS and occurred at a mean of 30 months (range 5 – 53 months) after diagnosis of pHTN. The mean TR jet velocity and peak RV pressure in patients who died was 2.8m/s and 39.5, respectively. Two of 83 patients (2 %) without pHTN died during this period, suggesting that pHTN markedly increased the death rate. In conclusion, our data confirm the high prevalence of pHTN in Hgb SS, SC, and Sβ thal. Although a higher prevalence of pHTN, higher TR jet velocities, and increased mortality were seen in patients with Hgb SS or Sβ0, mortality was also seen in patients with relatively mild pHTN. Moreover, our data suggest that the presence of proteinuria in patients with SS or Sβ0 is sufficient cause to screen for pHTN by echocardiography. The mechanism by which proteinuria and pHTN are associated remains to be determined.

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Jain, Dipty, Vinit Warthe, Roshan Colah et Graham Roger Serjeant. « Sickle Cell Disease in Central India : High Prevalence of Sickle/Beta Thalassemia and Severe Dsiease Phenotype ». Blood 126, n^o 23 (3 décembre 2015) : 4588. http://dx.doi.org/10.1182/blood.v126.23.4588.4588.

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Abstract Objectives: To assess the clinical, haematological and molecular features of sickle cell disease in central India where the disease has been reported to be more severe than the mild clinical course usually observed in the Asian haplotype of homozygous sickle cell (SS) disease. Methods: A cross-sectional assessment of 91 consecutive patients with sickle cell disease attending clinics at the Akola Government Medical College, Akola, Maharastra State, India. Results: Of the 91 patients, who were predominantly of the scheduled caste community, 49 had SS disease, 6 had sickle cell-HbD Punjab, and 36 had sickle cell-beta thalassaemia. Of the patients with sickle cell-beta thalassaemia, the beta thalassemia mutation was IVS1-5 G>C mutation in 25 patients (69%) while the rest had one of seven other molecular mutations identified (Table1). Contrary to commonly held beliefs, alpha thalassaemia occurred in only 9/90 (10%) of subjects but fetal haemoglobin (HbF) levels were markedly elevated with mean and median levels of 24.4%. All except 3 SS disease patients had the Xmn1(+/+) polymorphism. These patients exhibited many of the severe manifestations of sickle cell disease. Comparison of SS disease and sickle cell-beta thalassaemia showed no differences in the prevalence of dactylitis, bone pain crisis, acute chest syndrome, haemoglobin level, reticulocyte counts or hydroxyurea usage but patients with sickle cell-beta thalassaemia had significantly more hospital admissions, blood transfusions, and greater frequencies of splenomegaly and hepatomegaly. Conclusions: Many of the patients with sickle cell disease in central India appear to have relatively severe manifestations. This appears to be due to much lower frequencies of alpha thalassaemia and more frequent sickle cell-beta thalassaemia. There is a need for assessment of the indications and policies for blood transfusion and for hydroxyurea. Table 1. Beta Thalassemia mutations associated with HbS/Beta Thalassemia in Akola Mutation Expression Number IVS 1-5 (G>C) severe b+ 22 IVS 1-1 (G>A) bo 3 Cd 15 (-T) bo 2 Cd 30 (G>C) bo 2 Cd 15 (G>A) bo 1 Cd 39 (C>T) bo 1 Cd 41/42 (-CTTT) bo 1 619 bp deletion bo 1 Total 36 Disclosures No relevant conflicts of interest to declare.

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Castro, O., DJ Brambilla, B. Thorington, CA Reindorf, RB Scott, P. Gillette, JC Vera et PS Levy. « The acute chest syndrome in sickle cell disease : incidence and risk factors. The Cooperative Study of Sickle Cell Disease ». Blood 84, n^o 2 (15 juillet 1994) : 643–49. http://dx.doi.org/10.1182/blood.v84.2.643.643.

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Abstract The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within- person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

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Castro, O., DJ Brambilla, B. Thorington, CA Reindorf, RB Scott, P. Gillette, JC Vera et PS Levy. « The acute chest syndrome in sickle cell disease : incidence and risk factors. The Cooperative Study of Sickle Cell Disease ». Blood 84, n^o 2 (15 juillet 1994) : 643–49. http://dx.doi.org/10.1182/blood.v84.2.643.bloodjournal842643.

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The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within- person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

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Yee, Donald L., Rachel M. Edwards, Brigitta U. Mueller et Jun Teruya. « Thromboelastographic and Hemostatic Characteristics in Pediatric Patients With Sickle Cell Disease ». Archives of Pathology & ; Laboratory Medicine 129, n^o 6 (1 juin 2005) : 760–65. http://dx.doi.org/10.5858/2005-129-760-tahcip.

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Abstract Context.—Patients with sickle cell disease suffer from a variety of vaso-occlusive events that may be related to activation of the hemostatic system. Thromboelastography assesses the functionality of this system from a global standpoint and has demonstrated some utility in detecting hypercoagulable states in varied clinical settings, but it has not been systematically evaluated in patients with sickle cell disease. Objective.—To characterize the findings of thromboelastography in patients with sickle cell disease during periods of steady state and illness, to compare these results with those of healthy controls, and to correlate these profiles with other measured hemostatic parameters. Design.—In this cross-sectional study, we obtained thromboelastographic and other hemostatic data on specimens from 46 patients with sickle cell disease (35 with hemoglobin SS, 7 with hemoglobin SC, and 4 with hemoglobin S-β thalassemia) and 20 healthy race-matched controls. Data were obtained from patients with sickle cell disease at baseline conditions (n = 41) and in the setting of acute illness (n = 5). Results.—Patients with hemoglobin SS had lower reaction time and higher angle, maximum amplitude, and coagulation index values on thromboelastography than the control group. Hemoglobin SC patients had higher angle, maximum amplitude, and coagulation index values than controls. Hemoglobin S-β thalassemia patients showed no significant differences compared with controls. Five hemoglobin SS patients with recent or current illness demonstrated increased maximum amplitude and coagulation index compared with hemoglobin SS patients at baseline conditions. Conclusions.—Patients with sickle cell disease demonstrated a significant hypercoagulable state in thromboelastography profiles, with the degree of abnormality dependent on the type of sickle cell disease and perhaps the presence of acute illness. Continued follow-up of this patient cohort, as well as further study of larger and more homogeneous patient groups, is required to adequately assess the utility of thromboelastography in predicting complications of sickle cell disease.

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Koshy, M., SJ Weiner, ST Miller, LA Sleeper, E. Vichinsky, AK Brown, Y. Khakoo et TR Kinney. « Surgery and anesthesia in sickle cell disease. Cooperative Study of Sickle Cell Diseases ». Blood 86, n^o 10 (15 novembre 1995) : 3676–84. http://dx.doi.org/10.1182/blood.v86.10.3676.bloodjournal86103676.

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From 1978 to 1988, The Cooperative Study of Sickle Cell Disease observed 3,765 patients with a mean follow-up of 5.3 +/- 2.0 years. One thousand seventy-nine surgical procedures were conducted on 717 patients (77% sickle cell anemia [SS], 14% sickle hemoglobin C disease [SC], 5.7% S beta zero thalassemia, 3% S beta zero + thalassemia). Sixty-nine percent had a single procedure, 21% had two procedures, and the remaining 11% had more than two procedures during the study follow- up. The most frequent procedure was abdominal surgery for cholecystectomy or splenectomy (24% of all surgical procedures, N = 258). Of these, 93% received blood transfusion, and there was no association between preoperative hemoglobin A level and complication rates (except reduction in pain crisis). Overall mortality within 30 days of a surgical procedure was 1.1% (12 deaths after 1,079 surgical procedures). Three deaths were considered to be related to the surgical procedure and/or anesthesia (0.3%). No deaths were reported in patients younger than 14 years of age. Sickle cell diseases (SCD)-related complications after surgery were more frequent in SS patients who received regional compared with general anesthesia (adjusted for risk level of the surgical procedure, patient age, and preoperative transfusion status, P = .058). Non-SCD-related postoperative complications were higher in both SS and SC patients who received regional compared with those who received general anesthesia (P =.095). Perioperative transfusion was associated with a lower rate of SCD- related postoperative complications for SS patients undergoing low-risk procedures (P = .006, adjusted for age and type of anesthesia), with crude rated of 12.9% without transfusion compared with 4.8% with transfusion. In SC patients, preoperative transfusion was beneficial for all surgical risk levels (P = .009). Thus, surgical procedures can be performed safely in patients with SCD.

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Gill, FM, LA Sleeper, SJ Weiner, AK Brown, R. Bellevue, R. Grover, CH Pegelow et E. Vichinsky. « Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments] ». Blood 86, n^o 2 (15 juillet 1995) : 776–83. http://dx.doi.org/10.1182/blood.v86.2.776.bloodjournal862776.

