High Tricuspid Regurgitant Jet Velocity Research Articles

Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in sub-Saharan Africa (the BIOCADRE study).

Sickle cell anaemia (SCA) is a monogenic disease with a highly variable clinical course. We aimed to investigate associations between microvascular function, haemolysis markers, blood viscosity and various types of SCA-related organ damage in a multicentric sub-Saharan African cohort of patients with SCA. In a cross-sectional study, we selected seven groups of adult patients with SS phenotype in Dakar and Bamako based on the following complications: leg ulcer, priapism, osteonecrosis, retinopathy, high tricuspid regurgitant jet velocity (TRV), macro-albuminuria or none. Clinical assessment, echocardiography, peripheral arterial tonometry, laboratory tests and blood viscosity measurement were performed. We explored statistical associations between the biological parameters and the six studied complications. Among 235 patients, 58 had high TRV, 46 osteonecrosis, 43 priapism, 33 leg ulcers, 31 retinopathy and 22 macroalbuminuria, whereas 36 had none of these complications. Multiple correspondence analysis revealed no cluster of complications. Lactate dehydrogenase levels were associated with high TRV, and blood viscosity was associated with retinopathy and the absence of macroalbuminuria. Despite extensive phenotyping of patients, no specific pattern of SCA-related complications was identified. New biomarkers are needed to predict SCA clinical expression to adapt patient management, especially in Africa, where healthcare resources are scarce.

RASA3 is a candidate gene in sickle cell disease-associated pulmonary hypertension and pulmonary arterial hypertension.

Pulmonary hypertension (PH)is associated with significant morbidity and mortality. RASA3 is a GTPase activatingprotein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associatedPH and pulmonary arterial hypertension (PAH).Cis-expression quantitative trait loci (eQTL)were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC)of three SCD cohorts. Genome-wide single nucleotide polymorphisms (SNPs)near or in the RASA3 gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA,AA).We found that PBMC RASA3 expression was lower in patients with SCD-associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD-associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

Abstract 9695: RASA3 as a Novel Candidate Gene in Sickle Cell Disease-associated Pulmonary Hypertension and Pulmonary Arterial Hypertension

Introduction: Sickle cell disease (SCD)-associated PH is associated with increased mortality when tricuspid regurgitant jet velocity (TRV) is ≥2.5m/s and mPAP is ≥25mmHg on right heart catheterization. RASA3, a ubiquitously expressed GTPase-activating protein, is integral to angiogenesis and maintenance of endothelial barrier function. Hypothesis: Loss of RASA3 leads to the development of PH in patients with SCD-associated PH and PAH. Methods: Cis-eQTLs were queried for RASA3 using whole genome genotype arrays and gene expression profiles from PBMCs of subjects with SCD from 3 cohorts. Genome-wide SNPs near or in the RASA3 gene that may associate with lung RASA3 expression were identified using data from the Genotype-Tissue Expression project, reduced to 9 tagging SNPs for RASA3 and associated with TRV≥2.5m/s and RHC hemodynamics. Associations between the top RASA3 SNP and RHC hemodynamics were tested using whole genome genotype data from subjects in the PAH Biobank. PAECs collected from explanted lungs from patients with IPAH or control lungs were cultured with RASA3 expression evaluated on Western blot. Results: PBMC-derived RASA3 expression was significantly lower in patients with SCD-associated PH using TRV≥2.5m/s and RHC hemodynamics, with significantly higher mortality (Figure 1). The risk allele (T) at rs9525228, an eQTL for RASA3, correlated with PH risk, higher TRV and higher PVR among PBMCs associated with decreased RASA3 expression in patients with SCD-associated PH. The T allele at rs9525228 was significantly associated with increased mPAP (p=0.014), PVR (p=0.041) and mean right atrial pressure (p=0.04) in patients from the PAH Biobank. RASA3 expression was significantly lower in PAECs from patients with IPAH compared to control. Conclusions: RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

Prevalence and Factors Associated with Echocardiographic Abnormalities in Children with Sickle Cell Disease; Results from the Displace Study

IntroductionCardiopulmonary complications remain a leading cause of morbidity and mortality in adults with sickle cell disease (SCD) particularly for people with sickle cell anemia (SCA) who have lower hemoglobin and higher baseline hemolysis. Many cardiovascular complications are not identified until adulthood when patients have developed irreversible pathology. Previous studies have suggested that SCD-specific therapies like hydroxyurea (HU) may be beneficial in reducing the hemolysis associated vascular dysfunction and reducing cardiopulmonary complications. This study describes the prevalence of and factors associated with left ventricular hypertrophy (LVH), left atrial dilation and high tricuspid regurgitant jet velocity (TRJV) in children with SCA. We also describe the association between patent foramen ovale (PFO) and ischemic stroke in children with SCA.MethodThis crossectional study used data collected as part of the Dissemination and Implementation Stroke Prevention Looking at the Care Environment (DISPLACE) study. American society of echocardiography (ASE) guidelines and cutoff values were used to define abnormalities in the echocardiographic variables.ResultsA total of 1414 children were included in the analysis. The median age was 9 years (range 5-12 years) and median hemoglobin of 8.6 g/dl. The most common abnormal findings on echocardiogram was left atrial dilatation (61% of the children), LVH (20% of children) and high TRJV (23% of children). Children with abnormal echocardiographic variables were more likely to have lower hemoglobin level. Children with LVH were more likely to have left atrial dilation, high TRJV and abnormal left ventricular end diastolic diameter (LVIDD). Multivariable analysis of LVH was conducted and included variables: age, sex, hemoglobin, reticulocyte count, treatment with chronic red cell transfusion therapy (CRCT) or hydroxyurea therapy (HU). Baseline hemoglobin levels were associated with the lower odds of having LVH (OR: 0.71, 95% CI: 0.60 - 0.84). The odds of LVH increases for every one-year increase in age (OR: 1.07, 95%CI: 1.02-1.13). Similarly, the odds of LVH was lower among males than females (OR:0.59, 95%CI: 0.38-0.93). The odds of LVH were higher among those on HU compared to no therapy (OR: 1.83, 95% CI: 1.41 - 2.37).Although not all children had a bubble, study, a total of 90(6.3%) had an identified PFO. We assessed the relationship between PFO and ischemic stroke. 102 (7.2%) of the 1414 children had an ischemic stroke. Out of this 5 (5.6%) had PFO. We also assessed the relationship between PFO and abnormal TCD. 142 (10.0%) of the 1414 had abnormal TCD and only 9 (10%) of the 142 had PFO. There is no evidence that the odds of having stroke was higher among those with PFO compared to those without (OR: 1.49, 95% CI: 0.20- 11.03, p = 0.6994). Similarly, no evidence that the odds of having abnormal TCD is higher among those with PFO compared to those without (OR: 0.85, 95% CI: 0.17- 4.25, p = 0.8463).ConclusionOverall results of the study showed echocardiographic abnormalities are common in and occur at an early age in children with SCA. The risk of LVH increases with increasing age and with lower hemoglobin. Further, we found higher use of HU among those with LVH, suggesting that possibly children with more severe disease requiring HU are also at increased risk of cardiopulmonary complications.Given the fact that high TRJV is an independent risk factor for death in adults with SCD and left atrial dilatation has been shown to be an independent predictor of cardiac events, our data support further investigation into identifying early biomarkers of cardiovascular morbidity in children with SCD. [Display omitted] DisclosuresKanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Biomarker Discovery: Novel Insights into Red Blood Cell Metabolomics in Patients with Sickle Cell Disease at Risk for Early Mortality

