Early-onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait.

Adults with sickle cell trait (SCT) have a procoagulant state with increased risk of thromboembolism, but limited data are available for children. We compared the coagulation profile of children with SCT, different sickle cell disease (SCD) genotypes, and healthy controls. Compared to controls and similarly to HbSC patients, 41 SCT children (mean age 6.85 years; 20 males; 88% Africans) had a characteristic procoagulant profile: higher levels of factor VIII, von Willebrand factor (VWF) Ag and CBA, D-dimer; lower levels of ADAMTS 13 activity, ADAMTS13 activity: VWFAg, plasminogen activator inhibitor, tissue plasminogen activator. Moreover, 13/41 had clinical complications of SCD, five requiring hospitalization.

5-(Hydroxymethyl)furfural restores low-oxygen rheology of sickle trait blood in vitro.

Sickle cell trait (SCT) is the benign heterozygous carrier state for the sickle variant of the HBB gene. Most of the ~300 million people with SCT worldwide will not experience any significant complications. However, accumulating evidence finds SCT associated with increased risk for the common conditions of chronic kidney disease and venous thromboembolism, and severe but rare renal medullary carcinoma and exercise-induced rhabdomyolysis. The mechanism is uncertain, but probably involves pathological rheology of SCT blood in regions of low oxygen tension, resulting from sickle haemoglobin polymerization in SCT red cells and leading to reduced blood flow and further tissue hypoxia and damage. Here, we used an in vitro microfluidic flow system to study the oxygen-dependent rheology of SCT blood and show that 5-(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose-containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near-normal flow velocities at very low oxygen. While opinions regarding the clinical significance of the risks associated with SCT are still evolving, these results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT.

Spatial distribution of newborns with sickle cell trait in sergipe, brazil / Distribuição espacial de recém-nascidos com traço falciforme em sergipe

ABSTRACT Objective: To use the spatial distribution of the sickle cell trait (SCT) to analyze the frequency of hemoglobin S (HbS) carriers in Sergipe. Methods: The sample consisted of all individuals born in Sergipe from October 2011 to October 2012 who underwent neonatal screening in the public health system. Tests were carried out in basic health units and forwarded to the University Hospital laboratory, where they were analyzed. We used spatial autocorrelation (Moran's index) to assess the spatial distribution of heterozygous individuals with hemoglobinopathies. Results: Among 32,906 newborns, 1,202 showed other types of hemoglobin besides Hemoglobin A. We found a positive correlation between the percentage of black and multiracial people and the incidence of SCT. Most SCT cases occurred in the cities of Aracaju (n=273; 22.7%), Nossa Senhora do Socorro (n=102; 8.4%), São Cristóvão (n=58; 4.8%), Itabaiana (n=39; 4.2%), Lagarto (n=37; 4.01%), and Estância (n=46; 4.9%). Conclusions: The spatial distribution analysis identified regions in the state with a high frequency of HbS carriers. This information is important health care planning. This method can be applied to detect other places that need health units to guide and care for sickle cell disease patients and their families.

RESUMO Objetivo: Basear-se na distribuição espacial do traço falciforme (TF) para analisar a frequência dos portadores da hemoglobina S (HbS) em Sergipe. Métodos: A amostra foi constituída por todos os indivíduos nascidos em Sergipe, no período de outubro de 2011 a outubro de 2012, submetidos à triagem neonatal pelo Sistema Único de Saúde, ano de início da triagem universal no Estado. Os testes foram realizados em unidades básicas de saúde e encaminhados para o laboratório do Hospital Universitário, onde foram analisados. A análise da distribuição espacial dos indivíduos heterozigotos para hemoglobinopatias foi realizada por autocorrelação espacial (índice de Moran). Resultados: Dentre os 32.906 recém-nascidos estudados, 1.202 apresentaram outras hemoglobinas além da Hemoglobina A. Houve correlação positiva entre a porcentagem de negros e mestiços e a incidência de TF. A maioria dos casos foi encontrada nos municípios de Aracaju (n=273; 22,7%), Nossa Senhora do Socorro (n=102; 8,4%), São Cristóvão (n=58; 4,8%), Itabaiana (n=39; 4,2%), Lagarto (n=37; 4,01%) e Estância (n=46; 4,9%). Conclusões: Na análise de distribuição espacial por autocorrelação, identificaram-se regiões no Estado com maior frequência de HbS, o que é de extrema importância para o planejamento do sistema de saúde, podendo a mesma metodologia ser aplicada para identificação de outros locais com maior necessidade de centros para cuidados e orientações a portadores de doença falciforme e seus familiares.