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Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.

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Swensen, Jeffrey J., Archana M. Agarwal, Jose M. Esquilin, Sabina Swierczek, Ajay Perumbeti, Dottie Hussey, Margaret Lee et al. « Sickle cell disease resulting from uniparental disomy in a child who inherited sickle cell trait ». Blood 116, n^o 15 (14 octobre 2010) : 2822–25. http://dx.doi.org/10.1182/blood-2010-05-284331.

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Abstract Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/β-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the β-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.

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Chakraborty, Abhijit, Jayasri Basak, Deboshree Majumdar, Soma Mukhopadhyay, Sagnik Chakraborty et Ashis Mukhopadhyay. « Prevalence of Sickle Cell Anemia In Eastern India ». Blood 116, n^o 21 (19 novembre 2010) : 4822. http://dx.doi.org/10.1182/blood.v116.21.4822.4822.

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Abstract Abstract 4822 Background: Sickle cell disease is an inherited disorder of hemoglobin synthesis. This is due to replacement of Valine for Glutamic Acid in position six of the Beta globin chain of hemoglobin. This genetic alteration yields unstable RBC which lasts for 10–20 days. In stressful conditions the cells become sickle shaped and get lysed. There are about 20 million people with sickle cell disease in India. During January 2009- May2010 camps were held in various parts of West Bengal, Jharkhand, Chattisgarh. Along with various mutations of thalassemia, we also observed sickle cell anemia among them. This triggered our interest to study the spectrum of the sickle mutation co-inheritant with different mutations such as Homozygous Sickle Cell, Sickle Cell-Beta0 Thalassemia, Sickle Cell-Beta+ Thalassemia, Severe β+ thalassemia genes, Moderate β+ thalassemia genes, Mild β+ thalassemia genes Sickle cell-HbE Thalassaemia, Sickle cell-HPFH Thalassaemia, in said part of India. Since Indian patients with SS disease had higher hemoglobin, red cell counts and higher HbF levels and lower HbA2, MCHC, MCV, and reticulocyte counts, hence a high hemoglobin is a risk factor for painful crises and may also be a risk factor for avascular necrosis of the femoral head, proliferative sickle retinopathy, and acute chest syndrome. Methods: We have screened 332 individuals in eastern part of India during the period January 2009- May 2010. 3ml of peripheral blood was collected in EDTA vial from each individual. NESTROFT (Naked Eye Single Tube Red Cell Osmotic Fragility Test) was performed on spot. Then Complete Blood Count was done within 24 hours of collection. HPLC (High Performance Liquid Chromatography) was performed to identify the samples for confirmation. In our observation in case of sickle cell anaemia HbF (Fetal haemoglobin), Hb (haemoglobin), MCV (mean corpuscular volume) values ranges between 0–10 %, ≤7-10g/dl, 65–90fl respectively. ARMS (Amplification Refractory Mutation System) PCR (polymerase chain reaction) was done to confirm the mutation. Result: Conclusion: Of the total samples collected in the camps held at various places of Jharkand, Chattisgarh & West Bengal 87 of them was carriers of sickle cell anemia. There was 7 homozygous (SS), 14 sickle beta, 12 double heterozygous for HPFH (High Persistance of Fetal Hemoglobin) & sickle cell anemia. In conclusion, the manifestations of sickle cell disease are influenced by a variety of other genetic and environmental factors. The occurrence of the disease against different genetic and environmental backgrounds provides experimental models that contribute to understanding the variability in clinical and hematological expression of the disease. Disclosures: No relevant conflicts of interest to declare.

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Singer, Sylvia Titi, Yu Hou, Rajesh Sharma, Elliott P. Vichinsky, Adriane Meyer, Jennifer Martinez, Cindy Wu, Tracey Bishop et Shabnam Tavassoli. « Benefits of Targeted Next Generation Sequencing (NGS) for Identification of Newborn Hemoglobinopathies : The California Experience ». Blood 144, Supplement 1 (5 novembre 2024) : 1095. https://doi.org/10.1182/blood-2024-206092.

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Introduction Hemoglobinopathies are a heterogenous group of disorders comprised of variants in α-globin (HBA), β-globin (HBB) genes or both. Newborn screening (NBS) is aimed to identify clinically significant hemoglobin disorders and facilitate early delivery of specialized care and education before the onset of clinical symptoms. The rapid growth in Asian and Middle Eastern segments in the US population has resulted in higher frequency of non-sickling thalassemia disorders and has affected NBS practices in some states; In California, due to such demographic changes, NBS for α thalassemia (Hb H disease) is mandated. In many other states the reporting for α thalassemia is of a presumptive diagnosis, mostly due to the complexity and expense of such testing, causing delays in diagnosing clinically significant forms of α thalassemia. Our ‘Hb Reference Lab’ (https://hemoglobinlab.ucsf.edu) performs confirmatory testing following primary screening by HPLC (California NBS Program). The diagnostic approach targets the most common mutations or deletions (e.g., allele specific PCR) or analyzes the entire HBB and/or the HBA genes to identify the gene/s responsible for a Hb disorder (e.g. Sanger direct sequencing). Thus, different molecular techniques, in a sequential workflow, which cannot simultaneously assess both α and β genes, are required. It is therefore time consuming, a costly process and results in an extended turn-around time. Next-generation sequencing (NGS) has a wide application in detecting disease-causing variants in genetic disorders; while not widely adopted for Hb disorders due to cost and technical challenges, NGS has proven helpful in carrier screening and diagnosing complex cases. We sought to assess the effectiveness of targeted NGS for confirmatory diagnosis of hemoglobinopathies in newborns. Methods Genomic DNA was extracted from peripheral blood and based on initial protein chemistry analysis (HPLC, IEF) molecular essays for HBA, HBB or both were performed and hemoglobinopathy determined. 98 samples with a known genotype were then analyzed by amplicon based NGS (Devyser Thalassemia NGS) which detects variants in HBA1, HBA2 and HBB genes. Results NGS successfully identified both deletions and point mutations including compound heterozygous conditions: HBB gene; Hb SS, SC, S/ β +, SE, S/β variant, S trait, E / β variants, homozygous β 0, Hb EE, β traits, β variants; E, D carriers. HBA genes; deletional or non-deletional Hb H disease, a case of 4 alpha gene deletion and several benign α-variants. Previously unknown genotypes detected by NGS: A large β deletion making the diagnosis S/β0 thalassemia (instead of presumed Hb SS)3 cases of HPFH or a delta/beta deletion in patients with Hb SS9 homozygous and 26 heterozygous Xmn1 polymorphisms13 of 28 case of SCD had one alpha gene deletion (α3.7)3 cases of an α mutation carrier: Constant Spring (CS) and Hb Pakse. Genotypes not detected by NGS: We could not specify if α variants were located on HbA1 or HBA2. However, unique mutation to HBA2, such as CS and Pakse were correctly identified.A case a coinheritance of α -4.2 deletion and α2 triplication was not identified (as they balance out each other) Discussion The use of NGS Thalassemia assay accurately detected mutations and deletions and provided a comprehensive hemoglobin profile for all NB samples flagged during initial screening. The essay also revealed variants that were not identified through our standard approach. This capability is particularly advantageous in regions with a high prevalence of thalassemia, where traditional methods may not detect these important genetic variants, in particular of α thalassemia. The ability to simultaneously analyze the HBA and HBB genes, is a significant benefit in reducing laborious processes of multiple essays and extended turn-around time. Additionally, it can limit or eliminate the need to analyze parents' samples (currently done on an elective basis for abnormal NBS results). Beyond diagnosis of important NB hemoglobinopathies, the findings add clinically relevant data, such as presence of HPFH and a β deletion in patients diagnosed with Hb SS, which are therefore expected to have a milder phenotype, or knowledge of XMN1 status for considerations of hydroxyurea treatment. Some limitations exist due to a high degree of homology between HBA1 and HBA2 but have a limited impact on the accurate diagnosis of the expected clinical phenotype.

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Haider, M. Z., S. Ashebu, P. Aduh et A. D. Adekile. « Influence of α-Thalassemia on Cholelithiasis in SS Patients with Elevated Hb F ». Acta Haematologica 100, n^o 3 (1998) : 147–50. http://dx.doi.org/10.1159/000040890.

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Rhea, Jeanne M., David Koch, James Ritchie, Harsh V. Singh, Andrew N. Young, Tom Burgess et Ross J. Molinaro. « Unintended Reporting of Misleading Hb A1c Values When Using Assays Incapable of Detecting Hemoglobin Variants ». Archives of Pathology & ; Laboratory Medicine 137, n^o 12 (1 décembre 2013) : 1788–91. http://dx.doi.org/10.5858/arpa.2012-0714-oa.

