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1.
Br J Haematol ; 192(5): 932-941, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33506990

RESUMEN

Risk assessment for patients with sickle cell disease (SCD) remains challenging as it depends on an individual physician's experience and ability to integrate a variety of test results. We aimed to provide a new risk score that combines clinical, laboratory, and imaging data. In a prospective cohort of 600 adult patients with SCD, we assessed the relationship of 70 baseline covariates to all-cause mortality. Random survival forest and regularised Cox regression machine learning (ML) methods were used to select top predictors. Multivariable models and a risk score were developed and internally validated. Over a median follow-up of 4·3 years, 131 deaths were recorded. Multivariable models were developed using nine independent predictors of mortality: tricuspid regurgitant velocity, estimated right atrial pressure, mitral E velocity, left ventricular septal thickness, body mass index, blood urea nitrogen, alkaline phosphatase, heart rate and age. Our prognostic risk score had superior performance with a bias-corrected C-statistic of 0·763. Our model stratified patients into four groups with significantly different 4-year mortality rates (3%, 11%, 35% and 75% respectively). Using readily available variables from patients with SCD, we applied ML techniques to develop and validate a mortality risk scoring method that reflects the summation of cardiopulmonary, renal and liver end-organ damage. Trial Registration: ClinicalTrials.gov Identifier: NCT#00011648.


Asunto(s)
Anemia de Células Falciformes/mortalidad , Fenotipo , Medición de Riesgo , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Anemia de Células Falciformes/sangre , Nitrógeno de la Urea Sanguínea , Índice de Masa Corporal , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca , Válvulas Cardíacas/fisiopatología , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Modelos Biológicos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Adulto Joven
2.
Circ Res ; 116(2): 298-306, 2015 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-25378535

RESUMEN

RATIONALE: Patients with sickle cell disease (SCD) have markers of chronic inflammation, but the mechanism of inflammation and its relevance to patient survival are unknown. OBJECTIVE: To assess the relationship between iron, inflammation, and early death in SCD. METHODS AND RESULTS: Using peripheral blood mononuclear cell transcriptome profile hierarchical clustering, we classified 24 patients and 10 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll-like receptor system (TLR4, TLR7, and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed this classification and showed that ferritin light chain, TLR4, and interleukin-6 expression were >100-fold higher in patients than in controls (P<0.001). Further linking intracellular iron and inflammation, 14 SCD patients with a ferroportin Q248H variant that causes intracellular iron accumulation had significantly higher levels of interleukin-6 and C-reactive protein compared with 14 matched SCD patients with the wild-type allele (P<0.05). Finally, in a cohort of 412 patients followed for a median period of 47 months (interquartile range, 24-82), C-reactive protein was strongly and independently associated with early death (hazard ratio, 3.0; 95% confidence interval, 1.7-5.2; P<0.001). CONCLUSIONS: Gene expression markers of high intracellular iron in patients with SCD are associated with markers of inflammation and mortality. The results support a model in which intracellular iron promotes inflammatory pathways, such as the TLR system and the inflammasome, identifying important new pathways for additional investigation.


Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/genética , Marcadores Genéticos/genética , Hierro/sangre , Adulto , Anemia de Células Falciformes/mortalidad , Estudios de Cohortes , Femenino , Humanos , Inflamación/sangre , Inflamación/genética , Inflamación/mortalidad , Leucocitos Mononucleares/metabolismo , Masculino , Mortalidad/tendencias , Estudios Prospectivos , Sistema de Registros
3.
Am J Hematol ; 89(2): 187-93, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24136375

RESUMEN

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , GTP Ciclohidrolasa/genética , Predisposición Genética a la Enfermedad , Haplotipos , Dolor/etiología , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/etiología , Adulto , Alelos , Anemia de Células Falciformes/metabolismo , Biopterinas/análogos & derivados , Biopterinas/sangre , Biopterinas/metabolismo , Estudios de Casos y Controles , Endotelio/metabolismo , Endotelio/fisiopatología , Femenino , Regulación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Manejo del Dolor , Fenotipo , Pletismografía , Factores Sexuales , Transcriptoma , Adulto Joven
4.
BMC Psychiatry ; 14: 207, 2014 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-25047658