Background : In adults with sickle cell disease (SCD), an elevated tricuspid regurgitant jet velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. A TRV>2.9 m/s occurs in approximately 10% of patients with SCD, has a 67-75% positive predictive value for pulmonary hypertension identified by right heart cardiac catheterization, and is the most robust non-invasive biomarker of early mortality risk for patients with SCD identified to date. Metabolomics is an integrated biosystems approach to molecular fingerprinting that may be able to differentiate individual metabolic characteristics of patients at high vs. low risk of mortality based on TRV elevation.Objective: To compare the metabolic differences between patients with SCD at high risk for early mortality defined by a TRV>2.9 m/s on Doppler echocardiogram compared to a low risk group with a TRV<2.5 m/s.Methods: A liquid chromatography-high resolution mass spectrometry method was used to determine metabolites in sickle erythrocytes from 90 case-control selected participants from the walk-PHaSST screening cohort, matched for sickle genotype (Hb-SS), age, gender, hydroxyurea use and alpha-thalassemia trait, divided equally into patients with a TRV>2.9 m/s compared to those with a TRV<2.5 m/s. Statistical and bioinformatics analyses used one-way analysis of variance (ANOVA) and partial least-squares discriminant analysis (PLS-DA) to identify groupwise discriminatory factors contributing to 95% separation of high vs. normal TRV. Significant features with one-way ANOVA p-value<0.05 were used to perform pathway analysis.Results: Patient characteristics are summarized in Table 1. Differential expression analysis showed that 145 accurate mass m/z features extracted from C18 column with positive ionization mode were significantly different between the high TRV and normal TRV subjects based on one-way ANOVA with p<0.005 (FDR<0.2) and PLS-DA with VIP>2 but no significant metabolism pathways were identified. With less stringent threshold p<0.05, one-way ANOVA revealed 1702 significant features which can discriminate the samples according to TRV status. Pathway enrichment analysis using Mummichog and the 1702 significant features with p-value<0.05 revealed 9 significant pathways (Figure 1).Conclusions: Metabolic profiles in sickle erythrocytes differentiate SCD patients with a normal TRV and low mortality risk from those at high risk for early mortality with a TRV>2.9 m/s through unsupervised pathway enrichment analysis. The pathways identified are intriguing and warrant further study. Identification of the porphyrin metabolic pathway may be related to higher hemolytic rates, while carnitine shuttle holds importance in mitochondrial function. Cholecalciferol (vitamin D3) metabolism is of interest given this common vitamin deficiency in SCD and studies linking vitamin D to vaso-occlusive pain, while omega 3 fatty acid metabolism is critical to normal cell membrane function. This preliminary work identifies metabolic pathways for future targeted analysis, and may lead to novel mechanistic insight and therapies that target these pathways. [Display omitted] DisclosuresMorris:Lifetrients: Patents & Royalties: I am inventor of IP owned by USCF-Benioff Children's Hospital Oakland, licensed to Lifetrients, generating royalties; Nestle: Consultancy; Calithera Biosciences: Consultancy; MAST Therapeutics: Research Funding; Pfizer: Consultancy. Brown:Calithera: Research Funding. Kato:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; MAST Therapeutics: Research Funding; Bayer: Research Funding.

Comparative therapeutic effect of the L-arginine and sildenafil on beta-thalassemia children with increased tricuspid regurgitant jet velocity

BackgroundSecondary pulmonary hypertension (PH) is emerging as a significant cause of mortality and morbidity in patients with thalassemia. Tricuspid Regurgitant Jet Velocity (TRJV) can identify patients at risk for PH. Aim of the workTo study the effect of the L-arginine and Sildenafil on patients with β -thalassemia complicated by increased Tricuspid Regurgitant Jet Velocity. Patients and methodsA randomized controlled clinical trial was carried out on 60 children with β-thalassemia major, selected with high TRJV (TRJV>2.5 m/s). The children were selected from Hematology Unit, Pediatric Departments, Tanta University Hospital. They were classified into 3 groups: Group (I): Twenty children received L-arginine, group (II): Twenty children received Sildenafil therapy and group (III): Twenty children did not receive either L-arginine or sildenafil therapy as a control group. All Patients were matched in ethnicity, age and sex distribution. They underwent to full history taking and complete clinical examination. Investigations include; complete blood count, aspartate transaminase (AST), alanine transaminase (ALT), serum ferritin and Color Doppler Echocardiography to measure TRJV. Results: There was no statistically significant difference between three groups as regard platelet count, serum ferritin, serum ALT, AST. There was a significant decrease of TRJV after Sildenafil therapy and/or L-arginine therapy, with no statistically significant differences between group (I) and group (II) as regard to TRJV after treatment. ConclusionPediatric patients with thalassemia complicated by PH can get benefit from therapy with Sildenafil and/or arginine therapy.

Studying the Determinant of Sickle Cell Disease Vasculopathy in Sub-Saharan Africa : The Biocadre Study

