Elevated Tricuspid Regurgitation Velocity Research Articles

Screening for pulmonary hypertension in pregnant women with sickle cell disease in sub-Saharan Africa

BackgroundSickle cell disease (SCD) has evolved from a condition predominantly fatal in childhood to a chronic illness impacting many adults, including women of reproductive age. For females with SCD, pregnancy represents one of the greatest health threats, exacerbating existing health challenges and introducing new risks. Despite advancements in healthcare, routine screening for existing complications like pulmonary hypertension (PH) remains inconsistent, particularly in low- and middle-income countries (LMICs), where the prevalence of SCD is highest. ObjectiveThis study aimed to assess the feasibility of screening for PH in pregnant women with SCD in LMICs, with the goal of enhancing maternal health outcomes in this vulnerable population. Study DesignA prospective multi-center feasibility study was conducted from September 2022 to February 2023 at teaching hospitals in Ghana and Nigeria. The study included pregnant women with SCD between 28 and 34 weeks of gestation. Screening for PH utilized a tricuspid regurgitation velocity (TRV) criterion (>2.5 m/s), with adherence to American Society of Echocardiography guidelines. Statistical analysis included descriptive statistics and proportions. ResultsAmong 3091 pregnant women attending antenatal care, 88 had SCD (2.8%), and 55 were eligible for the study. We recruited 44 participants (mean age 28.9 years, SD 4.8), with 48% (21/44) SS genotype and 52% (23/44) SC genotype. Most participants (95.3%) had normal TRV (<2.5 m/s), with only one showing elevated TRV, successfully referred. Protocol adherence was 100%. Antenatal outcomes showed 95% echo uptake and 95.7% retention to term whilst postnatal echo follow-up was 43.5%. Notably, 27.1% (10/37) of deliveries required neonatal intensive care unit admission, and 18.2% were preterm. The sole participant with PH required intensive care unit care and experienced a preterm delivery with neonatal death on day 5. ConclusionScreening and referral for PH in pregnant women with SCD in LMICs are feasible but face challenges in early diagnosis, healthcare personnel availability, and postnatal follow-up. Strategic planning is crucial to address these challenges and improve outcomes in this high-risk population

Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. We identified 166 children from the UAB cohort (mean age: 13.49±4.47years) and 325 children from the SCCRIP cohort (mean age: 13.41±3.99years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p=.017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p=.028) after adjusting for age, sex, treatment, and site. This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

The Effect of Allogeneic Hematopoietic Stem Cell Transplantation on Sickle Cell Disease-Related Organ Damage: A Systematic Review and Meta-Analysis

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative treatment option for patients with sickle cell disease (SCD). One of the main indications for HSCT is SCD-related organ damage, which is a major cause of morbidity and early mortality. However, whether HSCT is effective in recovering SCD-related organ dysfunction has not been systematically reviewed. Methods This is a systematic review and meta-analysis investigating the effects of HSCT on organ function in patients with SCD. We performed a comprehensive search in MEDLINE/PubMed and EMBASE up to June 2023, focusing on studies reporting pulmonary, cardiac, renal, splenic, and/or cerebral function parameters, as well as retinopathy and/or avascular osteonecrosis (AVN) before and after HSCT. Continuous data were analyzed using the weighted inverse-variance random effects meta-analyses, reported as standardized mean difference (SMD) and 95% confidence intervals (95%-CI). Binomial data were analyzed using the Mantel-Haenszel random effects meta-analyses, reported as risk ratio (RR) and 95%-CI. A negative SMD indicates an improvement and a positive SMD indicates a worsening of the measured parameter post-HSCT. A RR &amp;lt;1 indicates a result in favor of the transplantation and a RR &amp;gt;1 indicates a worsening of the measured parameter after HSCT. The ‘Newcastle-Ottawa Quality Assessment Scale’ and the ‘Clinical Diversity in Meta-analysis’ (CDIM) tool were used to assess the quality and the clinical heterogeneity of the studies. Results Thirty-two of 476 studies met our inclusion criteria, of which 17 were used for the meta-analyses and 15 for the qualitative part of the review. Of the studies that were included in the meta-analyses, 4 comprised adult patients (n=184) and 13 pediatric and/or young adults &amp;lt;22 years old (n=591). The majority of donors were matched sibling donors (86.4%), and studies with both myeloablative and/or reduced intensity conditioning regimens were included. The CDIM score was low or moderate for all performed meta-analyses, suggesting fair clinical comparability among the studies. Summary plots of the meta-analyses are shown in Figure 1. Pulmonary function test parameters remained stable following HSCT (SMD -0.08, p=0.64 for forced expiratory volume in 1 second; SMD -0.13, p=0.35 for forced vital capacity; and SMD -0.95, p=0.30 for diffusing capacity). Mean tricuspid regurgitation velocity (TRV) did not change significantly in the meta-analysis (SMD -0.34, p=0.14). However, 3 studies used for the qualitative review reported normalization in patients with prior elevated TRV. Whole brain cerebral blood flow improved significantly after transplantation (SMD -1.39, p=&amp;lt;0.01). Several studies reported an absent or very low incidence of new (silent) cerebral infarcts and a decrease of transcranial Doppler velocities following successful HSCT. In pediatric patients, creatinine clearance decreased significantly after HSCT (SMD -0.80, p=0.01) and the presence of proteinuria increased (RR 2.00, p=&amp;lt;0.01). Furthermore, splenic uptake ( 99mTc) and phagocytic function of the spleen improved (RR 0.31, p=&amp;lt;0.01 and RR 0.23, p=&amp;lt;0.01, respectively). Retinopathy and AVN before and after HSCT were investigated in only 1 study in children with SCD, both showing no significant changes post-HSCT. Discussion and Conclusion Allogeneic HSCT has the potential to stabilize or recover pulmonary and cardiac function parameters in SCD patients. In pediatric patients, splenic function parameters showed impressive improvement following HSCT. On the other hand, creatinine clearance decreased significantly in children. This might be a reflection of either normalization of SCD-related hyperfiltration or transplantation-related toxicity, which may also have contributed to the increased prevalence of proteinuria after HSCT. With respect to cerebral damage, cerebral perfusion parameters improved and progression of silent cerebral infarctions was prevented following HSCT. Last, we demonstrate a paucity of evidence regarding the course of renal function, retinopathy, and AVN in adult SCD transplant recipients. More research is needed to define which patients with SCD-related organ damage might benefit most from HSCT and which organs are less likely to recover.