Thirty-year risk of ischemic stroke in individuals with sickle cell trait and modification by chronic kidney disease: The atherosclerosis risk in communities (ARIC) study.

Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long-term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987-2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95-1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16-4.12) than those without CKD (HR = 1.09; 95% CI: 0.74-1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01-1.42) overall, 1.44 (95% CI: 1.002-2.07) among those with CKD, and 1.15 (95% CI: 0.94-1.39) among those without CKD; P for interaction = .18. The long-term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.

Serious adverse events in African-American cancer patients with sickle cell trait and inherited haemoglobinopathies in a SEER-Medicare claims cohort.

African-American (AA) cancer patients have long-experienced worse outcomes compared to non-Hispanic whites (NHW). No studies to date have evaluated the prognostic impact of sickle cell trait (SCT) and other inherited haemoglobinopathies, of which several are disproportionately high in the AA population. In a cohort analysis of treated patients diagnosed with breast or prostate cancer in the linked SEER-Medicare database, the relative risk (RR) for ≥1 serious adverse events (AEs), defined as hospitalisations or emergency department visits, was estimated for 371 AA patients with a haemoglobinopathy (AA+) compared to patients without haemoglobinopathies (17,303 AA-; 144,863 NHW-). AA+ patients had significantly increased risk for ≥1 AEs compared to AA- (RR = 1.19; 95% CI 1.11-1.27) and NHW- (RR = 1.23; 95% CI 1.15-1.31) patients. The magnitude of effect was similar by cancer type, and in analyses of AA+ with SCT only. Our findings suggest a novel hypothesis for disparities in cancer outcomes.

Increased Prevalence of Type 2 Diabetes-Related Complications in Combined Type 2 Diabetes and Sickle Cell Trait.

OBJECTIVE: The prevalence of type 2 diabetes (T2D) is rapidly increasing in sub-Saharan Africa, where sickle cell trait (SCT) is also frequent. Although SCT is generally considered a benign condition, evidence suggests that SCT could exaggerate vascular dysfunction in T2D. However, it remains unclear whether SCT could increase the risk of the development of T2D complications. Therefore, this study was conducted to determine whether T2D complications were more prevalent among Senegalese individuals with SCT and T2D than among those with T2D only. RESEARCH DESIGN AND METHODS: Rates of hypertension, retinopathy, peripheral neuropathy, peripheral artery disease, and impaired renal function as well as arterial stiffness, blood rheology, and concentrations of plasma advanced glycation end products (AGEs) and cytokines were compared between groups of Senegalese individuals with combined SCT and T2D (T2D-SCT) (n = 60), T2D (n = 52), SCT (n = 53), and neither T2D nor SCT (control) (n = 56). Human aortic endothelial cell (HAEC) expression of inflammatory and adhesion factors was measured after treatment with tumor necrosis factor-α and subjects' plasma. Effects of AGE inhibition or tiron on HAEC expression of E-selectin were measured. RESULTS: Retinopathy, hypertension, and reduced renal function were more prevalent, and arterial stiffness, blood viscosity at high shear rates, and thixotropic index were higher, in the SCT group compared with the other groups. Multivariable analysis showed that plasma AGE concentration was significantly associated with arterial stiffness. E-selectin expression was elevated in HAECs treated with T2D-SCT plasma compared with the other groups, but AGE inhibition reversed this. CONCLUSIONS: SCT could potentially augment the risk of the development of T2D-related complications, including retinopathy, nephropathy, and hypertension.