Although most individuals with sickle cell disease (SCD) live in sub-Saharan Africa, the history of the disease in this continent remains largely unknown. SCD is characterized by chronic hemolytic anemia, acute-vaso occlusive events and progressive vascular organ damage. The CADRE study is a large cohort of SCD patients in five countries of West and Central Africa aiming at studying SCD-related vascular complications. The inclusion data of this study did not match the hyper-hemolysis paradigm (Dubert et al. Blood 2018), but several methodological limitations were raised, including probable mortality bias and questionable reliability of classical hemolysis markers in Africa. For the 5-year follow-up of the CADRE study, we designed a case-control study nested in the cohort, based on extreme phenotypes, to look for new markers of vasculopathy, including new markers of hemolysis. Patients and Methods SS adult patients of the CADRE cohort were selected in the centres of Dakar (Senegal) and Bamako (Mali), depending on the presence of none or at least one of the following complications at inclusion: tricuspid regurgitant jet velocity (TRJV)&gt;2,5 m/s (which may indicate pulmonary hypertension), albuminuria/creatininuria&gt;100 mg/g, leg ulcer, priapism, aseptic osteonecrosis and retinopathy. We chose the youngest patients with a vascular complication and the oldest without any complication. Overall, 6 groups of 40 SS patients with extreme phenotypes were constituted (20 in each centre). Patients were called for a specific visit and investigated at steady state. Besides clinical examination, usual laboratory blood tests and albuminuria measure, additional plasma and saliva samples were collected. A trained investigator isolated microparticles immediately after blood sampling by successive centrifugations, measured blood and plasma viscosities and assessed microcirculation function using peripheral arterial tonometry. A cardio-echography was performed by a trained cardiologist. Plasma samples were stored at -80 °C and shipped to Paris. High technology tests were performed in Paris, including blood cell derived microparticles, free hemoglobin, inflammatory cytokines, neutrophile extracellular trap (NETs). Using saliva DNA, we also genotyped the known SCD genetic modifiers and new candidate genes implicated in the catabolism of hemoglobin. Potential associations between those markers, usual hematological parameters, and the vascular complications were assessed statistically . Results We recalled 240 selected patients 5 years after their first visit: 38 could not be retrieved, 21 had deceased, 62 had at least one new complication, and only 15 still had no complication. Therefore, we selected 56 more patients to obtain at least 30 patients in each group. 237 SS adults were eventually investigated and the plasma samples of 232 SS patients were analyzable in Paris (106 from Bamako and 126 from Dakar). In these patients, at a mean age of 29 years (+/- 11), high TRJV was present in 58, macroalbuminuria in 33, leg ulcers in 36, priapism in 43, aseptic osteonecrosis in 45 and retinopathy in 31 whereas 28 had no vascular complication. A principal component analysis found no cluster of complications. Among patients with one "hyper-viscous" complication (retinopathy or osteonecrosis) or more, 78% also had at least one "hyper-haemolytic" complication (high TRJV, albuminuria, leg ulcer or priapism) and 49% of patients with a "hyper-haemolytic" complication also had a "hyper-viscous" complication. The microvascular function was not associated with any of the complications, whereas higher blood viscosity was associated with retinopathy. The results of the associations between the vascular complications and specific biological tests are presented in other publications. Conclusion This study illustrates the feasibility of high-technology experiments in SCD patients living in sub-Saharan Africa, but was particularly challenging because of the difficulty to prepare, store and transport frozen plasma samples. Moreover, in agreement with previously published data from the CADRE study, we found that the dichotomization of vascular complications into hyperhemolytic and hyperviscous subgroups is not clinically relevant in Africa. Other simple predictive markers of vascular complication are needed to optimize the follow-up of African patients with SCD. Disclosures No relevant conflicts of interest to declare.

CELL-Derived Microparticles and Sickle CELL Disease Chronic Vasculopathy in Sub-Saharan Africa

Introduction Although most individuals with sickle cell disease (SCD) live in sub-Saharan Africa, the history of the disease on this continent remains largely unknown. SCD is characterized by the association of chronic hemolytic anemia with episodes of acute vaso-occlusive events and progressive vascular organ damage. Several pathophysiological pathways in SCD result in the activation of circulating blood cells and the release of microparticles (MPs). In the present study, we investigated cell-derived MPs in patients with SCD living in Africa and analyzed their relationship with clinical complications. Patients and Methods This cross-sectional case-control study is nested in the CADRE cohort (clinical trials.gov identifier NCTO3114137). We included 232 SS adults in two African centers: Bamako (Mali) and Dakar (Senegal). Patients were chosen depending on the absence or the presence of at least one of the following complications: tricuspid regurgitant jet velocity (TRJV) &amp;gt;3 m/s (which may indicate pulmonary hypertension), macroalbuminuria, leg ulcer, priapism, aseptic osteonecrosis, and retinopathy. Overall, 7 groups of 40 SS patients were constituted (20 in each center). Patients were investigated at steady state (i.e.,at least 15 days after a vaso-occlusive crisis, 8 days after fever or infectious disease, and 3 months after a transfusion). MPs were isolated in the African centers immediately after blood sampling by successive centrifugations at increasing speed: 2,500g x2 and 21,000g x2. MPs pellets were stored at -80 °C. The cellular origin of the MPs, erythrocyte, reticulocyte, endothelial, platelet, and leucocyte, was determined using antibodies directed against CD235a, CD71, CD106, CD41, and CD45, respectively, at the National Institute of Blood TransfusioninParis. To maintain the background at an acceptable level, events of 0.16 µm size were excluded (Fig 1A). Only MPs positive for Annexin V and the cell-type-specific labelling were retained. Potential associations between cell-derived MPs, hematological parameters, and vascular complications were assessed using logistic regression with adjustment for age, sex and country. Results The MP pellets of 106 SS patients from Bamako and 126 from Dakar were analyzed in Paris. In these patients, at a mean age of 29 years (+/- 11), high TRJV was present in 64, microalbuminuria in 84, leg ulcers in 33, priapism in 43, aseptic osteonecrosis in 45, and retinopathy in 31 patients whereas 28 patients had no complication at the time of sampling. As a typical result, Fig 1B shows erythrocyte-derived MPs labelled by Annexin V and CD235a (quarter Q2). The MPs distribution was as follows: erythroid 52% [reticulocytes (CD235a+CD71+) 14%, erythrocytes (CD235a+ CD71-) 38%], leukocyte 18%, platelet 21%, and endothelial 9%. Neither erythrocyte- nor reticulocyte-derived MPs significantly correlated with hemolysis markers (LDH, unconjugated bilirubin or reticulocytes) or hemoglobin levels. Erythrocyte- and reticulocyte-derived MPs were significantly lower in patients with retinopathy (OR=0.48, p=0.003 and OR=0.68, p=0.005, respectively). Reticulocyte-derived MPs were negatively associated with a history of priapism (OR=0.76, p=0.020) and positively associated with a history of leg ulcers (OR=1.23, p=0.040). No correlation was found between MPs of other cellular origin and chronic complications, except for a negative association between endothelial-derived MPs and priapism (OR=0.76, p=0.036). Conclusion In our African patients with SCD, erythroid-derived MPs, although recognized cellular products of hemolysis, were not associated with other markers of hemolysis. We hypothesize that erythroid MPs are not only derived from hemolysis but also probably from the sickling process in this population. They were negatively associated with retinopathy and priapism and positively associated with leg ulcers, but not with the other complications classically associated with the hyperhemolytic sub-phenotype. The search for pertinent biomarkers of SCD complications in Africa is an essential challenge. To our best knowledge, this report is the first illustrating the feasibility of high-technology experiments in an African context. Disclosures No relevant conflicts of interest to declare.