Inferior vena cava diameter is associated with prognosis in patients with chronic heart failure independent of tricuspid regurgitation velocity

AimsA high, Doppler-derived, tricuspid regurgitation velocity (TRV) indicates pulmonary hypertension, which may contribute to right ventricular dysfunction and worsening tricuspid regurgitation leading to systemic venous congestion, reflected by an increase in inferior vena cava (IVC) diameter. We hypothesized that venous congestion rather than pulmonary hypertension would be more strongly associated with prognosis.Methods and results895 patients with chronic heart failure (CHF) (median (25th and 75th centile) age 75 (67–81) years, 69% men, LVEF 44 (34–55)% and NT-proBNP 1133 (423–2465) pg/ml) were enrolled. Compared to patients with normal IVC (< 21 mm) and TRV (≤ 2.8 m/s; n = 504, 56%), those with high TRV but normal IVC (n = 85, 9%) were older, more likely to be women and to have LVEF ≥ 50%, whilst those with dilated IVC but normal TRV (n = 142, 16%) had more signs of congestion and higher NT-proBNP. Patients (n = 164, 19%) with both dilated IVC and high TRV had the most signs of congestion and the highest NT-proBNP.During follow-up of 860 (435–1121) days, 239 patients died. Compared to those with both normal IVC and TRV (reference), patients with high TRV but normal IVC did not have a significantly increased mortality (HR: 1.41; CI: 0.87–2.29; P = 0.16). Risk was higher for patients with a dilated IVC but normal TRV (HR: 2.51; CI: 1.80–3.51; P < 0.001) or both a dilated IVC and elevated TRV (HR: 3.27; CI: 2.40–4.46; P < 0.001).ConclusionAmongst ambulatory patients with CHF, a dilated IVC is more closely associated with an adverse prognosis than an elevated TRV.Graphical

Association of Elevated Tricuspid Regurgitation Velocity with Kidney and Cerebrovascular Disease in Children with Sickle Cell Disease