RESUMEN

BACKGROUND: Sleep disturbance and depression are commonly encountered in primary care. In sickle cell disease, depression is associated with pain, poor treatment compliance, and lower quality of life. The prevalence of sleep disturbance and its effect upon quality of life in adults with sickle cell disease is unknown. The goal of this study was to determine the prevalence of sleep disturbance and if it is associated with pain and depression in sickle cell disease. METHODS: Three hundred twenty eight adults with sickle cell disease enrolled on the Bethesda Sickle Cell Cohort Study were assessed using the Pittsburgh Sleep Quality Index and Beck Depression Inventory II screening measures as a cross-sectional survey. Scores greater than 5 (Pittsburgh Sleep Quality Index) and 16 (Beck Depression Inventory II) defined sleep disturbance and depression, respectively. Clinical and laboratory parameters were also assessed. RESULTS: The mean Pittsburgh Sleep Quality Index score was 8.4 (SD ± 4.2) indicating a 71.2% prevalence of sleep disturbance. The mean Beck Depression Inventory II score was 8.0 (SD ± 8.9). Sixty five (20.6%) participants had a score indicating depression, and half of these (10.0%) had thoughts of suicide. Both Pittsburgh Sleep Quality Index and Beck Depression Inventory II scores were significantly correlated (p < .001). The number of days with mild/moderate pain (p = .001) and a history of headaches (p = .005) were independently associated with depression by multivariate regression analysis. Patients with sleep disturbance were older (p = .002), had higher body mass index (p = .011), had more days of pain (p = .003) and more frequent severe acute painful events (emergency room visits and hospitalizations) during the previous 12 months (p < .001). CONCLUSIONS: More than 70 percent of adults with sickle cell disease had sleep disturbance, while 21 percent showed evidence of clinical depression. Sleep disturbance and depression were correlated, and were most common among those with more frequent pain. Providers caring for adults with sickle cell disease and frequent pain should consider screening for these common co-morbidities. Additional study is needed to confirm these findings and to determine if treatments for pain, depression or sleep disturbances will improve quality of life measures in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00011648.


Asunto(s)
Anemia de Células Falciformes/epidemiología , Depresión/epidemiología , Dolor/epidemiología , Autoinforme , Trastornos del Sueño-Vigilia/epidemiología , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Escalas de Valoración Psiquiátrica , Calidad de Vida , Sueño , Suicidio/psicología , Estados Unidos/epidemiología
6.
Br J Haematol ; 149(3): 436-45, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20230401

RESUMEN

Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular haemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in SCD versus ethnically-matched healthy controls. Several cholesterol parameters correlated significantly with markers of anaemia, but not endothelial activation or PH. More importantly, serum triglyceride levels were significantly elevated in SCD compared to controls. Elevated triglyceride levels correlated significantly with markers of haemolysis (lactate dehydrogenase and arginase; both P < 0.0005), endothelial activation (soluble E-selectin, P < 0.0001; soluble P-selectin, P = 0.02; soluble vascular cell adhesion molecule-1, P = 0.01), inflammation (leucocyte count, P = 0.0004; erythrocyte sedimentation rate, P = 0.02) and PH (amino-terminal brain natriuretic peptide, P = 0.002; prevalence of elevated tricuspid regurgitant velocity (TRV), P < 0.001). In a multivariate analysis, triglyceride levels correlated independently with elevated TRV (P = 0.002). Finally, forearm blood flow studies in adult patients with SCD demonstrated a significant association between increased triglyceride/HDL-C ratio and endothelial dysfunction (P < 0.05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.


Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Hipertensión Pulmonar/etiología , Lípidos/sangre , Adulto , Anemia de Células Falciformes/fisiopatología , Biomarcadores/sangre , Estudios de Casos y Controles , Colesterol/sangre , HDL-Colesterol/sangre , Endotelio Vascular/fisiopatología , Femenino , Hemólisis , Humanos , Hipertensión Pulmonar/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangre
7.
J Nucl Med ; 60(1): 86-92, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29880507

RESUMEN

Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality. Chronic thromboembolic PH (CTEPH) is an important complication and contributor to PH in SCD but is likely underappreciated. Guidelines recommend ventilation-perfusion (V/Q) scintigraphy as the imaging modality of choice to exclude CTEPH. Data on V/Q scanning are limited in SCD. Our objective was to compare the performance of V/Q scanning with that of CT pulmonary angiography (CTPA) and to report clinical outcomes associated with abnormal V/Q findings. Methods: Laboratory data, echocardiography, 6-min-walk testing, V/Q scanning, CTPA, and right heart catheterization (RHC) were prospectively obtained. High-probability and intermediate-probability V/Q findings were considered to be abnormal. Included for analysis were 142 SCD adults (aged 40.1 ± 13.7 y, 83 women, 87% hemoglobin SS) in a stable state enrolled consecutively between March 13, 2002, and June 8, 2017. Results: V/Q results were abnormal in 65 of 142 patients (45.8%). CTPA was positive for pulmonary embolism in 16 of 60 (26.7%). RHC confirmed PH (mean pulmonary artery pressure ≥ 25 mmHg) in 46 of 64 (71.9%), of whom 34 (73.9%) had abnormal V/Q findings. Among those without PH by RHC (n = 18), 2 of 18 patients had abnormal V/Q findings. Thirty-three patients had a complete dataset (V/Q scanning, CTPA, and RHC); 29 of 33 had abnormal RHC findings, of whom 26 had abnormal V/Q findings, compared with 11 who had abnormal CTPA findings. There was greater concordance between V/Q findings and RHC (κ-value = 0.53; P < 0.001) than between CTPA and RHC (κ-value = 0.13; P = 0.065). The sensitivity and specificity for V/Q scanning was 89.7% and 75.0%, respectively, whereas CTPA had sensitivity of 37.3% and specificity of 100%. Abnormal V/Q finding swere associated with hemodynamic severity (mean pulmonary artery pressure, 35.2 ± 9.6 vs. 26.9 ± 10.5 mm Hg, P = 0.002; transpulmonary gradient, 21.5 ± 9.7 vs. 12.16 ± 11 mmHg, P = 0.005; and pulmonary vascular resistance, 226.5 ± 135 vs. 140.7 ± 123.7 dynes⋅s⋅cm-5, P = 0.013) and exercise capacity (6-min-walk distance, 382.8 ± 122.3 vs. 442.3 ± 110.6 m, P < 0.010). Thirty-four deaths were observed over 15 y. All-cause mortality was higher in the abnormal-V/Q group (21 [61.8%]) than in the normal-V/Q group (13 [38.2%]) (log-rank test, P = 0.006; hazard ratio, 2.54). Conclusion: V/Q scanning is superior to CTPA in detecting thrombotic events in SCD. Abnormal V/Q findings are associated with PH, worse hemodynamics, lower functional capacity, and higher mortality. Despite high sensitivity in detecting CTEPH, V/Q scanning is underutilized. We recommend the use of V/Q scanning in the evaluation of dyspnea in adult SCD patients given the important implications toward management.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico por imagen , Hipertensión Pulmonar/complicaciones , Gammagrafía de Ventilacion-Perfusión , Adulto , Femenino , Humanos , Masculino , Estudios Retrospectivos
8.
Blood Adv ; 2(20): 2672-2680, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30333099