Lactate Dehydrogenase to Carboxyhemoglobin Ratio As a Biomarker of Heme Release to Heme Processing Is Associated with Higher Tricuspid Regurgitant Jet Velocity and Early Death in Sickle Cell Disease

Background Chronic hemolysis is a hallmark of sickle cell disease (SCD). Intravascular hemolysis in particular is associated with severe vasculopathic complications including pulmonary hypertension (PH) and early mortality. Free heme causes oxidative damage and recently was identified as erythrocyte-derived Danger Associated Molecular Pattern (e-DAMP), associated with endothelial activation and vaso-occlusion in SCD (Belcher et al., Blood. 2014; Ghosh et al., J. Clin. Invest. 2013). Intravascular hemolysis is associated with elevated levels of serum lactate dehydrogenase (LDH). Heme catabolism leads to endogenous carbon monoxide (CO) production by heme oxygenase-1 (HO1), and CO is eliminated in exhaled breath. CO is transported primarily as the conjugate carboxyhemoglobin (HbCO), and end-alveolar CO (EACO) is an accepted proxy marker for its concentration in blood. We evaluated several lab values and ratios that might reflect the relative contribution of intravascular heme release and overall heme processing. Methods We investigated the relationship between EACO, HbCO (NCT01547793, cohort A) and other biomarkers of hemolysis in adults with SCD at steady state as part of the clinical cohort at the National Institutes of Health Clinical Center, Bethesda, Maryland, USA (NCT00011648, cohort B). Of the patients included in the cohort B, all routine samples with results on HbCO were included in the analyses. In a subgroup of the cohort B with data available on HbCO, echocardiography and/or mortality, we evaluated the correlation between LDH/HbCO ratio and echocardiographic markers of PH and all-cause mortality (cohort C). Combining all recognized available markers for hemolysis (total bilirubin, AST, absolute reticulocyte count, hemoglobin, median LDH, median HbCO and LDH/HbCO ratio) in a multivariate Cox proportional hazards model for survival led to selection of a predictive model encompassing three biomarkers: LD/HbCO ratio, AST and hemoglobin. Of these three markers, the LD/HbCO ratio was the most predictive factor. We also conducted univariate correlations with clinical outcome indicators. Main findings Erythropoietic and hemolytic laboratory parameters of the cohorts are provided in Table 1. HbCO concentrations and EACO were strongly correlated (Pearson's correlation r=0.66, p&lt;0.01). In both cohort A and cohort B, HbCO and EACO were not correlated to LDH. However, EACO and HbCO did correlate with absolute reticulocyte counts (respectively r=0.46, p&lt;0.01 and r=0.58, p&lt;0.01). The patients of cohort C were divided into low (peak TRV &lt;2.5m/s, N=34), intermediate (peak TRV 2.5-3m/s, N=38) and high risk (peak TRV &gt;=3.0m/s, N=13) categories, based upon prior cut-points determined by risk of development of PH and early mortality (Mehari A. et al. JAMA. 2012) (Figure 1, panel A). LDH/HbCO ratios were positively correlated with TRV (r=0.38, p&lt;0.01), and were significantly higher in patients with TRV &gt;=3.0m/s (Mann-Whitey U test; p=0.02). In contrast, LDH values alone were not discriminative. All patients (25/25) with a LDH/HbCO ratio &lt;1,200 had a TRV &lt;3.0m/s; 94% (15/16) of the patients with catheterization-proven PH had a LDH/HbCO ratio &gt;1,200. In the intermediate risk subgroup, PH was only diagnosed in individuals with LDH/HbCO ratios exceeding 1,200. Median follow-up was 12.1 years (IQR 10.3; 16.3), 25% (23/91) of the patients died during follow-up. Five-year, 10-year and 15-year overall survival in the group with LDH/HbCO ratio &gt;1,200 were respectively 92.1%, 76.0% and 69.1%, whereas 5-year, 10-year and 15-year overall survival in the group with LDH/HbCO ratio &lt;1,200 were respectively 100%, 92.9% and 88.0% (Figure 1, panel B). LDH/HbCO ratios were associated with all-cause mortality in a Cox proportional hazards model (p&lt;0.01) and remained significantly associated with all-cause mortality when adjusted for age, C-reactive protein and ferritin (p=0.02). LDH alone was not associated with all-cause mortality in the unadjusted analysis. Main conclusions A ratio of two readily available clinical laboratory markers, LDH and HbCO, is promising as a potential biomarker in SCD. Increased LDH/HbCO ratios are strongly associated with elevated TRV and all-cause mortality, and thereby might improve the individual risk prediction in SCD patients. These markers deserve additional validation in future prospective trials. Disclosures van Wijk: Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Minniti:Doris Duke Foundation: Research Funding. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding. van Beers:Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Splenectomy is not associated with a higher tricuspid regurgitant jet velocity in people with sickle cell anemia.

Vascular complications such as pulmonary hypertension (PH) occur at an increased rate following splenectomy in patients with various hemolytic blood disorders including thalassemia. The goal of this retrospective cross-sectional analysis was to assess the independent association of splenectomy with an elevated tricuspid regurgitation velocity (TRV) in people with homozygous sickle cell disease (HbSS). TRV is a noninvasive screening test for PH and a surrogate marker of prognosis in sickle cell disease (SCD). Data were obtained from the multicenter Walk-PHaSST (treatment of pulmonary hypertension and sickle cell disease with sildenafil therapy) study of PH (NCT00492531). We compared TRV in the cohort of patients with HbSS who were surgically splenectomized with patients who were not surgically splenectomized. We found no significant differences in TRV between the two groups. The lack of difference in TRV between the two groups is most likely because members of the comparator nonsurgical group in many cases experienced autoinfarction of the spleen in childhood. Splenectomy does not seem to confer additional risk for the development of a higher TRV in HbSS, unlike in patients with thalassemia or other hemolytic anemias. This could be an important consideration when weighing the risks and benefits of splenectomy in patients with HbSS.

The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease.

Pulmonary hypertension (PH) is multifactorial in origin and may develop early in children with sickle cell disease (C-SCD). Potential etiologies are hemolysis-induced endothelial dysfunction, left ventricular (LV) dysfunction, and chronic hypoxia. Nocturnal hypoxia (NH) in C-SCD is known to be a sequela of obstructive sleep apnea (OSA). The primary objective of this study is to correlate polysomnographic evidence NH with echocardiographic measures of PH in C-SCD. We performed a retrospective chart review of 20 C-SCD (Hemoglobin SS), who had polysomnography and echocardiogram performed within a narrow time interval, and 31% of them had pre-existing cardiac conditions. Tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s was considered as an indicator of PH. Twenty-five percent of the subjects had NH. Forty percent of C-SCD, predominantly male, had evidence of PH based on an elevated TRJV. Children with NH compared to non-NH had significantly worse baseline hypoxemia (p < 0.001), higher TRJV (p = 0.005), and higher LV end-diastolic diameters (p = 0.009). The severity of NH was influenced by OSA. However, PH was not associated with OSA or duration of hydroxyurea therapy. Our study indicates that NH is associated with PH in C-SCD, and that screening for NH may help to identify C-SCD with higher morbidity risk.