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Context.—It is recommended that hemoglobin (Hb) A1c (Hb A1c) not be used to assess average glycemia in patients who have altered red blood cell life span. Objective.—To investigate the frequency of reporting an Hb A1c value for Hb variant samples that do not include Hb A. Design.—Hb A1c samples (n = 500) were procured and screened for Hb variants that may affect Hb A1c interpretation (Hb SS, Hb SC, and Hb S–β-thalassemia). Five of each of these samples were tested by ion-exchange high-performance liquid chromatography, immunoturbidimetric assay, second-generation immunoturbidimetric assay, and affinity chromatography. Results.—Eleven (2.2%) homozygous Hb SS, 6 (1.2%) Hb SC, and 5 (1.0%) Hb S–β-thalassemia samples were identified out of the 500 samples tested. Three of 4 instruments investigated in this study are known to not be plagued by analytic interference from these Hb variants but disturbingly reported Hb A1c values in the absence of Hb A. Conclusions.—The improved analytic specificity of Hb A1c platforms has by and large eliminated interferences from the most common heterozygous Hb variants. A consequence, however, is the potential for unintended reporting of Hb A1c results in the presence of homozygous and compound heterozygous Hb variants that lack Hb A and the inability to distinguish those samples not recommended to be used for patient care. The ability to identify samples harboring Hb variants that preclude the utility of Hb A1c may be beneficial in high prevalence populations.

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Kiger, Laurent, Sandia Adypagavane, Laura Bencheikh, Nicolas Hebert, Stephane Moutereau, Frédéric Galactéros, Michael Marden, Yves Beuzard, France Pirenne et Pablo Bartolucci. « Interest of a New Method for Free Plasma Heme Related Species Dosages in Sickle Cell Disease and Beta Thalassemia ». Blood 134, Supplement_1 (13 novembre 2019) : 3381. http://dx.doi.org/10.1182/blood-2019-130600.

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Introduction: Hemolytic anemia combines 3 components to various extents: extravascular hemolysis, intravascular hemolysis and dyserythropoiesis. Global hemolysis in excess to defense lines induces oxidative and inflammatory syndromes and vascular damages in various organs. Therefore, accurate hemolysis biomarkers are required for a better evaluation of hemolytic disorders, such as sickle cell disease (SCD) or thalassemia syndromes and to evaluate the efficacy of various therapies. Accordingly, we have developed a new spectrophotometric method to measure and calculate several hemolysis biomarkers in plasma or serum including Hemoglobin in various forms (HbO2, HbCO, MetHb), Heme or Hemin bound to albumin or to hemopexin, total bilirubin and total hemopexin. Patients and Method : Blood samples were collected at steady-state for 77 SCD adults (mean age 39.8 ± 10.2 yrs, M/F ratio 0.64) and 23 beta thalassemia patients (mean age 42.7 ± 16 yrs, M/F ratio 0.91); SCD patients (SS or Sb0-Thalassemia) were either treated with Hydroxycarbamide (HU: 27) or not (NT: 50). For comparison, plasma samples from healthy volunteers (HV) were also analyzed. Continuous variables were expressed as means ± SD or medians [interquartile range], depending on their normal or asymmetric distributions. Categorical variables were expressed as numbers (%). Univariate analyses were done using Student's t-test or Mann-Whitney non-parametric test, depending on the distribution. Correlation were analyzed using a spearman test. The dosage methodology is based on the light absorption spectrophotometry of plasma samples using an appropriate mathematical conversion of the signal, reference spectra of the different species and some chemical modifications of the iron redox and ligation states. Results: The levels of plasma Hb were statistically higher in homozygous SCD patients compared to beta-thalassemia patients (p=0.001) and healthy volunteers, with median of 6.3 [3.4-11], 2.6 [1-5.4] and 1.7 [0.5-3] µM respectively (Table 1). Interestingly levels of plasma heme were higher in beta thalassemia patient compared to SCD patients (p=0.0001) and HV, with a mean of 1.05 [0.05-3], 10.5 [3.5-24] and ≤ 0.2 µM level of detection respectively (Table 1). A significant negative correlation was found between heme and hemopexin levels in both diseases (p<0.0001; r=0.85). Among 77 SS or Sb0-Thalassemia patients, 29 were treated by HU without any difference for plasma Hb, plasma Heme and Hemopexin values compared to non-treated patients. Discussion and Conclusions: plasma Hb is a more accurate dosage for intra vascular hemolysis than other biomarkers which are not specific of intra vascular hemolysis and could be biased by other pathological conditions: LDH or ASAT can be increased in hepatic or muscular cytolysis, bilirubin is dependent on the heme oxygenase and glycuronyl transferase activities, and reticulocytes are dependent on erythropoiesis. Our results showed that the intra-vascular hemolysis is more pronounced in SCD compared to beta-thalassemia based on the plasma Hb levels. The elevated plasma heme concentration in beta thalassemia is a new finding that should be investigated in more details. It could reflect the ineffective erythropoiesis or heme export from erythroblasts or macrophages involving hemopexin scavenging. Disclosures Bencheikh: Hemanext: Research Funding. Bartolucci:HEMANEXT: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Quinn, Charles T., Nancy J. Lee, Zora R. Rogers et George R. Buchanan. « Survival of Children with Sickle Cell Disease : An Update from the Dallas Newborn Cohort. » Blood 106, n^o 11 (16 novembre 2005) : 3812. http://dx.doi.org/10.1182/blood.v106.11.3812.3812.

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Abstract The Dallas Newborn Cohort is the largest newborn inception cohort of individuals who have sickle cell disease (SCD), and it has provided modern pediatric SCD survival data (Blood2004;103:4023–7). The Cohort includes subjects who were diagnosed at birth by universal newborn screening and followed at our center up to 18 years of age. All subjects with sickle cell anemia (SS) or sickle-β° thalassemia (Sβ°) were prescribed prophylactic penicillin until 5 years of age. The first report from the Cohort showed an overall survival of 85.6% at 18 years for individuals with SS or Sβ°. The standard error of this estimate was high because only 8 individuals remained at risk at 18 years of age at the time of the analysis, which included follow-up until July 2002. Accrual and follow-up of cohort members has continued. We therefore sought to update the survival estimates through age 18 by including three further years of follow-up. By definition the Dallas Newborn Cohort includes all individuals with SS, Sβ°, sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were born in Texas after November 1, 1983, diagnosed by the newborn screening program of Texas, and seen at least once in our center. New members of the Cohort who came to our center between July 2002 and July 2005 were identified. Follow-up of existing members was updated. All deaths and their causes were determined. Subjects were analyzed in two separate groups because of known clinical similarities: SS/Sβ° and SC/Sβ+. Overall survival was analyzed by the Kaplan-Meier method. Subjects were censored at the time of their last clinical encounter. We identified 115 new subjects, and included 1627 additional patient-years of follow-up. The cohort now includes 826 subjects (SS 503, Sβ° 18, SC 247, Sβ+ 58; male:female 427:399) and it provides 7275 patient-years of follow-up. Mean follow-up was 8.9 years (range 0.9–19.5 years). 62 patients (7.5%) were lost to follow-up. There were 25 deaths in the cohort; none was new and all were previously reported. Of the deaths, 15 were likely related to SCD (5 sepsis, 3 acute chest syndrome, 2 multi-organ failure syndrome, 5 other) and 10 were apparently unrelated to SCD (4 trauma or accidental death, 6 other diseases). There were 22 and 3 deaths in the SS/Sβ° and SC/Sβ+ groups, respectively. All the SC/Sβ+ deaths were apparently unrelated to SCD. Overall survival at 18 years for SS/Sβ° and SC/Sβ+ subjects was 92.4% (standard error [SE] 1.9; 52 at risk) and 98.1% (SE 1.3; 12 at risk), respectively. The overall incidence of death through 18 years of age was 0.46 and 0.12 per 100 patient-years, respectively. In conclusion, this updated survival analysis of the Dallas Newborn Cohort now shows that over 90% of children with SS/Sβ° survive childhood, and nearly 100% of children with SC/Sβ+ become adults.

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Basu, Srijeeta, Vishalkumar Kathrotiya, Shubham Darda, Divyesh Vinubhai Patel, Vedangi Desai, Shivangi Solanki et Jitendra Lakhani. « Musculoskeletal Involvement and Persistent Spleen - Regional Variation and Underexplored Risk Factors in Sickle Cell Disease : 2 Case Reports ». Journal of Integrated Health Sciences 12, n^o 2 (juillet 2024) : 176–79. https://doi.org/10.4103/jihs.jihs_42_24.

