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1.  Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom 
PLoS ONE  2014;9(7):e99489.
Background
The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.
Methods and Results
We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥3.0 m/s cuttof, which has a 67–75% positive predictive value for mean pulmonary artery pressure ≥25 mm Hg was used. Among 572 subjects, 11.2% had TRV≥3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV≥3.0 m/sec. At 24 months the cumulative survival was 83% with TRV≥3.0 m/sec and 98% with TRV<3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1–30.1; p<0.0001) for TRV≥3.0 m/sec, 4.6 (1.8–11.3; p = 0.001) for NT-proBNP≥160 pg/mL, and 14.9 (5.5–39.9; p<0.0001) for both TRV≥3.0 m/sec and NT-proBNP≥160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III–IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.
Conclusions
A TRV≥3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable.
The study is registered in ClinicalTrials.gov with identifier
NCT00492531
doi:10.1371/journal.pone.0099489
PMCID: PMC4079316  PMID: 24988120
2.  Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease* 
Objectives
We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study.
Methods
Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20 years were studied at four centers in a cross-sectional manner. A sub-group (n=293) was followed for a median of 21 months (range 9-35).
Results
A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (p<0.0001), older age (p=0.001), >3 severe pain episodes in the preceding 12 months (p=0.002), higher tricuspid regurgitation velocity (TRV) (p=0.028), and higher white blood cell (WBC) count (p=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (p=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.4; p<0.0001) and younger age (odds ratio 0.9; p=0.010) were independently associated with developing a new episode during follow-up.
Conclusions
Asthma history, frequent pain and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD.
doi:10.1111/ejh.12118
PMCID: PMC3689858  PMID: 23560516
sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain
3.  Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease 
Background: Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH.
Objectives: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization.
Methods: Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression.
Measurements and Main Results: Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05–2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09–3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP − pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23–3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14–2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09–1.89 per Wood unit increase; P = 0.009) as risk factors for mortality.
Conclusions: Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.
doi:10.1164/rccm.201207-1222OC
PMCID: PMC3707372  PMID: 23348978
sickle cell; pulmonary hypertension; mortality; autopsy
4.  Echocardiographic Markers of Elevated Pulmonary Pressure and Left Ventricular Diastolic Dysfunction are Associated with Exercise Intolerance in Adults and Adolescents with Homozygous Sickle Cell Anemia in the US and UK 
Circulation  2011;124(13):1452-1460.
Background
Non-invasively assessed pulmonary pressure elevations and left ventricular diastolic dysfunction (LVDD) are associated with increased mortality in adults with sickle cell disease (SCD), but their relationship to exercise intolerance has not been evaluated prospectively.
Methods and Results
Echocardiography, six-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the US and UK Walk-PHaSST study. Tricuspid regurgitation velocity (TRV), which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/sec (mean±SD 2.8±0.1) in 26% of the subjects and ≥3.0 m/sec (3.4±0.4) in 11%. LV lateral E/e′ ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in SCD, was significantly higher in the groups with TRV ≥2.7 m/sec. Increased hemolysis (P<0.0001), LV lateral E/e′ ratio (P=0.0001), BUN (P=0.0002) and erythropoietin (P=0.002) were independently associated with an increased TRV. Further, female gender (P<0.0001), older age (P<0.0001), LV lateral E/e′ ratio (P=0.014), and TRV (P=0.019) were independent predictors of a shorter six-minute walk distance.
Conclusions
Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e′ ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LVDD will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered.
doi:10.1161/CIRCULATIONAHA.111.032920
PMCID: PMC3183314  PMID: 21900080
sickle cell anemia; pulmonary hypertension; left ventricular diastolic dysfunction; echocardiography; six-minute walk
5.  Relative Systemic Hypertension in Patients with Sickle Cell Disease is Associated with Risk of Pulmonary Hypertension and Renal Insufficiency 
American Journal of Hematology  2008;83(1):15-18.
We analyzed entry data from 163 adult hemoglobin SS and Sβ0 thalassemia patients enrolled in the prospective Sickle Cell Pulmonary Hypertension Screening Study and stratified their ECHO-determined tricuspid regurgitant jet velocity (TRV) and serum creatinine concentration according to three blood pressure categories. TRV was ≥2.5 m/sec in 27% of the patients with systolic blood pressure (SBP) <120 mm Hg and diastolic blood pressure (DBP) <70 mm Hg, in 37% with SBP 120–139 mm Hg or DBP 70–89 mm Hg, and in 93% with SBP 140 mm Hg or DBP 90 mm Hg or higher (P <0.0005 for trend). Serum creatinine concentration was 1.0 mg/dL or higher in 7% of patients with SBP <120 mm Hg and DBP <70 mm Hg, in 17% with SBP 120–139 mm Hg or DBP 70–89 mm Hg and 50% with SBP 140 mm Hg or DBP 90 mm Hg or higher (P <0.0005 for trend). Over two years of follow-up, there were trends for more frequent progression to elevated TRV (P = 0.073) or creatinine (P = 0.038) values according to the higher systemic blood pressure categories. Our findings suggest that systolic SBP 120–139 mm Hg or DBP 70–89 mm Hg defines a category of relative systemic hypertension in patients with sickle cell disease that is associated with increased risk for pulmonary hypertension and renal dysfunction. Whether antihypertensive and/or nitric oxide donor therapy in sickle cell disease patients with relative hypertension prevents these and other complications should be determined by clinical trials.
doi:10.1002/ajh.21016
PMCID: PMC3398810  PMID: 17696198
6.  Hydroxyurea and Acute Painful Crises in Sickle Cell Anemia: Effects on Hospital Length of Stay and Opioid Utilization During Hospitalization, Outpatient Acute Care Contacts, and at Home 
Context
Exploratory findings from the randomized double-blind placebo-controlled multicenter study of hydroxyurea (MSH) in sickle cell anemia (SS). Recurrent acute painful crises may be mild, moderate or severe in nature and often require treatment at home, in acute care facilities as outpatients, and in the hospital with oral and/or parenteral opioids.