Evaluation of Tricuspid Regurgitant Jet Velocity in Thalassemia Patients with Splenectomy

Background: β-thalassemia is an inherited disorder of β-globin biosynthesis. Dysfunction in hemoglobin chain production, ineffective erythropoiesis, and hemolysis occur in β-thalassemia. Pulmonary arterial hypertension (PAH) is increasingly detected in patients with β-thalassemia, and splenectomy which decreases the need for blood transfusion increases the pulmonary artery pressure (PAP). Objectives: This study aimed to assess the PAP in patients with β-thalassemia (male or female and major or intermedia) who had undergone splenectomy. Methods: A total of 137 patients suffering from β-thalassemia were evaluated during the study. All subjects were referred for cardiac evaluation. Clinical history, presence of cardiac symptoms, and previous splenectomy were noted. Standard M-mode, 2D, and Doppler echocardiographic examinations were performed for all subjects. Patients with a tricuspid regurgitant jet velocity (TRV) ≥ 2.5 m/s were considered at risk for PAH. Results: Average age of the patients was 21.15 ± 6.68 years. No significant difference was observed in the PAP between the 2 groups of thalassemia major and intermedia and also the 2 sex groups. Indeed, 6.6% of the patients had an increased PAP. The significant finding of the study was that the patients who had had splenectomy were significantly at an increased risk of PAH (P = 0.046). Conclusions: The etiology of PAH in thalassemia is multifactorial such as inflammatory mediators. Also, the absence of the spleen plays an important role in developing a high TRV and PAH.

Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy

A high tricuspid regurgitant jet velocity (TRV) signifies a risk for or established pulmonary hypertension (PH), which is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia subgroups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients (15 with hereditary spherocytosis), and 12 healthy controls. An elevated TRV (>2.5m/s) was found in 25/76 (33%) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non or late-transfused patients (76% splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1), and hemolysis (LDH, plasma-free Hb), while hypercoagulable and inflammatory markers were not significantly increased. The same markers were increased in the seven patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.

Transthoracic Echocardiography and 6-Minute Walk Test in Kuwaiti Sickle Cell Disease Patients

Objective: The aim of this study was to investigate cardiac abnormalities in Kuwaiti sickle cell disease (SCD) patients using markers such as tricuspid regurgitant jet velocity (TRJV), pulmonary artery systolic pressure (PASP), and the 6-minute walk (6MW) test and correlate these findings with clinical, hematological, and biochemical parameters. Materials and Methods: Seventy-three patients with SCD and 70 matched controls were studied. The cardiac status was investigated using transthoracic echocardiography in 57 patients; the 6MW test was carried out in patients and controls. Complete blood counts and hemolytic parameters were assessed. Results: Reticulocytes, bilirubin, and lactate dehydrogenase were significantly higher (p < 0.0001) in patients, while hemoglobin (Hb) and haptoglobin were lower (p < 0.0001) than in controls. The mean fetal Hb among patients was 15.85 ± 8.7%. Of the 57 patients, 14 (24.5%) and 15 (26%) had mild tricuspid and mitral regurgitation, respectively. The mean ejection fraction, TRJV, and PASP were 63.9 ± 6.3%, 1.7 ± 0.5 m/s, and 23.0 ± 7.3 mm Hg, respectively. Three (5.2%) patients had mildly raised TRJV (2.6-2.97 m/s, normal range <2.5 m/s) while 8 (14%) had high PASP (mean 35.3 ± 5.1 mm Hg, normal range <30 mm Hg). Hb, hematocrit, and reticulocytes were different (p = 0.010, p = 0.006, and p = 0.011, respectively) between patients with normal and high PASP. All 3 patients who had a high TRJV had a high PASP, and 2 of these patients died during follow-up. The systolic and diastolic blood pressure, oxygen saturation before and after the 6MW test, and distance walked were lower (p = 0.006, p = 0.000, p = 0.002, p = 0.000, and p = 0.000, respectively) in patients compared to controls. Conclusion: Raised PASP was common in Kuwaiti SCD patients while raised TRJV was not.

Elevated Tricuspid Regurgitant Jet Velocity In Lebanese Patients With Sickle Cell Disease Is Associated With Severe Disease and Is Clustered In Families