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Painful bony crises and avascular necrosis (AVN) of the femur is commonly described as musculoskeletal involvement in sickle cell disease (SCD). We are presenting two cases of SCD, having diffused, disseminated, and varied musculoskeletal involvement. These are representative cases which highlight underexplored risk factors and regional variation which includes adulthood morbidities, sickle cell beta thalassemia disorder, undiagnosed musculoskeletal problems, and persistent fetal hemoglobin (HbF) as well as spleen. The first case is having homozygous SCD (SS), having frequent admissions for bony crises, poor medication adherence having AVN of both hips, right olecranon bursitis, and having hepatosplenomegaly. The second case is of sickle cell beta thalassemia disorder with bilateral AVN of the hip with ischemic infarcts involving lumbar 4 and 5 vertebrae having severe anemia with splenomegaly and thrombocytopenia. There are unique challenges faced by Indian SCD patients and their persistent spleen and HbF levels including frequent rheumatological issues and possible multiorgan involvement.

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Nagel, RL, S. Erlingsson, ME Fabry, H. Croizat, SM Susuka, H. Lachman, M. Sutton, C. Driscoll, E. Bouhassira et HH Billett. « The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients ». Blood 77, n^o 6 (15 mars 1991) : 1371–75. http://dx.doi.org/10.1182/blood.v77.6.1371.1371.

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Abstract We have previously determined that in African sickle cell anemia (SS) patients three different beta-like globin gene cluster haplotypes are associated with different percent G gamma (one of the two types of non- alpha chains comprising hemoglobin F [HbF]), mean percent HbF, and percent dense cells. We report now that in adult New York SS patients, the presence of at least one chromosome with the Senegal haplotype is associated with higher Hb levels (1.2 g/dL higher) than is found for any other non-Senegal haplotype (P less than .004). The percent reticulocytes and the serum bilirubin levels were lower in these patients. When the effect of alpha-gene number was analyzed by examining a sample of SS patients with concomitant alpha-thalassemia, the same results were obtained. Because the HbF level is significantly higher among the Senegal haplotype carriers in this sample, the inhibitory effect on sickling of this Hb variant may be one of the reasons for the haplotype effect. We conclude that the Senegal beta- like globin gene cluster haplotype is associated with an amelioration of the hemolytic anemia that characterizes sickle cell disease.

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Nagel, RL, S. Erlingsson, ME Fabry, H. Croizat, SM Susuka, H. Lachman, M. Sutton, C. Driscoll, E. Bouhassira et HH Billett. « The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients ». Blood 77, n^o 6 (15 mars 1991) : 1371–75. http://dx.doi.org/10.1182/blood.v77.6.1371.bloodjournal7761371.

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We have previously determined that in African sickle cell anemia (SS) patients three different beta-like globin gene cluster haplotypes are associated with different percent G gamma (one of the two types of non- alpha chains comprising hemoglobin F [HbF]), mean percent HbF, and percent dense cells. We report now that in adult New York SS patients, the presence of at least one chromosome with the Senegal haplotype is associated with higher Hb levels (1.2 g/dL higher) than is found for any other non-Senegal haplotype (P less than .004). The percent reticulocytes and the serum bilirubin levels were lower in these patients. When the effect of alpha-gene number was analyzed by examining a sample of SS patients with concomitant alpha-thalassemia, the same results were obtained. Because the HbF level is significantly higher among the Senegal haplotype carriers in this sample, the inhibitory effect on sickling of this Hb variant may be one of the reasons for the haplotype effect. We conclude that the Senegal beta- like globin gene cluster haplotype is associated with an amelioration of the hemolytic anemia that characterizes sickle cell disease.

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Johansen, Max E., Wenche Jy, Pamela B. Dudkiewicz et Yeon S. Ahn. « Red Cell Microparticles (RMP) and Other Cell-Derived Microparticles (C-MP) in Hemolytic Anemias ». Blood 120, n^o 21 (16 novembre 2012) : 5158. http://dx.doi.org/10.1182/blood.v120.21.5158.5158.

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Abstract Abstract 5158 Introduction: The lifespan of red cells (RBC) are shortened by several mechanisms in hemolytic anemias (HA): Ab-mediated hemolysis in autoimmune hemolytic anemia (AIHA), complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), microangiopathy in thrombotic thrombocytopenic purpura (TTP) and hemoglobinopathy in sickle cell anemia (SS) and thalassemia (Thal). During hemolysis, RMP are released along with MP from platelets (PMP), endothelia (EMP) and leukocytes (LMP). The role of MP in HA is unknown but may be involved in complications of HA. Methods: We investigated RMP and other MP profiles in the following hemolytic anemias in active phase: 14 patients with AIHA, 10 with TTP, 4 with PNH, 8 with SS or Thalassemia (SS - Thal), along with 60 healthy controls. Whole, citrated blood was centrifuged at 1600xgfor 10 minutes to yield platelet-poor plasma (PPP). Microparticles in the PPP were measured by FITC- or PE-conjugated mAb specific to the aforementioned cell types. Control plasma was prepared in an identical fashion from healthy volunteers. We compared RMP profiles and other MP in HA during active phase and in remission. Associations with clinical features were calculated using the R statistical software. Results: Means and standard deviations of C-MP in the different types of HA are shown in the TABLE. Mean RMP and PMP were highest in SS-Thal, followed by AIHA. Mean Annexin V binding procoagluant MP were higher in all subgroups of HA and highest in SS-Thal, followed by TTP. EMP in all subgroups was similar or lower than controls. Regarding clinical associations, high RMP levels were associated with low hemoglobin (p=0. 01), high reticulocytes (p=0. 003), and high LDH (p=0. 01) across all groups. High reticuloctye counts (>3. 0 %) were also associated with significantly elevated PMP (p=0. 04) and total MP counts by Ulex (p=0. 003). HAs in remission had marginally lower RMP levels than controls (p=0. 05). None of the subtypes had significantly higher EMP, LMP, or PMP compared to each other or controls. Conclusion: The small population yielded large standard deviations in the MP counts and did not allow statistical study among subgroups of patients with HA. However prothrombotic MPs such as Annexin V, PMP tend to be higher in HA. A larger scale future study will clarify this issue. The constellation of elevated LDH, reticulocytes, and decreased hemoglobin were associated with increased RMP. Therefore we suggest that elevated RMP may be viewed as an additional, new diagnostic marker of active hemolysis. Disclosures: No relevant conflicts of interest to declare.

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Quinn, Charles T., Kimberly Thomas, Zora R. Rogers et George R. Buchanan. « Improved Survival of Children and Adolescents with Sickle Cell Disease. » Blood 112, n^o 11 (16 novembre 2008) : 1425. http://dx.doi.org/10.1182/blood.v112.11.1425.1425.

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Abstract The survival of children with sickle cell disease (SCD) has improved over the past several decades, especially for very young children. However, we know less about mortality during adolescence, and we do not accurately know the current proportion of children born with SCD who survive to adulthood. The first report from the Dallas Newborn Cohort (DNC), which included follow-up through June 2002, estimated overall survival at 18 years of age to be 85.6% (95% C.I.: 73.4 – 97.8) for individuals with sickle cell anemia (SS) or sickle-β0-thalassemia (Sβ0) (Blood2004;103:4023–7). The confidence interval of this estimate was wide because only 8 cohort subjects were 18 years old at the time. Here we update the survival analysis with 5 more years of accrual and follow-up to provide an accurate, contemporary estimate of mortality for patients with SCD through 18 years of age. The DNC includes all individuals with SS, Sβ0, sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were diagnosed by the newborn screening program of Texas (initiated November 1, 1983) and seen at least once in our center. Subjects were analyzed in two separate groups because of clinical similarity: SS/Sβ0 and SC/Sβ+. Overall survival was analyzed by the Kaplan-Meier method. Subjects were censored at the time of their last clinical encounter. Between July 2002 and July 2007 we identified 229 new members of the DNC and added 3,201 additional patient-years of follow-up. The cohort now includes 940 subjects (572 SS, 284 SC, 63 Sβ+, 21 Sβ0; 52.8% male), and it provides a total of 8,857 patient-years of follow-up (5,819 SS/Sβ0 patient-years, 3,039 SC/Sβ+ patient-years). Mean follow-up is 9.4 years (range 0.1– 20.6 years), and 97 subjects are now at least 18 years of age at last follow-up. To date, 92 subjects (9.8%) have been lost to follow-up (not seen for >5 years), and 33 subjects have died (30 SS/Sβ0, 3 SC/Sβ+). There were 7 new deaths in DNC patients since 2002, all of which occurred in patients who were 18 years of age or older. Of all deaths, 23 were SCD-related (5 acute chest syndrome, 5 sepsis, 4 multi-organ failure syndrome, 9 other), and 10 were apparently unrelated to SCD (4 trauma or accidental death, 6 unrelated medical conditions). All SC/Sβ+ deaths were apparently unrelated to SCD. Overall survival at 18 years was 93.9% (95% C.I. 90.3 – 96.2; 81 patients > 18 years of age) for SS/Sβ0 subjects and 98.4% (95% C.I. 94.4 – 99.5; 16 patients > 18 years) for SC/Sβ+ subjects. The overall incidence of death in the SS/Sβ0 and SC/Sβ+ subgroups was 0.52 and 0.10 per 100 patient-years, decreased from 0.59 and 0.24 in the original DNC analysis. Survival also appears to be improving across cohort eras (Figure). In conclusion, approximately 6% of children with SS or Sβ0 die during childhood, but almost all children with SC or Sβ+ live to become adults. Although early childhood mortality has greatly decreased, we show that many adolescents and young adults still die from SCD. Notably, acute chest syndrome and multi-organ failure have now surpassed sepsis as the leading causes of death. These data provide the accurate, contemporary foundation for the counseling of parents of newborns with SCD and for genetic counseling for prospective parents. Finally, given the marked decrease in early mortality we show here, new efforts to improve survival in SCD should focus on adolescents and young adults. Figure Figure