Objectives
The objectives of this study were to determine the effects of hydroxyurea (HU) on length of hospital stay (LOS) and opioid utilization during hospitalization, outpatient acute care contacts, and at home.
Methods
Data from patient diaries, follow-up visit forms and medical contact forms on the 299 patients enrolled in the MSH were analyzed. Types and dosages of at-home, acute care, and in-hospital analgesic usage were explored descriptively.
Results
At home analgesics were used on 40% of diary days and 80% of two-week follow-up periods, with oxycodone and codeine the most frequently used. Responders to HU used analgesics on fewer days. During hospitalization, 96% were treated with parenteral opioids, with meperidine the most frequently used; oxycodone was the most commonly used oral medication. The average LOS for responders to HU was about two days less than for other groups and their cumulative time hospitalized during the trial was significantly less than for nonresponders or placebo groups (P<0.022). They also had the lowest doses of parenteral opioids during acute care crises (P=0.015).
Conclusion
Beneficial effects of HU include shortening the duration of hospitalization due to acute painful episodes and reducing the net amount of opioid utilization.
doi:10.1016/j.jpainsymman.2010.03.020
PMCID: PMC3005988  PMID: 20864308
Sickle cell anemia; hydroxyurea; painful crisis; opioid utilization; hospitalization
7.  Association of G6PD202A,376G with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia 
British journal of haematology  2010;150(2):218-225.
The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD202A and G6PD376G alleles and α-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD202A,376G (G6PD A-) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide.
The prevalence of G6PD202A,376G was 13.6% in males and 3.3% in females with an overall prevalence of 8.7%. G6PD202A,376G was associated with a 10 g/l decrease in haemoglobin concentration (P=0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P>0.09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double α-globin deletions were associated with progressively higher haemoglobin concentrations (P=0.005 for trend), progressively lower values for haemolytic component (P=0.007), and increased severe pain episodes (P<0.001).
Conclusions
In conclusion, G6PD202A,376G may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis.
doi:10.1111/j.1365-2141.2010.08215.x
PMCID: PMC2906678  PMID: 20507315
sickle cell anaemia; G6PD; haemolysis; alpha-thalassaemia; haemoglobin concentration
8.  Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease 
PLoS ONE  2009;4(11):e7956.
Background
Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well.
Design and Methods
Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor–BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined.
Results
Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi.
Conclusions
Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated.
doi:10.1371/journal.pone.0007956
PMCID: PMC2776981  PMID: 19956689
9.  Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients 
British journal of haematology  2009;147(3):352-359.
Summary
Low steady state haemoglobin oxygen saturation in patients with sickle cell anaemia has been associated with the degree of anaemia and haemolysis. How much pulmonary dysfunction contributes to low saturation is not clear. In a prospective study of children and adolescents with sickle cell disease aged 3–20 years at steady state and matched controls, 52% of 391 patients versus 24% of 63 controls had steady state oxygen saturation <99% (P < 0·0001), 9% of patients versus no controls had saturation <95% (P = 0·008) and 8% of patients versus no controls had exercise-induced reduction in saturation ≥3%. Decreasing haemoglobin concentration (P ≤ 0·001) and increasing haemolysis (P ≤ 0·003) but not pulmonary function tests were independent predictors of both lower steady-state saturation and exercise-induced reduction in saturation. Neither history of stroke nor history of acute chest syndrome was significantly associated with lower steady-state oxygen saturation or exercise-induced reduction in saturation. Tricuspid regurgitation velocity was higher in patients with lower steady state haemoglobin oxygen saturation (P = 0·003) and with greater decline in oxygen saturation during the six-minute walk (P = 0·022). In conclusion, lower haemoglobin oxygen saturation is independently associated with increasing degrees of anaemia and haemolysis but not pulmonary function abnormalities among children and adolescents with sickle cell disease.
doi:10.1111/j.1365-2141.2009.07854.x
PMCID: PMC2769929  PMID: 19694721
sickle cell disease; paediatric; oxygen saturation; six-minute walk; pulmonary hypertension
10.  Hemoglobin and MCV Values in 4,074 Healthy Black Children and Adolescents 
Hemoglobin and mean corpuscular volume values appear to be lower among black than among white children. Blood hemoglobin concentration and red cell mean corpuscular volume were measured in 4,074 black boys and girls aged 1 through 20 years who lived near sea level. This is the largest hematologic survey of healthy American black children and adolescents to date. Children with sickle cell disease and elevated hemoglobin F were excluded from the study, but children with the traits for hemoglobin S, hemoglobin C, thalassemia, and iron deficiency were not. The 3rd and 97th percentile values reported here are close to the 95 percent confidence limits, and are adjusted for age and sex.
PMCID: PMC2571325  PMID: 3820334
12.  Advanced Renal Failure in Patients with Sickle Cell Anemia: Clinical Course and Prognosis 
Advanced renal failure occurred in nine adult sickle cell disease patients. There were six men and three women with a mean age of 38.6 years. Eight patients had homozygous SS disease, one had sickle cell thalassemia. Three patients had acute renal failure from which they partially recovered. Six developed endstage kidney disease requiring dialysis. Two of these received a kidney transplant, and there was one death in the immediate postoperative period. Angina pectoris, hyperkalemia, and severe anemia complicated chronic dialysis, suggesting that early transplantation should be considered for sickle cell anemia patients with renal failure.
PMCID: PMC2561347  PMID: 6757451

Results 1-12 (12)