Association between Sickle Cell Trait and the Prevalence and Severity of Diabetic Retinopathy.

PURPOSE: To determine whether Sickle cell trait (SCT) is associated with an increased severity of diabetic retinopathy. METHODS: This was a single center retrospective study case control study of 100 eyes of 100 patients with diabetes mellitus (DM) with SCT (SCT group) and 100 eyes of 100 age-matched patients with DM without SCT (control group). The main outcome measure was the difference in the prevalence of sight threatening DR [here defined as diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR)], between the SCT and control groups. Secondary outcome measures included differences in visual acuity, ocular comorbidities, intraocular pressure, glycemic control as assessed by random blood glucose measurement, diabetes duration, nephropathy, hyperlipidemia and hypertension. RESULTS: The SCT group had statistically significantly shorter duration of DM (median [25% quartile] 15 [8.3] years versus 20 [14.7] years, respectively)(P<0.001) and presented with statistically better metabolic control (mean difference 1.6 mmol/l, (95% confidence interval [CI], 0.1-3.3;P = 0.03). The prevalence of PDR and/or DME was significantly lower in the SCT group (58%) compared to the control group, (95%)(P<0.001). The absence of SCT (adjusted odds ratio [AOR] = 24; 95% CI, 8-72; P<0.001) and longer duration of DM (AOR = 1.1 [95% CI, 1.02-1.13]; P = 0.003) were independent predictors of PDR and/or DME. CONCLUSIONS: SCT seems to protect against the development and progression of DR. This may have implications for monitoring and screening. Prospective studies are required to confirm this association. If true, this association may indicate an increased blood glucose buffering capacity of abnormal hemoglobin.

Sickle cell trait: what are the costs and benefits of screening?

INTRODUCTION: Eight percent of African Americans are carriers of the sickle cell trait. Some regard this as a benign anomaly, but others point to incidents of sudden exercise-related death, calling for a preliminary screening of either all athletes or those of African-American ancestry. This brief review considers the costs and benefits of such screening. EVIDENCE ACQUISITION: The Ovid/Health Star data-base was searched from 1996 to June 2015. 2014. The terms "exercise", "exercise therapy", "sports", "athletes", "physical activity/motor activity" and "physical fitness" were combined to yield 227,120 citations. Likewise, the terms "sickle cell trait", "sickle cell disease", "splenic infarction", "hemoglobin S" and "rhabdomyolysis" identified 12,325 citations. A combination of the 2 searches yielded 416 abstracts. EVIDENCE SYNTHESIS: Excluding items relating to animal research or forms of rhabdomyolysis other than sickling left 375 abstracts; 115 papers merited full examination. This material covered the risks of sickle cell trait and of screening (55 items), effects upon physical performance (31 items), cellular mechanisms (23 items), nutrition (4 items), and other topics (2 items). Supplemented material was drawn from reference lists and personal files. The tendency to sickling was provoked by excessive exercise relative to physical condition in hot or hypoxic conditions, and by local tissue acidosis, conditions that were best avoided by all athletes. The condition had little impact upon physical performance, but the relative risks of heat illness, exertional rhabdomyolysis, splenic infarction and sudden death were all increased by the sickle cell trait. The absolute number of critical incidents was nevertheless small, calling for close assessment of the costs and putative benefits of widespread screening. CONCLUSIONS: Sports physicians should be aware of the clinical picture of sickling and be prepared to treat it. Screening may be cost-effective if targeted to black athletes involved in certain sports, although it has yet to be demonstrated how far the diagnosis of sickle cell trait reduces the risk of death when exercising in an adverse environment. A better tactic may be to reduce risks for all competitors by educating athletes and their coaches to adopt an intensity of training appropriate to the individual's physical condition, to maintain full hydration, and to avoid exposure to excessive heat and hypoxia.