RESUMEN

A key inflammatory mechanism recently identified in platelets involves the Nod-like receptor nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK), which control activation of caspase-1 within inflammasome complexes. We investigated platelet caspase-1 activity in the context of sickle cell disease (SCD) directly in platelets isolated from SCD patients (n = 24) and indirectly by incubating platelets from healthy subjects with plasma obtained from SCD patients (n = 20), both in steady state and during an acute pain crisis (paired samples). The platelet NLRP3 inflammasome was upregulated in SCD patients under steady state conditions compared with healthy controls, and it was further upregulated when patients experienced an acute pain crisis. The results were consistent with indirect platelet assays, in which SCD plasma increased caspase-1 activity of platelets from healthy subjects in an NLRP3-dependent fashion. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) was elevated in plasma of SCD subjects compared with healthy controls and correlated with caspase-1 activity in platelets. Pharmacological or antibody-mediated inhibition of HMGB1, Toll-like receptor 4, and BTK interfered with sickle plasma-induced platelet caspase-1 activation. In Townes SCD mice, caspase-1 activity and aggregation of circulating platelets were elevated, which was suppressed by IV injection of an NLRP3 inhibitor and the BTK inhibitor ibrutinib. Activation of the platelet NLRP3 inflammasome in SCD may have diagnostic and therapeutic implications.


Asunto(s)
Anemia de Células Falciformes/genética , Proteína HMGB1/genética , Inflamasomas/metabolismo , Receptor Toll-Like 4/genética , Adulto , Agammaglobulinemia Tirosina Quinasa , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Animales , Femenino , Proteína HMGB1/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptor Toll-Like 4/metabolismo , Regulación hacia Arriba
9.
Int J Lab Hematol ; 40(6): 704-709, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30152174

RESUMEN

INTRODUCTION: Sickle cell disease (SCD) is a multisystemic disorder, the pathology being driven by recurrent inflammation particularly during a vaso-occlusive crisis. GlycA, a composite measure of protein glycation, is a sensitive biomarker for disorders associated with vascular inflammation. We determined the utility of GlycA as a biomarker of inflammation in SCD. METHODS: Stored plasma samples from patients with SCD recruited to two clinical studies were analyzed. One study encompasses 488 patient samples with SCD (HbSS, HbSß0 and HbSC) at steady state and 52 race-matched, healthy controls. The other study included paired plasma samples during steady state and acute pain crisis from (HbSS) patients with SCD. Plasma GlycA was measured using a proton NMR on the Vantera® Clinical Analyzer. We performed analysis comparing patients with SCD, healthy controls, and paired samples analysis. RESULTS: The mean plasma GlycA level was lower in SCD compared with healthy controls (324.6 ± 70.4 µmol/L vs. 386.3 ± 74.6 µmol/L, P < 0.0001). Within the same patient, mean plasma GlycA during acute pain crisis was lower than steady state, although the difference was not significant (300.5 ± 36.3 µmol/L vs 314.2 ± 34.8 µmol/L, P = 0.020). Plasma GlycA correlated inversely with serum LDH (P = 0.009). CONCLUSION: GlycA is not a suitable biomarker of inflammation in SCD. We surmise that its signal is confounded by hemolysis leading to a depletion of haptoglobin, one of the major plasma proteins included in the composite NMR signal. Hemolysis is further exacerbated during an acute pain crisis, hence the lower GlycA levels in crisis compared to steady state.


Asunto(s)
Anemia de Células Falciformes/sangre , Productos Finales de Glicación Avanzada/sangre , Resonancia Magnética Nuclear Biomolecular , Adulto , Biomarcadores/sangre , Femenino , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad
10.
PLoS One ; 10(11): e0141706, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26576059

RESUMEN

BACKGROUND: Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. OBJECTIVES: We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. METHODS: An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. RESULTS: Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. CONCLUSIONS: Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Hidroxiurea/uso terapéutico , Adolescente , Adulto , Anciano , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/mortalidad , Antidrepanocíticos/farmacología , Femenino , Hemoglobina Fetal/metabolismo , Humanos , Hidroxiurea/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
11.
PLoS One ; 8(11): e79923, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24224021

RESUMEN

BACKGROUND: Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort. METHODS: Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation. RESULTS: Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality. CONCLUSIONS: Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov/


Asunto(s)
Anemia de Células Falciformes/mortalidad , Anemia de Células Falciformes/fisiopatología , Adulto , Anemia de Células Falciformes/metabolismo , HDL-Colesterol/metabolismo , Femenino , Ferritinas/metabolismo , Hematócrito , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo
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