Introduction: Adult patients with sickle cell disease (SCD) develop progressive end-organ injury leading to multi-organ disease and increased mortality. It is plausible that this multi-organ damage begins in pediatric patients. Tricuspid regurgitation velocity (TRV), measured by echocardiography is a surrogate marker for pulmonary hypertension that is a poor prognostic factor in adults with SCD. The utility of screening echocardiograms as a marker of disease severity is being studied in pediatrics. In this study, we assessed associations between elevated TRV with early development of chronic kidney disease (albuminuria), and cerebrovascular disease (CVD). Methods: We performed an IRB approved cross-sectional study to evaluate the prevalence of elevated TRV ≥ 2.5 m/s and its associations with albuminuria and CVD in patients with SCD ages 1-21 years. We included children with a diagnosis of SCD who had at least one echocardiogram performed during an outpatient clinic visit at steady-state for screening for pulmonary hypertension. We categorized patients as receiving either transfusion therapy (chronic transfusion for >12 months), SCD modifying therapy (hydroxyurea, voxelotor, crizanlizumab, or L-glutamine), or no therapy. Patients on both transfusion and a SCD modifying therapy were defined as being on transfusion therapy. We defined albuminuria as patients with two of three consecutive albumin creatinine ratios ≥30mg/g measured during standard clinic visits. Cerebrovascular disease was defined as having either 1) an overt stroke, 2) silent cerebral stroke defined by MRI, 3) vasculopathy by abnormal magnetic resonance angiography (MRA), 4) transient ischemic event defined by stroke symptoms that resolved within 24 hours, or 5) abnormal TCD (>200 cm/second). We performed bivariate analysis utilizing t-test (or Kruskal-Wallis test) and Cochran-Mantel-Haenszel test for continuous and categorical variables respectively. To determine the association between elevated TRV and albuminuria, and elevated TRV and CVD, logistic regression was fit and adjusted for variables that were significant in the bivariate analysis. Using the TRV <2.5m/sec as the reference group, adjusted odds ratios with their accompanying confidence intervals were calculated for those with albuminuria and those with CVD in separate models. All reported P values were 2-sided. Statistical significance was defined as p<0.05. All analyses were performed using Statistical Analysis Software 9.4, (SAS Institute, Cary, NC). Results: Among 166 children with echocardiography, the prevalence of an elevated TRV was 21%. On bivariate analysis, elevated TRV was significantly associated with persistent albuminuria (OR 2.85 (95% CI: 1.27-6.43) and cerebrovascular disease (OR: 2.46 (95% CI: 1.09-5.53) (Table 1). An elevated TRV was also significantly associated with increased age (15.6 vs 12.9 yrs, p=0.005), lower hemoglobin F% (2.5 vs 4.6%, p=0.01), higher absolute reticulocyte count (0.5 vs 0.4 x 106/ µL p=0.005) and chronic transfusion therapy (p=0.04). After adjusting for age, absolute reticulocyte count, HbF and treatment in a multivariable logistic regression, the associations between elevated TRV with either persistent albuminuria (OR: 1.82 (0.71 - 4.67)) and cerebrovascular disease (OR: 1.15 (0.43-3.10)) were no longer statistically significant (Table 1). Our data suggests that with an odds ratio of 2.9 and a prevalence of elevated TRV of 20%, a prospective study of 166 adolescent patients with SCD would be needed to detect the association between elevated TRV and persistent albuminuria with 80% power and 233 children would be needed to detect this difference with 90% power. Conclusion: This data provides additional evidence that around 20% of pediatric patients have an elevated TRV and those patients may also have an increased risk for developing chronic kidney disease and cerebrovascular disease. A larger, prospective cohort study should be conducted to confirm these findings and determine the role of screening echocardiography in pediatric SCD. At minimum, our data suggests that pediatric patients with known chronic kidney disease or cerebrovascular disease should be screened for cardiac complications. Furthermore, longitudinal studies are needed to evaluate the association between elevated TRV in children with early end-organ complications in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 9402: Venous Thromboembolism During Pregnancy is Associated with Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Introduction: In patients with sickle cell disease (SCD), a tricuspid regurgitation velocity (TRV) &gt; 2.5 m/s by echocardiogram is a non-invasive marker for underlying pulmonary hypertension (PH), and associated with increased mortality. During pregnancy, maternal and fetal adverse events are increased in women SCD, and in women with PH. Data on pregnancy outcomes in women with both SCD and elevated TRV are sparse; we hypothesized increased adverse events in this group. Methods: We retrospectively compared pregnancy outcomes in women with SCD and elevated TRV (&gt;2.5 m/s) to those with SCD and normal TRV (≤ 2.5 m/s). Results: We identified 59 pregnancies in 43 women (mean age 28 ± 5 years at delivery) with SCD (31 pregnancies in women with elevated TRV, 28 with normal TRV). There was a trend towards more lifetime transfusions, and significantly lower hemoglobin in women with elevated TRV ( Figure A-B ). As expected, right ventricular systolic pressure was different between the groups, however other baseline characteristics, including SCD genotype, left ventricular systolic function, and pre-pregnancy venous thromboembolism (VTE) were similar ( Figure C-F ). No maternal deaths occurred in pregnancy or 1-year postpartum. VTE occurred in 7 (12%) pregnancies, only in women with elevated TRV; and postpartum readmission was more common in women with elevated TRV ( Figure G ). Other cardiac and hematologic outcomes occurred with similar incidence between the groups ( Figure G ). In viable pregnancies, preterm birth was more common in women with elevated TRV, while other adverse obstetric and fetal outcomes did not differ between the groups ( Figure G ). Conclusion: In conclusion, we identified a higher incidence of VTE, preterm birth and postpartum readmission in pregnant women with SCD and elevated TRV. These complications may be associated with worse SCD burden; however, the potential mechanistic link between pregnancy, VTE and PH as assessed by elevated TRV requires further study.