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Fraiwan, Arwa, Muhammad Noman Hasan, Ran An, Julia Z. Xu, Amy J. Rezac, Nicholas J. Kocmich, Tolulope Oginni et al. « International Multi-Site Clinical Validation of Point-of-Care Microchip Electrophoresis Test for Hemoglobin Variant Identification ». Blood 134, Supplement_1 (13 novembre 2019) : 3373. http://dx.doi.org/10.1182/blood-2019-129336.

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Introduction: Nearly 24% of the world's population carry hemoglobin (Hb) gene variants, with the large majority of affected births occurring in low-income countries. The most prevalent structural Hb variants are the recessive β-globin gene mutations, βS or S, βC or C, and βE or E1. Hb S mutation is prevalent in sub-Saharan Africa and in Central India. Hb C is common in West Africa, and Hb E is common in Southeast Asia and in India. Homozygotes or compound heterozygotes with βS (e.g., Hb SS or SC) have sickle cell disease (SCD), a chronic sickling disorder associated with pain, chronic multi-organ damage, and high mortality. While Hb EE causes only a mild microcytic anemia, Hb E in combination with β-thalassemia can lead to transfusion dependent thalassemia. Though carriers are typically asymptomatic, they may pass the mutations to their offspring. Screening is needed so that these disorders can be diagnosed early and managed in a timely manner2. For example, in low-income countries, due to lack of nationwide screening and comprehensive care programs, up to 80% of babies born with SCD are undiagnosed and less than half of them survive beyond 5 years of age2. The unmet need for affordable, portable, accurate point-of-care tests to facilitate decentralized hemoglobin testing in resource-constrained countries is well-recognized 2,3. Here, we present international multi-site clinical validation results and high diagnostic accuracy of the 'HemeChip' (Fig. 1), an affordable, 10-minute point-of-care microchip electrophoresis test for identifying common Hb variants S, C, and E. Methods: Institutional Review Board approvals were obtained at each study site, and blood samples were collected as part of the standard clinical care. Tests were performed by local users, including healthcare workers and clinical laboratory personnel. 315 children (6 weeks to 5 years of age) were tested in Kano, Nigeria. Study participants were enrolled at three hospitals, Amino Kano Teaching Hospital, Murtala Mohammed Specialist Hospital, and Hasiya Bayero Pediatric Hospital. 124 subjects (7 weeks to 63 years old) were included in the study at Siriraj Thalassemia Center in Bangkok, Thailand. 298 subjects (8 months to 65 years old) were tested at a referral testing facility of ICMR-National Institute of Research in Tribal Health, located at Late Baliram Kashayap Memorial Medical College, Jagdalpur, Chhattisgarh, India. Blood samples were tested with both HemeChip and the standard reference methods, high performance liquid chromatography or cellulose acetate electrophoresis. Reference test results were not available to the HemeChip users. Similarly, HemeChip test results were not available to the users of the standard reference tests. Clinical validation studies presented here were performed with a fully functional, portable HemeChip prototype developed at Case Western Reserve University (Fig. 1A). A commercial product has been developed based on this technology by Hemex Health Inc. under the product name, GazelleTM(Fig. 1B). Results and Discussion: Among the total 768 tests performed with HemeChip in all test sites, 732 were valid tests, as defined by the Standards for Reporting Diagnostic Accuracy (STARD)4. HemeChip correctly identified all subjects with Hb SS, Hb SC, Hb AS, Hb AE, and Hb EE with 100% accuracy (Table 1). Nine subjects with normal Hb (Hb AA) were identified as HbSS in Nigeria. No subjects with disease were identified as normal or trait by HemeChip. Three subjects with compound heterozygous Hb Sβ-thalassemia (2 subjects with Hb Sβ+-thalassemia, 1 subject with Hb Sβ0-thalassemia) were identified as Hb SS. Sensitivity was 100% for all Hb types tested. Specificity was 98.7% for Hb SS versus other Hb types, and 100% for all other Hb types tested. HemeChip displayed an overall diagnostic accuracy of 98.4% in comparison to standard reference methods for the Hb variants tested in all clinical testing sites (Table 1). HemeChip is a versatile point-of-care system that enables affordable, accurate, decentralized hemoglobin testing in resource-limited settings. References: 1. Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79(8):704-712. 2. Mburu J, Odame I. International Journal of Laboratory Hematology. 2019;41(S1):82-88. 3. Alapan Y, Fraiwan A, Kucukal E, et al. Expert Review of Medical Devices. 2016;13(12):1073-1093. 4. Bossuyt PM, Reitsma JB, Bruns DE, et al. BMJ : British Medical Journal. 2015;351:h5527. Disclosures Fraiwan: Hemex Health, Inc.: Equity Ownership, Patents & Royalties. Hasan:Hemex Health, Inc.: Equity Ownership, Patents & Royalties. An:Hemex Health, Inc.: Patents & Royalties. Thota:Hemex Health, Inc.: Employment. Piccone:Hemex Health, Inc.: Patents & Royalties. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding. Gurkan:Hemex Health, Inc.: Consultancy, Employment, Equity Ownership, Patents & Royalties, Research Funding.

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BOUZENDA, Khaled, Esma MAHDJOUB, Amina LEMRABET et Hadjer Zineb ROUABEH. « Hemoglobinopathies in the Constantine region : frequency and difficulties in diagnosing rare variants ». Batna Journal of Medical Sciences (BJMS) 12, n^o 1 (7 mars 2025) : 90–94. https://doi.org/10.48087/bjmsoa.2025.12118.

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Aims. Hemoglobinopathies are among the most frequent genetic diseases in the world. Algeria has some endemic areas, mainly for β-thalassemia and sickle-cell anemia, but some rarer variants are sometimes found, whose diagnosis is difficult and may escape interpretation. The aim of this work is to shed light on the cases of rare hemoglobinopathies observed in the Constantine region and the difficulties encountered in their diagnosis. Material and methods. This is a descriptive crosssectional study of 517 capillary hemoglobin electrophoresis profiles on Capillarys and MINICAP Flex Piercing (SEBIA) machines, performed as part of the diagnosis or follow-up of hemoglobinopathies in the hemobiology/blood transfusion department of Constantine University Hospital. Diagnosis is based on clinical findings, blood count results and other biological parameters, family investigation, and hemoglobin studies. Result. 71% of the profiles studied were pathological, 26.70% of pathological cases were thalassemic syndromes, of which 26.53% were homozygous β-thalassemia and 67.35% heterozygous, 02 cases of heterozygous δ-thalassemia and 04 cases of heterozygous δβ-thalassemia, 73.3% of pathological profiles were hemoglobinoses, of which 58.74% had a major sickle cell syndrome (SS, Sβthal, SC), 24.54% with heterozygous sickle cell disease, 06.69% with heterozygous hemoglobinosis C and 05 homozygous hemoglobinosis C cases, one C/βthal and 02 C/α thal cases, 02 composite S/PHHF cases and 02 S/O-Arab cases, 02 composite S/D cases, 02 S/αthal cases, 03 heterozygous PHHF cases, one heterozygous O-Arab case, one heterozygous hemoglobinosis D case, 03 heterozygous lepore cases and 03 heterozygous hemoglobinosis J cases. Conclusion: a precise diagnosis of rare hemoglobin variants is not always obvious, and sometimes only molecular study can provide it.

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Pearson, Howard A., Diane Gallagher, Robert Chilcote, Edmund Sullivan, Judith Wilimas, Mark Espeland et A. Kim Ritchey. « Developmental Pattern of Splenic Dysfunction in Sickle Cell Disorders ». Pediatrics 76, n^o 3 (1 septembre 1985) : 392–97. http://dx.doi.org/10.1542/peds.76.3.392.