Genetic variant in the BCL11A (rs1427407), but not HBS1-MYB (rs6934903) loci associate with fetal hemoglobin levels in Indian sickle cell disease patients.

India along with Nigeria and DRC contribute to 57% of the world sickle cell anemia population. The annual number of newborns in India with SCA was estimated at 44,000 in 2010. Even with this high prevalence there is minimal information about genetic factors that influence the disease course in Indian patients. The current study was conducted on 240 patients with SCD and 60 with sickle cell trait, to determine the association of genetic variants at the BCL11A (rs1427407) and HBS1-MYB (rs6934903) loci with fetal hemoglobin levels (HbF). Both these loci have been implicated with influencing HbF levels, a powerful modulator of the clinical and hematologic features of SCD. Our results indicate the BCL11A rs1427407 G>T variant to be significantly associated with HbF levels {19.12±6.61 (GG), 20.27±6.92 (GT) and 24.83±2.92 (TT) respectively} contributing to ~23% of the trait variance. Interestingly no association of the HBS1L-MYB rs6934903 with the HbF levels was seen. The present study indicates the BCL11A (rs1427407) but not HMIP (rs6934903) to be associated with elevated HbF levels in Indian patient. Further interrogation of additional variants at both the loci; as also a GWAS which may help uncover new loci controlling HbF levels.

Serum angiogenin level in sickle cell disease and beta thalassemia patients.

INTRODUCTION: Angiogenesis has been investigated in different kinds of anemia. However, its role as a marker of angiogenesis has not been investigated in thalassemia or sickle cell disease (SCD). OBJECTIVES: We aimed to investigate serum angiogenin level in children and adolescents with beta thalassemia or SCD and its relation to possible risk factors of angiogenesis. MATERIALS AND METHODS: This study included; 32 ß-thalassemia major (ß-TM) patients aged 14.2 ± 3.8 years, 20 ß-thalassemia intermedia (ß-TI) patients aged 14.3 ± 4.8 years, 20 SCD patients aged 14.1 ± 2.4 years; 8 with (HbSS) and 12 with sickle thalassemia (HbS/ß-thalassemia) and 35 age and sex-matched controls. Data collected regarding; age, sex, disease duration, blood transfusion frequency, transfusion index, chelation type and duration, CBC, Hb electrophoresis, serum ferritin and serum angiogenin level (by ELISA). RESULTS: Angiogenin level was significantly higher in patients with SCD [250 (100-300) pg/mL] compared to ß-TM [180 (140-230) pg/mL] and controls [89 (80-103) pg/mL] (P < .001) especially those with HbSS (P = .06). There was a significant negative correlation between serum angiogenin and age of patients, age of onset and duration of chelation in ß-TM (P < .01, P < .001, P = .003) and ß-TI (P = .009, P = .03, P < .001) and with serum ferritin in ß-TI group (r = -0.573, P = .008). In SCD, angiogenin level was negatively correlated with both frequency of blood transfusion (r = -0.731, P < .001) and duration of hydroxyurea therapy (P = .017). CONCLUSIONS: High angiogenin level detected among patients with SCD may be negatively influenced by regular blood transfusion and hydroxyurea therapy, while; early onset of chelation therapy may decrease angiogenin level in ß-TM.

Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinical data were obtained over 6 months in 2011. Among 5319 African-American patients, 542 (10.2%) patients had sickle cell trait, and 129 (2.4%) patients had hemoglobin C trait; no other hemoglobinopathy traits were present. Sickle cell trait was more common in this cohort than the general African-American population (10.2% versus 6.5%-8.7%, respectively, P<0.05). Among 5002 patients (10.3% sickle cell trait and 2.4% hemoglobin C trait) receiving ESAs, demographic and clinical variables were similar across groups, with achieved hemoglobin levels being nearly identical. Patients with hemoglobinopathy traits received higher median doses of ESA than patients with normal hemoglobin (4737.4 versus 4364.1 units/treatment, respectively, P=0.02). In multivariable analyses, hemoglobinopathy traits associated with 13.2% more ESA per treatment (P=0.001). Within subgroups, sickle cell trait patients received 13.2% (P=0.003) higher dose and hemoglobin C trait patients exhibited a similar difference (12.9%, P=0.12). Sensitivity analyses using weight-based dosing definitions and separate logistic regression models showed comparable associations. Our findings suggest that the presence of sickle cell trait and hemoglobin C trait may explain, at least in part, prior observations of greater ESA doses administered to African-American dialysis patients relative to Caucasian patients.