Introduction Pulmonary hypertension (PHT) is a known complication of sickle cell disease (SCD), and it is indirectly assessed by measurement of the tricuspid regurgitant jet velocity (TRV). Despite the fact that PHT was found to be associated with early mortality in adults SCD patients, the association between elevated TRV and SCD severity and mortality is still controversial particularly in children and adolescents. The objective of this study was to investigate the relationship between elevated TRV and parameters of disease severity in children, adolescents and young adults with SCD. Methods The study is a retrospective review of medical records of patients with SCD followed at the comprehensive sickle cell clinic at the American University of Beirut Medical Center between April 2002 and January 2012. These include 115 patients with homozygous hemoglobin S disease, 8 with sickle β0-thalassemia, and 24 with sickle β+-thalassemia who have had at least one echocardiogram done as part of their routine medical care. All echocardiograms were done at steady state, at least four weeks after the last vasoocclusive crisis (VOC) or acute chest syndrome (ACS). Elevated TRV was defined as peak TRV of 2.5 meters per second or higher. Disease severity was assessed by comparing hemolysis biomarkers, rate of transfusions, VOCs and ACS and other SCD complications. In patients with sequential echocardiograms, changes in hydroxyurea (HU) doses were examined against TRV variation. Results 147 patients were studied over a mean number of 3.77 ± 1.96 years. The mean age was 15.07 ± 8.62 years, ranging from 18 to 43.4 years, with 66% being below 18 years of age. Elevated TRV was found in 57 patients (38.8%). T-tests and chi-square tests did not show any statistically significant differences between the patients with normal and elevated TRV with respect to age, gender, SCD subtype, time of follow-up, presence of stroke, AVN, ulcers and splenectomy. In addition, hemoglobin (mean=9.43±1.46 in normal TRV group versus 9.20±1.19 in high TRV, p=0.309) mean corpuscular volume (MCV, mean=93.04±16.96 vs. 96.56±15.03, p=0.203), reticulocyte count (mean= 9.51 ± 4.81 vs 9.97±5.55, p=0.596), bilirubin (indirect bilirubin mean=1.40±1.28 vs. 1.44±1.04, p=0.883) and lactate dehydrogenase (LDH, mean=423.20±192.00 vs. 451.40±399.40, p=0.398) did not show any significant differences between the two groups. Among patients with elevated TRV, 71.9% were on HU at a mean dose of 16.27 mg/kg/day compared to 70% of patients with low TRV who were on a mean HU dose of 15.13 mg/kg/day. HU was started in both groups for indications including pain crises, ACS and low hemoglobin but not TRV alone. Initially markers of hemolysis including MCV, reticulocyte count, bilirubin and LDH were significantly higher and hemoglobin lower in patients with elevated TRV, but these differences between the two groups were no longer evident after the dose of HU was optimized. In the 99 patients with 2 or more echocardiograms, no trend in TRV variation was observed after HU dose adjustment and sequential TRV readings. The mean transfusion rate per patient did not differ between the two groups. However, RBC alloimmunization was found in 6.2% of patients with normal TRV compared to 15% of patients with elevated TRV. Results of the Poisson models demonstrated that the VOC rate was 1.4 times higher among subjects with TRV ≥ 2.5 compared to subjects with TRV &lt; 2.5 (rate ratio = 1.4; 95% CI = 1.04 to 2.02; p=0.029). Additionally, ACS rate was almost 3 times higher among subjects with high TRV (rate ratio = 2.8; 95% CI = 1.3 to 6.2; p=0.01). No deaths were reported in either study groups. Fisher's exact test and the generalized linear mixed model (GLMM) both indicated the presence of familial clustering of elevated TRV (Fisher's p-value: 0.009; GLMM p-value: 0.026). Conclusion The overall prevalence of elevated TRV in our study population was 38.8%. Despite improvement in hemolyis after introducing and optimizing hydroxyurea doses, patients with elevated TRV still had more severe disease as defined by higher rates of VOC, ACS and alloimmunization. Familial clustering of elevated TRV was observed in our highly consanguineous population. These findings suggest that elevated TRV is a marker that defines patients with more severe SCD even among children and young adults. Disclosures: No relevant conflicts of interest to declare.

Risk Factors for Death in 632 Patients with Sickle Cell Anemia in the United States and United Kingdom

AbstractAbstract ▪3240▪This icon denotes a clinically relevant abstractThe role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods:Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results:Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV < 3.0 m/sec (p<0.0001). The unadjusted hazard ratios for death were 11.14 (95% CI 4.1–30.1; p<0.0001) for patients with TRV above and below 3.0 m/sec and 4.55 (95% CI 1.8–11.3; p=0.001) for patients with NT-proBNP above and below 160 pg/mL. For patients with both high TRV (≥ 3.0 m/sec) and high NT-proBNP (≥ 160 pg/mL), the unadjusted hazard ratio was 14.86 (95% CI 5.5–39.9; p<0.0001). Overall, an increased risk of death was observed for both age and gender, with males at higher risk relative to females (HR=2.48, 95% CI 1.0–6.1; p=0.05), and patients older than 47 years (HR=2.02, 95% CI 1.1–3.8; p=0.03). Associations with mortality were also observed for chronic transfusions (HR=3.00, 95% CI 1.2–7.8; p=0.02) and a NYHA/WHO class value or III or IV (HR=4.52, 95% CI 1.4–14.3; p=0.01). Other variables associated with mortality in our cohort included a high hemolytic component, aspartate aminotransferase (AST), ferritin, and creatinine. Variables not associated with mortality included current hydroxyurea use, SC disease, self-reported history of painful episodes, and six-minute walk distance. In stepwise multiple proportional hazards regression analysis, the association between TRV and mortality remained significant after adjustment for all other risk factors, including ferritin, AST, creatinine and even NT-proBNP (HR 4.27, 95%CI 1.3–14.1; p=0.04). Conclusions:Using a more conservative cut-off value of TRV ≥ 3.0 m/sec as defining PH in a large screening population of sickle cell disease patients, PH occurs in approximately 10% of unselected screened patients and is associated with the highest unadjusted and adjusted risk for death of any measured variable. Disclosures:Gladwin:Bayer Corp: Consultancy, Research Funding; NIH and NHLBI: Research Funding; Gilead Sciences: Research Funding. Barst:Ventripoint: Stock options Other; Actelion, Eli Lilly, Gilead, Glaxo Smith-Kline (GSK), Medtronics, Bayer, Ikaria, Pfizer, Novartis, VentriPoint: Consultancy, Honoraria. Girgis:NIH/NHLBI: Research Funding, Travel support Other. Rosenzweig:NIH: Research Funding. Badesch:NIH: Research Funding. Lanzkron:NIH: Research Funding.

Renal Disease in Sickle Cell: Clinically Varied and Associated with Increased Mortality