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Splenic function in sickle hemoglobinopathy syndromes was assessed to determine the developmental pattern of splenic dysfunction. Nonvisualization of the spleen using technetium-99 metastable (99mTc) spleen scans correlated strongly with pocked (vesiculated) RBCs ≥3.5%. Cross-sectional analysis of pocked RBC data from 2,086 patients showed differences in the developmental pattern of splenic dysfunction between several disorders. In hemoglobin SS disease (sickle cell anemia) and hemoglobin Sβ° thalassemia, splenic dysfunction (≥3.5% pocked RBCs) often occurred in the first 6 to 12 months of life. In hemoglobin Sβ+ thalassemia, splenic dysfunction occurred less frequently and later. Splenic dysfunction in hemoglobin SC disease (sickle cell-hemoglobin C) was intermediate. The level of pocked RBCs was inversely associated with fetal hemoglobin (P < .007) and directly associated with age (P ≤ .001). These patterns of splenic dysfunction reflect the known severity of hemolysis and intravascular sickling and are consistent with the epidemiology of severe bacterial meningitis and sepsis in these diseases. Serial measurement of pocked RBCs permits determination of the onset of splenic dysfunction and the time of increased susceptibility to severe bacterial infections.

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Adekile, Adekunle, Nagihan Akbulut Jeradi, Maria Fernandez et Rasha Al-Khaldi. « The Diagnosis of HbS Genotypes and Identification of β-Thalassemia Mutations in Patients with Hbsβ-Thalassemia Using Next Generation Sequencing ». Blood 136, Supplement 1 (5 novembre 2020) : 38. http://dx.doi.org/10.1182/blood-2020-139869.

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The conventional diagnosis of sickle cell disease (SCD) depends on RBC morphology, Hb electrophoresis and/or high-performance liquid chromatography (HPLC). However, these methods are fraught with ambiguities especially in areas where HbSβ-thalassemia is common. The distinguishing laboratory feature between patients with HbSS and HbSb-thalassemia is the level of HbA2. Unfortunately, when HbA2 is estimated with HPLC in patients with Sβthalassemia, it tends to be spuriously high because it co-migrates with glycated HbS. HbSβ-thalassemia accounts for 30 - 40% of the SCD patients being followed in Kuwait. Patients with a presumptive diagnosis of HbSS and/or Sβ-thalassemia, by HPLC were referred to the Hemoglobin Research Laboratory of Department of Pediatrics, Kuwait University for confirmatory molecular diagnosis. The DNA samples collected from 1994 to 2018 were recently subjected to NGS. DNA was isolated from peripheral leukocytes using the phenol-chloroform method. The Illumina Ampliseq custom DNA panel was used to genotype the DNA samples. For theHBBlocus, all β-globin mutations and variants were confirmed by arrayed primer extension (APEX) or Sanger sequencing methods. In addition, genotyping of modifier SNPs inBCL11Aon chromosome 2 and theHBS1L-MYBintergenic region on chromosome 6 was carried out to identify their influence on HbF expression among our patients. In all, 126 SNPs were genotyped. We hereby, report the false positive and false negative rates for the diagnosis of Sb-thalassemia with HPLC compared to NGS. We also report the spectrum of β-thal mutations among our patients with Sβ-thalassemia. The DNA samples were from 232 patients aged from 1 to 59 with a mean of 12.7 ± 11.2 years. Analysis of the initial HPLC diagnosis showed that 27.7% were reported to have Sβ-thalassemia, while after NGS assessment, 29.4% were found to truly fit the diagnosis. Three individuals who were diagnosed as HbSS turned out to be HbAS and 1 each turned out to be HbAA and β-thalassemia trait respectively. Twelve patients that were originally thought to be Sβ-thalassemia turned out to be HbSS, i.e. a false positive rate of 5%, while 30 who were thought to be SS, turned out to be Sβ-thalassemia, i.e. a false negative rate of 13%. A total of 12 mutations were identified in 61 Sβ-thalassemia patients. Of these, the most common were the β0 IVS-1 del 25 and the IVS-II-1 (G/A) in 9 (14.8%) each. The most common β+ mutation was the IVS-I-110 (G/A) in 8 (13.1%), followed by the IVS-I-5 (G/C) in 7 (11.5%). While the Sβ0-thalassemia patients had no HbA on HPLC, the Sβ+ were associated with varying concentrations of HbA, ranging from 0 for those carrying the IVS-I-5 (G/C) mutation to a mean of 15.5 +/- 6.2% in the patients with IVS-I-110 (G/A) and 25.1% in the Sβ++patient with IVS-I-6 (C/T). Indeed, HPLC is far from deal in detecting HbSβ-thalassemia with significant rates of false positivity and negativity. NGS is very versatile; it can interrogate thousands of genes simultaneously, making it ideal for use in SCD. The HbS genotype, β-thalassemia mutation, haplotype and different modifier polymorphisms can be determined in one run. It is therefore very useful for personalized diagnosis that can document prognostic factors, making for purposeful counseling and follow-up from an early age. Disclosures No relevant conflicts of interest to declare.

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Quinn, Charles T., Elizabeth P. Shull, Naveed Ahmad, Nancy J. Lee, Zora R. Rogers et George R. Buchanan. « Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia ». Blood 109, n^o 1 (29 août 2006) : 40–45. http://dx.doi.org/10.1182/blood-2006-02-005082.

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Abstract Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of outcome could guide clinical care. To determine whether early vaso-occlusive complications predicted subsequent adverse outcomes in the Dallas Newborn Cohort, we studied all members with SS or sickle-β0-thalassemia who presented in their first year of life and had 5 years or more of follow-up. We defined 3 potential early predictors: hospitalizations in the first 3 years of life for (1) painful events other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We studied the associations of these predictors with the following late adverse outcomes (occurring after the third birthday): death, first overt stroke, use of disease-modifying therapy, and hospitalizations for pain events and ACS. None of the early events predicted death or stroke. Early pain and ACS both predicted a modest, temporary increase in the number of later painful episodes, but early ACS strongly increased the odds of more frequent ACS throughout childhood. Dactylitis had limited utility as a predictor. Although we still lack a useful prognostic framework for young children with SS, those who experience early ACS might be candidates for higher risk interventions to mitigate or cure their disease.

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Song, Liu-Jiang, Xin-Hua Zhang, Jun Zhu, Jue-Lian Wu, Xiao-Ling Yin et Meng-Qun Tan. « Recombinant scAAV2 Vector-Mediated Ex Vivo Transduction of Primary Human Hematopoietic Stem Cells from a β-Thalassemia Patient and Human β-Globin Gene Expression in a Murine Xenograft Model in Vivo ». Blood 124, n^o 21 (6 décembre 2014) : 5951. http://dx.doi.org/10.1182/blood.v124.21.5951.5951.

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Abstract Background: The most severe form of β-thalassemia, β°-thalassemia major, is characterized by the complete absence of normal β-globin chain, and is often lethal. Autologous transplantation of genetically-modified hematopoietic stem cells (HSCs) using lentiviral vectors have been used successfully to achieve clinical efficacy in one patient, although clonal expansion of a myeloid cell population also occurred in this patient which was associated with the activation of a cellular proto-oncogene, HMGA2. We reasoned that recombinant vectors based on a non-pathogenic human parvovirus, the adeno-associated virus (AAV), might offer a safer alternative. We have previously documented that although the conventional single-stranded (ss) AAV2 vectors mediated β-globin gene transfer and expression in primary human fetal liver cells and in human HSCs from patients with β-thalassemia patients in vitro, the level of transgene expression was sub-optimal. In the present study, we investigated whether double-stranded self-complementary (sc) AAV2 vectors could overcome this limitation. Methods: Human HSCs, obtained from a β-thalassemia homozygous patient, were mock-transduced or transduced with recombinant scAAV2-β-globin vectors at 5×104 vgs/cell, followed by i.v. injection into sub-lethally irradiated NOD/SCID mice (2.65 cGy total body irradiation), which were also pre-treated with 200 µg purified anti-IL2RB/CD122 monoclonal antibody. Recipient mice were sacrificed 12 weeks post-transplantation. Bone marrow cells from recipient mice were analyzed by BFU-E assays. Human β-globin gene expression in human erythroid progenitor cells from transplanted mice was evaluated by RT-PCR. Results: Pre-treatment of NOD/SCID mice with anti-CD122 antibody improves engraftment of human HSCs in bone marrow of receipt mice. Human β-actin (538-bp) and β-globin (272-bp) transcripts were detected by RT-PCR in bone marrow cells from all recipient mice, indicating that recombinant scAAV2-β-globin–transduced HSCs from a patient with β-thalassemia were successfully transduced and transplanted in these mice and that human β-globin gene was transcriptionally active 12 weeks post-transplantation. Conclusion: Our results indicate that human HSCs from β-thalassemia patients can be efficiently transduced by recombinant scAAV2-β-globin vectors followed by expression of normal human β-globin gene. These studies provide the proof-of-concept that scAAV2 vector-mediated gene transfer into human HSCs might be a potentially safer alternative approach for gene therapy of β-thalassemia. Disclosures No relevant conflicts of interest to declare.