A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/ß(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

Antioxidant vitamins C and E supplementation increases markers of haemolysis in sickle cell anaemia patients: a randomized, double-blind, placebo-controlled trial.

Erythrocytes from sickle cell anaemia (SCA) patients continuously produce larger amounts of pro-oxidants than normal cells. Oxidative stress seems to primarily affect the membrane and results in haemolysis. The use of antioxidants in vitro reduces the generation of pro-oxidants. To evaluate the impact of vitamins C (VitC) and E (VitE) supplementation in SCA patients, patients over 18 years were randomly assigned to receive VitC 1400 mg + VitE 800 mg per day or placebo orally for 180 d. Eighty-three patients were enrolled (44 vitamins, 39 placebo), median age 27 (18-68) years, 64% female. There were no significant differences between the two groups regarding clinical complications or baseline laboratorial tests. Sixty percent of the patients were VitC deficient, 70% were VitE deficient. Supplementation significantly increased serum VitC and E. However, no significant changes in haemoglobin levels were observed, and, unexpectedly, there was a significant increase in haemolytic markers with vitamin supplementation. In conclusion, VitC + VitE supplementation did not improve anaemia and, surprisingly, increased markers of haemolysis in patients with SCA and S-ß(0) -thalassaemia. The exact mechanisms to explain this findings and their clinical significance remain to be determined.

Anemia drepanocítica y embarazo. Experiencia en el Instituto de Hematología e Inmunología, Cuba / Sickle cell disease and pregnancy. Experience at the Instituto de Hematologia e Inmunología, Cuba

El embarazo en la anemia drepanocítica (AD) es considerado una situación de alto riesgo por la alta incidencia de la morbimortalidad materno-fetal. En Cuba, el programa de atención integral a las embarazadas se incluye desde el nivel primario de salud y la captación se realiza antes de las 12 sem de gestación y los partos son institucionales. Todas las embarazadas con AD en La Habana son atendidas en el Instituto de Hematología e Inmunología (IHI) por un equipo multidisciplinario y los partos se realizan en el Servicio de Obstetricia del Hospital General Docente Enrique Cabrera . Desde enero del año 2000 hasta diciembre del 2009, 68 embarazadas con AD fueron atendidas por un equipo multidisciplinario. La frecuencia de las consultas fue quincenal hasta las 32 sem de la gestación y posteriormente semanal hasta la sem 36 en que fueron ingresadas; el embarazo se interrumpió en la semana 38. Las pacientes que presentaron algún evento fueron hospitalizadas y en ellas la interrupción se realizó en la semana 36 si el feto era viable. El bienestar fetal fue evaluado desde la semana 28 cada 2 semana hasta el nacimiento. No se realizaron transfusiones ni exanguinotransfusiones profilácticas y solo fueron indicadas según los criterios del equipo médico tratante; 16 pacientes recibieron transfusiones de glóbulos y la exanguinotransfusión se realizo en 4, todas en el tercer trimestre del embarazo. En 47 pacientes se realizó cesárea y siempre por indicación obstétrica; 17 recién nacidos tuvieron bajo peso pero solo uno tuvo un conteo de Apgar bajo. Ocurrieron 2 muertes fetales y una neonatal; se reportó una muerte materna