AbstractAbstract 90▪▪This icon denotes a clinically relevant abstractThe Walk-Phasst Study of sickle cell disease (SCD) affords a unique opportunity to examine renal function in a large number of adults with SCD. Extensive clinical and laboratory data were obtained on 463 adults with HbSS and 127 adults with HbSC. Where possible, correlates for estimated glomerular filtration rate (eGFR, calculated by the 4-value MDRD equation) and albuminuria/proteinuria were also evaluated in historical data, from SS adults in the CSCCD cohort and the Multicenter Study of Hydroxyurea (MSH) in sickle cell disease.Adjusted decline in eGFR was more rapid in SS compared with SC, at −2.6 and −0.92 ml/min/1.73 m2/year, respectively (p<0.001). In SS, similar declines in cross-sectional eGFR with age were seen in adults in the CSCCD (n=705) and MSH (n=298) cohorts, at −2.9 and −1.9 ml/min/year (BSA corrected), respectively. Multivariate analysis of the SS cohort in of Walk-Phasst revealed that depressed eGFR values were associated with an elevated estimated pulmonary arterial systolic pressure (as reflected in a higher tricuspid regurgitant jet velocity, measured by echocardiogram, p=0.007) and with evidence for inflammation (an elevated white blood cell count, p=0.018). In SC adults, in contrast, lower eGFRs were primarily associated with a diminished erythroid reserve (depressed absolute reticulocyte counts, P=0.005).Albuminuria (≥30 mg albumin/gm creatinine) was detectable in 66 and 41 % of adults with HbSS and HbSC in Walk-Phasst (185/287 evaluable SS and 25/61 evaluable SC, p=0.001). In Walk-Phasst, albuminuria in SS was associated with evidence of increased red cell destruction (lower total hemoglobin (P=0.07), higher LDH (P<0.001), and higher reticulocyte count (P=0.017)). In SC, albuminuria was associated with a higher LDH (P=0.01). 159/657 (24%) of adult SS subjects in the CSCCD cohort had trace to 4+ proteinuria, using a method (urine dipstick analysis) that is less sensitive and less quantitative than the albumin-to-creatinine ratio used in Walk-Phasst. Multivariate analyses again suggested a strong association between a depressed Hgb and proteinuria (P<0.001) in CSCCD, and LDH was also associated with proteinuria, in univariate analyses (P<0.001). In Walk-Phasst the absence of albuminuria in all subjects with SCD was associated with lesser mortality in multivariate analyses (Hazard ratio 0.62 (0.4–0.9, P=0.02). No similar association was seen between eGFR and mortality.Subjects with SS in Walk-Phasst had depressed serum bicarbonate levels, of 23.8±3.4 compared with 24.7±3.2mEq/dL in SC (p<0.005) and 24.8±3.3 mEq/dL in the non-CKD general population (Shah et al, 2009). In multivariate analyses, acidemia was associated with both increased destruction and decreased production of red cells, e.g. higher EPO (P=0.003) and total bilirubin levels (P<0.001), but lower reticulocyte counts (P=0.06). Impaired physiologic functioning in acidemic subjects with HbSS, manifest as a depressed 6MWD (P<0.001) and a lower eGFR (P<0.001), was seen. No effect of bicarbonate level on mortality in SCD patients was evident in Walk-Phasst.In conclusion, renal function is perturbed in sickle cell syndromes in several ways, including more rapid decrement in eGFR, highly prevalent albuminuria, and, in SS, marked abnormalities in acid-base balance. Albuminuria is associated with anemia in two large cohorts of sickle cell disease patients and, in Walk-Phasst, with evidence for enhanced red cell destruction. Importantly, albuminuria correlated with an increased risk for mortality in sickle cell disease.(We acknowledge the many contributions made by the Walk-PHASST Investigators: Badesch DB, Barst RJ, Castro OL, Girgis RE, Gibbs JS, Goldsmith JC, Hannoush H, Hassell KL, Kato GJ, Krishnamurti L, Lanzkron S, Machado RF, Morris CR, Novelli EM, Rosenzweig EB, Sachdev V, Schraufnagel DE, Taylor JG 6th.) Disclosures:No relevant conflicts of interest to declare.

Reduction of the Six-Minute Walk Distance in Children with Sickle Cell Disease Is Correlated with Silent Infarct: Results From a Cross-Sectional Evaluation in a Single Center in Belgium.

AbstractAbstract 2107▪▪This icon denotes a clinically relevant abstractThe 6-minute walk test (6MWT) evaluates the sub-maximal functional exercise capacity and can be used together with the tricuspid regurgitant jet velocity (TRV) and pro-BNP to screen pulmonary hypertension in adults with sickle cell disease (SCD). A reduced 6-minute walk distance (6MWD) is observed in adults with SCD with chronic pain, hip avascular necrosis and osteopenia. In children with SCD, baseline elevated TRV is associated with a decline in age-standardized 6MWD.The aim of our study is to explore the submaximal exercise capacity of children with SCD followed at the Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium and to analyze the factors affecting the 6MWT and the 6MWD.Since September 2011, all patients with SCD above 6 years of age were screened with the 6MWT as part of their follow-up in order to test if their functional capacity was altered. The age-standardized predicted value of the 6MWD was established as reported by Geiger. The 6MWT was considered as normal if the 6MWD was more than 80% of the age-standardized predicted value, moderately decreased between 60–80%, and severely altered less than 60%. Baseline hematological values, clinical events, cerebro-vascular disease, cardio-pulmonary parameters and disease-modifying treatment (DMT) were compared between those with normal and abnormal 6MWT and according to the 6MWD.Forty-six patients (20 boys and 26 girls) with a median age of 12 yrs were investigated. Forty-three were HbSS or HbSβ°, 2 HbSC and 1 HbSβ+. Thirty-two patients had a normal 6MWT and 14 an abnormal 6MWT. Only one patient had a severely altered test. These 2 groups were similar for age, sex, genotype and history of vaso-occlusive crisis or acute chest syndrome (ACS) as well as for the number of patients receiving DMT (either hydroxyurea (HU) or chronic transfusion). The proportion of patients with normal, conditional or abnormal transcranial doppler was also similar in both groups. Silent infarct (SI) on routine cerebral magnetic resonance imaging was found in 42.9% in the group with abnormal 6MWT versus only 19.4% in the group with normal 6MWT (p= 0.087). Pulmonary functional test, blood pressure, heart rate, systolic function and TRV were identical in both groups and only one patient had TRV >2.5m/sec. Baseline pulse oxymetry was slightly but significantly decreased in patients with abnormal 6MWT (98 versus 100%; p=0.022). Biological parameters were not statistically different between both groups. The 6MWD was not modified according to Hb, MCV, HbF, LDH and reticulocytes count or previous history of clinical event, except for the presence of SI (Table 1). Patients with or without SI were similar for age, sex, previous ACS or painful crisis as well as for hemolytic parameters (LDH: 945 versus 825 UI/l, p=0.832; reticulocytes: 273 versus 329 × 103/μl, p=0.548) and basal Hb (9.7 versus 8.8 g/dl, p=0.06). However patients without SI had significantly higher HbF and MCV values, and lower PMN count reflecting that most of them were treated with HU.In this cross-sectional study, the majority of children with SCD have a normal 6MWT. Abnormal 6MWT was not predicted by any clinical or biological features despite a trend to more SI in the group of children with abnormal test. In this series with only one high TRV patient, the sole factor which influences the 6MWD is the presence of SI. The lower exercise capacity of children with SCD with silent stroke may reflect some subclinical motor or sensitive impairment. Our data suggest also that HU might prevent SI which needs to be confirmed by larger prospective studies.Table 16-minute walk distance (6MWD) in 46 SCD children according to their biological values and clinical complicationsMean 6MWD in meters (SD)p valueMean Age in years (SD)p valueHemoglobin (g/dl)· ≥ 9 (N = 24)531.5 (95.4)0.17311.2 (2.8)<0.001· < 9 (N = 22)569.8 (92.2)14.5 (2.7)MCV (fL)· ≥ 90 (N = 24)536.1 (100.7)0.25112.6 (3.5)0.518· < 90 (N = 22)568.3 (86.8)13.2 (2.8)HbF (%)*· ≥ 10% (N = 30)544.0 (101.7)0.36013.2 (3.5)0.352· <10% (N = 15)570.1 (81.8)12.6 (2.4)LDH (UI/l)· ≥ 1000 (N = 14)526.8 (86.5)0.22911.8 (3.0)0.105· < 1000 (N = 32)562.3 (97.4)13.4 (3.1)Previous ACS*· Yes (N = 38)548.6 (98.3)0.62513.5 (3.1)0.453· No (N = 7)566.9 (85.5)12.5 (4.2)Silent Infarct· Yes (N = 12)502.5 (113.9)0.03512.1 (2.2)0.374· No (N = 34)568.9 (82.0)13.2 (3.4)*Missed information for 1 patient. Disclosures:No relevant conflicts of interest to declare.