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Quinn, Charles T., et Naveed Ahmad. « Prevalence and Predictors of Steady-State Hypoxemia in Sickle Cell Disease. » Blood 104, n^o 11 (16 novembre 2004) : 1662. http://dx.doi.org/10.1182/blood.v104.11.1662.1662.

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Abstract Individuals with sickle cell disease (SCD) may have arterial oxygen desaturation during the steady-state that is mainly due to a right shift of the oxyhemoglobin dissociation curve. This right shift has both non-specific causes (increased concentration of 2,3-DPG due to chronic anemia) and SCD-related causes (an effect of the intracellular concentration of hemoglobin (Hgb) S and an enhanced Bohr effect). Another possible cause is chronic cardiopulmonary disease that may be related to past acute chest syndrome (ACS). We aimed to describe the distribution of steady-state peripheral oxygen saturation (SpO2) in a large population of children with SCD and to determine whether any simple laboratory or clinical features were predictive of SpO2. We hypothesized that most of the variation in SpO2 was not explained by steady-state Hgb alone, and that a history of ACS could explain some of this variability. Using our center’s comprehensive database we identified all subjects with sickle cell anemia (SS), sickle-hemoglobin C disease (SC), sickle-β+-thalassemia (Sβ+), or sickle-β0-thalassemia (Sβ0) who had been evaluated within the past 5 years for whom steady-state Hgb concentration, reticulocyte count (retic), and SpO2 were available. All steady-state values are rolling averages calculated at routine well clinic visits. SpO2 was determined by pulse oximetry in room air. Individuals receiving chronic transfusions were excluded. Lifetime rates of ACS were known for a subset of subjects with SS and Sβ0. A standard multiple regression analysis was performed between steady-state SpO2 as the dependent variable, and steady-state Hgb and retic, age, and sex as independent variables. 585 subjects were analyzed (390 SS/Sβ0, 195 SC/ Sβ+; 47% female, 53% male). Mean age was 9.4 years (SD 5.6, range 0.2 – 19.7). Mean SpO2 was 96.3% (SD 3.0) for SS/Sβ0 and 98.7% (SD 1.7) for SC/ Sβ+ subjects. The percentage of subjects with SpO2 <96% and <90% was 33.1 and 2.8 for SS/Sβ0 and 3.6 and 0.5 for SC/ Sβ+. Bivariate analyses showed no correlation between Hgb and SpO2 for SC/ Sβ+ subjects (N=195, Pearson R=0.024, P=0.74) and no correlation between ACS rate and SpO2 in those with SS/Sβ0 (N=183, Pearson R=−0.043, P=0.56). Thus, only the 390 subjects with SS/Sβ0 were included in the multivariate analysis, and ACS rate was not included in the model as an idependent variable. All 4 independent variables (Hgb, retic, age, and sex) contributed significantly to prediction of SpO2. Altogether, about 45% (adjusted 44%) of the variability in SpO2 was explained by the model. Multiple correlation coefficient (R = 0.67) showed a significant linear relationship between independent variables and SpO2 (F = 78.07, p < 0.001). The estimated model can be given as: SpO2 = 94.24 + (0.58 * Hgb) − (0.16 * Age in years) + (0.64 * Female sex) − (0.20 * Retic in %). In summary, steady-state hypoxemia is common among individuals with SS and Sβ0, in whom decreased steady-state SpO2 is related to decreased steady-state Hgb, increased steady-state retic, increased age, and male sex. This relationship was not found for individuals with SC and Sβ+. Only 5% of the variation in SpO2 was explained by Hgb while controlling for other variables, and ACS rate was not associated with SpO2. We conclude that most steady-state hypoxemia in individuals with SCD is explained by factors other than chronic anemia, and that hypoxemia appears to be unrelated to prior episodes of ACS.

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Kulozik, AE, BC Kar, RK Satapathy, BE Serjeant, GR Serjeant et DJ Weatherall. « Fetal hemoglobin levels and beta s globin haplotypes in an Indian populations with sickle cell disease ». Blood 69, n^o 6 (1 juin 1987) : 1742–46. http://dx.doi.org/10.1182/blood.v69.6.1742.1742.

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Abstract To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta degrees, 7 A beta, degrees and 12 AA) Indians from the state of Orissa. The beta s globin gene was found to be linked almost exclusively to a beta S haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta s haplotype). By contrast, the majority of beta A and beta degree thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta s globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.

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Kulozik, AE, BC Kar, RK Satapathy, BE Serjeant, GR Serjeant et DJ Weatherall. « Fetal hemoglobin levels and beta s globin haplotypes in an Indian populations with sickle cell disease ». Blood 69, n^o 6 (1 juin 1987) : 1742–46. http://dx.doi.org/10.1182/blood.v69.6.1742.bloodjournal6961742.

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To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta degrees, 7 A beta, degrees and 12 AA) Indians from the state of Orissa. The beta s globin gene was found to be linked almost exclusively to a beta S haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta s haplotype). By contrast, the majority of beta A and beta degree thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta s globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.

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Brousse, Arnaud, Lesprit, Quinet, Odièvre, Etienne-Julan, Guillaumat et al. « Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening : A Real-World Nation-Wide Study in France ». Journal of Clinical Medicine 8, n^o 10 (2 octobre 2019) : 1594. http://dx.doi.org/10.3390/jcm8101594.

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This study’s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006–2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

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Lalla, Poonam, Vinky Rughwani et Manoj Chugh. « Evaluating the performance of ErbaQik sickle cell rapid test card with HPLC method ». International Journal of Recent Innovations in Medicine and Clinical Research 6, n^o 4 (15 novembre 2024) : 122–27. http://dx.doi.org/10.18231/j.ijrimcr.2024.063.

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Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by the presence of abnormal hemoglobin, primarily hemoglobin S (HbS), resulting from a point mutation in the β-globin gene. ErbaQik Sickle Cell Rapid Test Card developed by Transasia Diagnostics Pvt Ltd will aid in rapid detection of Sickle cell disease particularly in resource & laboratory infrastructure limited settings.To ensure the accuracy of ErbaQik Sickle Cell Rapid Test Card, a robust validation was conducted and compared with gold standard HPLC method to check the sensitivity, specificity, precision and clinical utility. This study was conducted under the guidance of Consultant Paediatrician, from Dec 2023 to Feb 2024 at Nagpur center run by Thalassemia and Sickle cell Society of India in collaboration with Rughwani Child Care Centre to evaluate the performance of ErbaQik Sickle Cell Rapid Test Card with HPLC method which is the benchmark for comparison in this study. A total of 181 blood samples were analyzed for hemoglobin variants. The evaluation of the ErbaQik Sickle Cell Rapid Test Card produced significant findings For Sickle-SS 32 samples were tested, all of which were correctly identified, yielding a sensitivity and specificity of 100%. Similarly 27 Trait-AS samples were all accurately detected, maintaining 100% sensitivity and specificity. These results indicate the test's high reliability and precision in identifying Sickle Cell Disease and Trait conditions. For Wild-Normal samples, the test was performed on 120 samples resulting in 100% sensitivity and specificity. In the case of Thalassemia samples, only 2 samples were tested, with 1 correctly identified, resulting in a sensitivity and specificity of 50%. The ErbaQik Sickle Cell Rapid Test Card demonstrated high sensitivity and specificity for detecting Sickle Cell Disease (SS) and Trait (AS), aligning with gold-standard methods like HPLC.

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Minniti, Caterina, Concetta Perrotta, Di Raimondo Francesco, Alessandra Quota et James G. Taylor. « Patients with Sickle Cell Disease in Sicily Have Lower Rates of End Organ Damage, Allo-Immunization and Opioid Prescription Compared to a US Cohort ». Blood 128, n^o 22 (2 décembre 2016) : 3664. http://dx.doi.org/10.1182/blood.v128.22.3664.3664.