Pregnancy in women with sickle cell disease (SCD) is a high-risk situation associated with increased incidence of maternal and fetal morbidity and mortality. In Cuba, the maternal care program includes the primary level and the gestational age at booking is before the 12 week of gestation and all deliveries are institutional. All pregnant women with SCD in La Habana are attended at the Institute of Hematology and Immunology (IHI) by a multidisciplinary team and labor takes place at the obstetrics service of the General Hospital next to the IHI. From January 2000 to December 2009, 68 pregnant women with SCD were attended in labor; the frequency of the visits is every two weeks from gestational age at booking until week 32 of pregnancy and weekly until week 36 when they are hospitalized, in week 38 induction of labor is made. Patients were hospitalized upon the appearance of any event and in such cases induction of labor was made in week 36, if fetus was mature. The fetal well-being was evaluated starting from week 28 and every two weeks until childbirth. Non prophylactic blood transfusion or prophylactic exchange transfusions were indicated as this depends on the criteria of attending team; only 16 patients presented alert signs of requiring blood transfusion, 4 requiring blood exchange transfusions. All these procedures were carried out in the third trimester of pregnancy; 47 patients required caesarea indicated by the obstetrician; 17 newborns were underweight but only one with low apgar score. Two fetal deaths occurred and one new born had early neonatal death. Only one maternal death was reported

Elevated plasma levels and platelet-associated expression of the pro-thrombotic and pro-inflammatory protein, TNFSF14 (LIGHT), in sickle cell disease.

Chronic vascular inflammation and endothelial activation may initiate vaso-occlusion in sickle cell disease (SCD). TNFSF14 (CD258; LIGHT), a recently-identified pro-thrombotic and pro-inflammatory tumour necrosis factor (TNF)-superfamily cytokine, has a potent activating effect on endothelial cells. We evaluated whether TNFSF14 production is altered in SCD and whether platelets contribute to this production. TNFSF14 was measured in platelet-free plasma from healthy-control individuals (CON), steady-state sickle cell anaemia (SCA), SCA on hydroxycarbamide therapy (SCAHC) and haemoglobin SC (HbSC) patients. Mean plasma TNFSF14 was significantly increased in SCA, SCAHC and HbSC, compared to CON individuals. In SCA/SCAHC patients, plasma TNFSF14, showed no correlation with haematological variables, but was significantly correlated with serum lactate dehydrogenase and inflammatory markers (CD40LG , IL8 and ICAM1). Platelet-membrane TNFSF14 expression was significantly augmented on SCA platelets, and correlated with platelet activation; furthermore, measurement of platelet TNFSF14 release indicated that platelets may be a major source of circulating TNFSF14 in SCA. Interestingly, high plasma TNFSF14 was significantly associated with elevated tricuspid regurgitant velocity (≥2·5 m/s) in a population of SCA/SCAHC patients. The pro-inflammatory and atherogenic cytokine, TNFSF14, could contribute to endothelial activation and inflammation in SCA; future investigations may confirm whether this protein contributes to major clinical complications of the disease, such as pulmonary hypertension, and represents a potential therapeutic target.

Effects of regular physical activity on skeletal muscle structural, energetic, and microvascular properties in carriers of sickle cell trait.

To assess the effects of regular physical activity on muscle functional characteristics of carriers of sickle cell trait (SCT), 39 untrained (U) and trained (T) hemoglobin (Hb)AA (CON) and SCT subjects (U-CON, n = 12; U-SCT, n = 8; T-CON, n = 10; and T-SCT, n = 9) performed a graded exercise and a time to exhaustion (T(ex)) test, and were subjected to a muscle biopsy. Maximal power, total work performed during T(ex), citrate synthase and cytochrome c oxidase (COX) activities, respiratory chain complexes I and IV content, and capillary density (CD), diameter (COD), and surface area (CSA) were upregulated by the same proportion in T-CON and T-SCT compared with their untrained counterparts. These proportionally similar differences imply that the observed discrepancies between U-SCT and U-CON remained in the trained subjects. Specifically, both CD and COX remained and tended to remain lower, and both COD and CSA remained and tended to remain higher in T-SCT than in T-CON. Besides, carriers of SCT displayed specific adaptations with regular physical activity: creatine kinase activity; complexes II, III, and V content; and type I fiber surface area and capillary tortuosity were lower or unchanged in T-SCT than in U-SCT. In summary, our results show that 1) carriers of SCT adapted almost similarly to CON to regular physical activity for most of the studied muscle characteristics, 2) oxidative potential remains altered in physically active carriers of SCT compared with HbAA counterparts, and 3) the specific remodeling of muscle microvascular network persists in the trained state.