Misclassification of Pulmonary Hypertension in Adults with Sickle Hemoglobinopathies Using Doppler Echocardiography

To compare the diagnostic utility of Doppler echocardiography-derived tricuspid regurgitant jet velocity (TRV) ≥ 2.5 m/s to right heart catheterization (RHC) in defining pulmonary hypertension (PH) in adult patients with sickle cell disease (SCD). This is a retrospective chart review of adults with SCD who had a TRV ≥ 2.5 m/s and RHC. A TRV ≥ 2.5 m/s is suggestive of PH. Pulmonary arterial hypertension (PAH) was defined as a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg and pulmonary capillary wedge pressure ≤ 15 mm Hg. Pulmonary venous hypertension was defined as an mPAP ≥ 25 mm Hg and pulmonary capillary wedge pressure >15 mm Hg. Twenty-five patients with SCD met the inclusion criteria. Nine of the 25 (36%) patients had an mPAP ≥ 25 mm Hg. Of these 9, 3 (33%) had PAH and 6 (66%) had pulmonary venous hypertension. Patients with PH did not have a higher TRV (3.1 ± 0.68 vs 2.70 ± 0.16 m/s; P = 0.12), but they did have higher cardiac outputs (10.4 ± 2.7 vs 7.81 ± 1.85 L/min; P = 0.012. The specificity of TRV equal to 2.51 m/s in diagnosing PH was 18.8%. At a TRV of 2.88 m/s, the specificity increased to 81%. In adults with SCD, a TRV of 2.5 m/s lacks specificity for use as a screening tool in the diagnosis of PH. Using a TRV of ≥ 2.88 m/s allows the TRV to be used as a screening tool and reduces the false-positive rate and need for unnecessary RHC.

Correlations Between Lung, Cardiac Functions and Hematologic Parameters in SCA-Chidren

Abstract 1067▪▪This icon denotes a clinically relevant abstract Background:Elevation of tricuspid regurgitant jet velocity (TRJV) predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell anemia (SCA). To date, few studies have reported the concomitant analysis of lung alterations and high TRJV in SCA-children. Objective:To evaluate the relationship between lung function, TRJV and hematologic parameters in SCA-children. Patients and Methods:SCA-children of the Creteil-CHIC cohort were assessed at steady state on the same day by cardiac echocardiography, pulmonary function tests (PFT), clinical and biological parameters. All data were recorded in the CHIC database. Forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO) were measured with the single-breath technique. DLCO was adjusted to hemoglobin and to the alveolar volume (KCOc). Univariate and multivariate linear regression analyses were performed to evaluate factors correlating with TRJV and KCOc and logistic regression was applied to evaluate the risk factors associated with elevated TRJV (≥ 2.5 m/s). Results:A total of 228 check-ups with cardiac and lung assessment, performed in 163 SCA-patients (160 SS, 3 SB0) was analyzed. Check-ups were performed at the median age of 13.2 years (range: 5.7–19.9). Among the 228 check-ups, 151 were performed after intensification (59 on hydroxyurea, 57 on transfusion program and 38 after hematopoietic stem cell transplantation (HSCT). TRJV (median value: 2.2 m/s, range 1.4–3.1) was significantly positively correlated with age (r=0.164, p=0.013), was not correlated with TLC but was significantly and negatively correlated with FVC before b2 (r=−0.145, p=0.03) and after b2 (r=−0.184, p=0.008), FEV1 before b2 (r=−0.213, p=0.001) and after b2 (r=−0.178, p=0.012), FEV1/FVC before b2 (r=23?0.165, p=0.013) and positively correlated with KCOc (r=0.379, p<0.001). Multiple linear regression analysis including age and all significant PFT data retained only KCOc as a significantly correlated factor (standardized beta: 0.390, p<0.001). Among biological parameters, TRJV was not correlated to HbF %, platelets, LDH and proBNP but significantly correlated to hemoglobin, hematocrite, reticulocytes, WBC, neutrophils, HbS %, ASAT and bilirubin. Multiple linear regression including all these biological significant biological parameters retained only reticulocytes as significantly associated with TRJV (standardized beta: 0.361, p=0.008). The addition of KCOc to the model retained reticulocytes (standardized beta: 0.198, p=0.010) and KCOc (standardized beta: 0.327, p<0.001) as significantly correlated. Among the biological parameters significantly correlated with KCOc (hemoglobin, reticulocytes, LDH, WBC, platelets, HbS%, ASAT, bilirubin), multiple linear regression analysis retained HbS% (standardized beta: 0.190, p=0.027) and reticulocytes (standardized beta: 0.212, p=0.014) as significantly and positively independent correlated factors. Elevated TRJV (≥ 2.5 m/s) was observed in 39 patients. Reticulocytes per 1×109/L increase (OR: 1.005; 95% CI:1.001–1.009; p=0.007) and KCOc per 1% increase (OR: 1.022; 95% CI:1.007–1.037; p=0.004) were retained as independent and significant factors associated to the risk of TRJV ≥ 2.5 m/s by multivariate logistic regression. When comparing the check-ups in patients without intensification, only those performed after HSCT showed significantly lower KCOc (p<0.001), reticulocytes (p<0.001) and TRJV (p=0.035) Conclusion:In this study, we confirm that SCA-children have an elevated gas transfer per unit lung volume (KCOc) correlated to hemolysis and HbS%. We show for the first time that an increase in KCOc significantly raises the risk for TRJV ≥ 2.5 m/s, even after adjustment for reticulocytes. Only HSCT, which resulted in significantly lower reticulocytes and KCOc, is significantly associated with lower TRJV. These data are encouraging and suggest that HSCT could be recommended to patients with elevated TRJVNo intensificationHydroxyureaTransfusion programHSCTHSCT vs no intensificationn77565738mean (SD)p (t-test)TRJV2.17 (0.28)2.23 (0.25)2.19 (0.31)2.05 (0.26)0.035Reticux109/L273.5 (95.4)184.9 (84.5)249.7 (114.0)59.7 (38.6)<0.001KCOc118.3 (34.4)120.2 (31.6)115.2 (24.3)91.6 (20.6)<0.001 Disclosures:No relevant conflicts of interest to declare.