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Abstract Background: In developed countries, childhood mortality in sickle cell disease (SCD) is less than 5%, where the SCD morbidity and mortality burden has shifted to adults. As age increases, so do end organ complications like chronic pain. Environmental factors like health economics and genetic factors may influence such outcomes. Recent data from UK, showed higher than expected survival (ASH 2015) in the setting of a national health care system. The Hospital of Gela, Sicily has a well characterized Caucasian SCD population, which also has consistent access to health care via a nationalized system. We hypothesized that traditional disease severity markers including end organ damage, the rate of red blood cell (RBC) alloimmunization and opioid use would be lower in Sicily, compared to a modern US population of African ancestry with inconsistent access to healthcare. Methods: 90 SCD patients in Sicily were followed for over 9 years (2006-2014) to identify clinical complications, alloimmunization rates and survival. Demographics and sickle and alpha globin genotypes were documented. In the US, 632 SCD patients (excluding those with SC) had the same parameters collected as part of the Bethesda Sickle Cell Cohort Study. Laboratory and clinical complications were compared between populations according to phenotype groups (SS/SB0 or SB+ thalassemia). Clinical manifestations included hospitalizations for pain per year, RBC alloimmunization, hydroxyurea prescription rate. Statistical analysis utilized univariate comparisons (t and Chi square tests). Results: In Sicily, 51 patients had SS/SB0 and 28 SB+. All were of self-described Caucasian ancestry. No SC patients were identified in Sicily, therefore all comparisons were limited to SS/SB0 and SB+ thalassemia. Sicilian SS/SB0 patients were older than the US (p<0.0001), had lower AST (p=0.04) and creatinine (p=0.005), and higher HbF (p<0.0001). SB+ patients had similar characteristics (Table 1). Sixteen Sicilian patients (18%) died at a mean age of 53 years (range 31-77). As suggested by these survival data, SCD complications were less frequent for both SS/SB0 and SB+ groups in Sicily compared to the US (Table 2). More Sicilians were prescribed hydroxyurea, especially among those with SB+, although this was not a significant difference. The pain crisis hospitalizations per year was also higher in the US (p=0.008). Consistent with less frequent hospitalizations, only 4 of the Sicilian patients (3 SS/SB0, 1 SB+) were taking long acting opioids, compared to more frequent opioid use in the US. Finally, RBC alloimmunization, another surrogate measure for disease severity, was twice as common in SS/SB0 patients from the US (30%) as in Sicily (14%, p=0.01). Conclusions: These data suggest that end organ complications, like chronic pain and alloimmunization, in self-described Caucasians with uniform access to health care in Sicily, are less common than in a US cohort of adults. These differences could be attributable to access to specialized care, genetic differences in the proportion of African ancestry or environmental factors like more frequent use of preventative therapies like hydroxyurea. RBC alloimmunization in Sicily is significantly lower than reported in the US , but is still higher than observed in thalassemics in Italy. Perhaps this could be explained a matched genetic background between blood donors and recipients in Sicily, as has been suggested as a strategy to reduce RBC alloimmunization in the US. Further studies comparing unique SCD populations from different geographic regions may be helpful to elucidate genetic or environmental risk factors for end organ complications and disease severity. Table 1. Table 1. Table 2. Table 2. Disclosures No relevant conflicts of interest to declare.

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De Castro, Laura M., Felicia C. Lennon-Graham, Allison G. Ashley-Koch, Jude C. Jonassaint, James J. Eckman, Eugene P. Orringer et Marilyn J. Telen. « Current Prevalence of Specific Clinical Outcomes in Adult Patients with Hb SS or Hb Sβ0 Thalassemia. » Blood 108, n^o 11 (16 novembre 2006) : 1201. http://dx.doi.org/10.1182/blood.v108.11.1201.1201.

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Abstract Over the last five years, we have enrolled 541 unrelated adult patients (age >18) with HbSS or HbSβ0 at three major comprehensive sickle cell centers in a study designed to identify factors associated with clinical outcomes in sickle cell disease. Our database includes demographic, clinical, and laboratory data on all participants. Medical history was obtained by both patient interview and review of medical records. The average age of patients enrolled was 34.0 yrs, median age 31.9, and 61 were ≥ 50 yrs; 54% were female. 81% of patients had finished high school, and 35% smoked tobacco products. History of SCD-related complications was as follows: acute chest syndrome - 76%, priapism (males only) - 41%, stroke - 16%, TIA - 5%, seizure - 12%, AVN of shoulders or hips - 30%, leg ulcers - 26%, heart failure - 7%, gallstones - 66%, and retinopathy - 22%. 68% of patients had undergone cholecystectomy, 11% splenectomy, and 11% major joint replacement. 136 patients had echocardiography data reported, and of these 39% had findings consistent with pulmonary hypertension, as defined as TRjet ≥ 2.5 m/s. 7% were receiving chronic transfusion therapy, and 6% were receiving iron chelation therapy. Significant proteinuria (≥ 1+) was present in 27% of patients, while only 4% had hematuria. Review of medication usage revealed that 40% were taking hydroxyurea (HU) at the time of enrollment, and 23% used long-acting narcotics daily. 14% of patients took medication for hypertension, 9% took antidepressants, and 6% used bronchodilators. Interviews and review of records showed that 21% had not required hospitalization during the past year, while 25% were hospitalized only once, 46% were hospitalized 2–4 times, and 8% were hospitalized >4 times during the past year. Hematologic values and HU status were available for 433 patients. Hematologic Values On HU Not On HU Mean Std Dev N Mean Std Dev N p value Hb 8.9 1.62 174 8.29 1.46 259 <0.001 Hct 25.85 4.62 174 24.25 4.39 259 0.0003 WBC 10.52 4.06 173 12.31 5.04 259 0.0001 Platelets 409.03 142.03 173 405.61 144.21 258 0.75 Patients not on HU had significantly higher total bilirubin values (3.51±2.66 vs 2.91±2.93, p=0.02) and insignificantly higher ferritin levels (1297±2118 vs 1089±1535, p=0.5). However, patients taking HU had higher LDH (p=0.0019) and uric acid levels (p<0.0001). In summary, despite frequent use of HU, resulting in statistically higher hemoglobin levels and lower WBC, the prevalence of end-organ complications associated with SCD remains high. More than half of all patients were hospitalized at least twice annually, and almost one-quarter required daily long-acting narcotics. 30% of patients have AVN, and more than 10% of patients had already undergone major joint surgery. Further research into HU prescribing patterns and patient compliance might lead to improvement in patient outcomes, but other interventions are likely to be required in order to ameliorate the persistently high complication rate of SCD.

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Perrine, SP, BA Miller, DV Faller, RA Cohen, EP Vichinsky, D. Hurst, BH Lubin et T. Papayannopoulou. « Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia ». Blood 74, n^o 1 (1 juillet 1989) : 454–59. http://dx.doi.org/10.1182/blood.v74.1.454.454.

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Abstract Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.

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Perrine, SP, BA Miller, DV Faller, RA Cohen, EP Vichinsky, D. Hurst, BH Lubin et T. Papayannopoulou. « Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia ». Blood 74, n^o 1 (1 juillet 1989) : 454–59. http://dx.doi.org/10.1182/blood.v74.1.454.bloodjournal741454.

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Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.

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Rosse, Wendell F., Mohandas Narla, Lawrence D. Petz et Martin H. Steinberg. « New Views of Sickle Cell Disease Pathophysiology and Treatment ». Hematology 2000, n^o 1 (1 janvier 2000) : 2–17. http://dx.doi.org/10.1182/asheducation.v2000.1.2.2.

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Abstract This review addresses several areas of concern in the care of patients with sickle cell disease. In Sections I and II, the fundamental pathogenetic mechanisms of sickle cell disease and their clinical consequences are discussed. Dr. Narla presents the evidence for abnormal cell adhesiveness by SS cells and Dr. Rosse examines the role of the increased whole blood viscosity. In Section III, Dr. Petz reviews common and uncommon alloimmune consequences of transfusion in sickle cell disease and discusses the diagnosis and management of sickle cell patients with hyperhemolysis after transfusion. In Section IV, Dr. Steinberg gives an update on the use of hydroxyurea in the treatment of sickle cell disease, including the SC and S-β thalassemia variants.

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Rosse, Wendell F., Mohandas Narla, Lawrence D. Petz et Martin H. Steinberg. « New Views of Sickle Cell Disease Pathophysiology and Treatment ». Hematology 2000, n^o 1 (1 janvier 2000) : 2–17. http://dx.doi.org/10.1182/asheducation.v2000.1.2.20000002.

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This review addresses several areas of concern in the care of patients with sickle cell disease. In Sections I and II, the fundamental pathogenetic mechanisms of sickle cell disease and their clinical consequences are discussed. Dr. Narla presents the evidence for abnormal cell adhesiveness by SS cells and Dr. Rosse examines the role of the increased whole blood viscosity. In Section III, Dr. Petz reviews common and uncommon alloimmune consequences of transfusion in sickle cell disease and discusses the diagnosis and management of sickle cell patients with hyperhemolysis after transfusion. In Section IV, Dr. Steinberg gives an update on the use of hydroxyurea in the treatment of sickle cell disease, including the SC and S-β thalassemia variants.

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