Haplotipos del gen de la globina beta en portadores de hemoglobina S en Colombia / Beta globin haplotypes in hemoglobin S carriers in Colombia

Introducción. La mutación de la hemoglobina S (HbS) va acompañada por otras mutaciones en la región del cromosoma 11, conocida como conjunto de la globina beta(beta globin cluster). El patrón de combinación de estos polimorfismos da lugar a los haplotipos que se heredan junto con la mutación de la hemoglobina S, se denominan haplotipos de la mutación bs y revisten gran importancia epidemiológica y clínica. Objetivo. Determinar la frecuencia de los principales haplotipos asociados al gen HBB en pacientes colombianos heterocigotos para hemoglobina S. Materiales y métodos. En la Clínica Colsanitas se han estudiado a la fecha 1.200 muestras de sangre periférica de niños en busca de hemoglobinopatías, y se ha encontrado el rasgo falciforme como la hemoglobinopatía más frecuente. Se determinaron los haplotipos del gen HBB que presentaron la mutación beta-S en 33 niños con patrón electroforético de hemoglobina AS, mediante reacción en cadena de la polimerasa (PCR) y enzimas de restricción. Se determinaron el patrón electroforético de la hemoglobina, el nivel de hemoglobina fetal y los parámetros hematológicos de cada individuo. Resultados. Los haplotipos de la hemoglobina S encontrados con mayor frecuencia en la muestra analizada son de origen africano y su orden de aparición fue mayor para el haplotipo Bantú (36,4 %), seguido por Senegal (30,3 %), Benín (21,2 %) y Camerún (12,1 %). La electroforesis de hemoglobina confirmó el fenotipo AS; la dosificación de hemoglobina fetal mostró niveles por debajo de 1 % y los parámetros hematológicos analizados mostraron valores normales en el 100 % de los individuos. Conclusión. Los haplotipos de la HbS encontrados con mayor frecuencia en la muestra estudiada eran de origen africano y su distribución variaba de acuerdo con el lugar de prodedencia del individuo. La mayor frecuencia correspodió al haplotipo Bantú.

Introduction. The hemoglobin S (HbS) mutation is accompanied by other mutations in the region of chromosome 11 known as "beta globin cluster". The pattern of combination of these polymorphisms giving rise to the haplotypes that co-inherit the HbS mutation, are called haplotypes bs, and are of great epidemiological and clinical significance. Objective. The frequencies of major haplotypes associated with S beta-globin gene was determined in Colombian patients heterozygous for hemoglobin S. Materials and methods. As part of the national neonatal screening program at Clínica Colsanitas, located in major cities of Colombia, nearly 1,200 children from different areas of the country were examined for hemoglobinopathies. The sickle cell trait was identified as the most common. S beta-globin gene haplotypes were determined by PCR and restriction enzymes in 33 children with AS hemoglobin electrophoretic patterns (carrier state). In addition, electrophoretic patterns of hemoglobin, fetal hemoglobin levels and hematologic parameters of each individual were identified. Results. The most frequent haplotypes in Colombia were the Bantú haplotype (36.4 %), followed by Senegal (30.3 %), Benin (21.2 %) and Cameroon (12.1 %) haplotypes. Hemoglobin electrophoresis confirmed the AS phenotype in all patients, and fetal hemoglobin levels below 1%. Other hematological parameters were normal in all cases. Conclusion. The HbS haplotypes found more frequently in the sample were of African origin, and their distribution varied according to the place of origin of the individual. The most frequent corresponded to the Bantu haplotype.