Association of Thrombospondin-1 Gene Polymorphism with Elevated Tricuspid Regurgitant Velocity in Sickle Cell Anemia

Background: Pulmonary hypertension (PH) is associated with premature mortality in adults with sickle cell anemia (SCA). Decreased nitric oxide bioavailability has been implicated in the pathogenesis of SCA associated PH. Thrombospondin-1 (TSP1) protein encoded by THBS1 gene inhibits nitric oxide/cGMP signaling and has been hypothesized to promote PH in SCA (Novelli et al. Am J Physiol Lung Cell Mol Physiol 2019). Recently in a cross-sectional targeted gene analysis in adults with SCA, THBS1 gene single nucleotide polymorphisms (SNPs) rs1478605-G and rs1478604-T were found to be associated with PH, as estimated by its surrogate echocardiogram marker tricuspid regurgitant velocity (TRV). However, neither of these SNPs were validated in an external cohort (Jacob et al. Am J Hematol. 2017).Objective: To test the hypothesis that THBS1 gene SNPs were associated with TRV, we first validated the association of previously reported THBS1 gene SNPs (rs1478605-G and rs1478604-T) with TRV as quantitative and binary variables (elevated TRV: < or ≥ 2.5m/sec) in a longitudinal, pediatric, SCA patient cohort. We then assessed the associations of 8 other common THBS1 SNPs with false discovery rate controlled at 0.1. Finally, we sought to generate a polygenic score (PGS) incorporating this region genomic data and determine its association with TRV.Methods: Our cohort was comprised of children aged 5-18 years with HbSS or HbS/β 0thalassemia enrolled in either Long-Term Effects of Erythrocyte Lysis Trial (ELYSIS, NCT00842621) (Yates et al. Pediatr Blood and Cancer. 2019) and Sickle Cell Clinical and Intervention Program (SCCRIP, NCT02098863). All participants underwent prospective measurement of TRV by 2D-echocardiogram at baseline steady state (≥ 4 weeks from transfusion, hospitalization) and then repeated two years later (Rai et al. Blood Adv. 2021). Generalized linear mixed models were used to assess the association between quantitative or elevated TRV and genetic markers, after adjusting for age at baseline, sex, time point, NT-pro-BNP, creatinine and 5 principal components (PC). Three SNPs, rs1478605-G, rs753599-A and rs1051442-T statistically significant at levels given above for either quantitative or elevated TRV and whose pairwise linkage disequilibrium R 2 ≤ 0.1 were selected to build a PGS. The PGS was defined as the summed number of TRV-increasing unfavorable alleles carried by each individual across all selected SNPs. Two-stage iterative resampling (TSIR) approach was used to internally discover and validate the associations of PGS with TRV at an overall type I error rate of 0.05 with randomly sampled half of samples as the discovery cohort and the remaining as the validation cohort (Kang et al. J Hum Genet. 2015).Results: Our cohort included 138 children (276 data points) with SCA with mean age of 9.9 years (SD 3.25 years). We validated the association of quantitative TRV with previously reported two SNPs rs1478605 (estimate = -0.11, standard error [SE] = 0.04, p = 0.003) and rs1478604 (estimate = -0.09, SE = 0.04, p = 0.014). We further identified new associations of elevated TRV with THBS1 SNPs rs10551442 odds ratio (OR) 0.26 (95% CI 0.09, 0.77; p = 0.017), rs17633107 OR 0.26 (95% CI 0.09, 0.77; p=0.017), rs3743125 OR 4.4 (95% CI 1.2, 1.7; p = 0.03), and rs753599 OR 5.3 (95% CI 1.4, 2.1; p=0.018). Two of these SNPs rs10551442 (estimate = -0.13, SE = 0.05, p = 0.013) and rs17633107 (estimate = -0.13, SE = 0.05, p = 0.013) were also associated with quantitative TRV. One unfavorable allele increase in PGS was associated with a 0.1 m/sec increase in TRV (Figure 1A) and a 2.1 increase in log-odds of having an elevated TRV (Figure 1B). The associations of PGS with quantitative and elevated TRV were discovered and validated in 36 and 21 out of 100 repetitions by the TSIR analysis, respectively.Conclusion: We validated two previously published variants in the THBS1 gene rs1478605 and rs1478604 in an external and independent pediatric cohort with quantitative TRV. We also identified associations of common SNPs rs10551442, rs17633107, rs3743125, and rs753599 with TRV ≥ 2.5m/sec and of rs10551442 and rs17633107 with quantitative TRV in a pediatric population and created a PGS incorporating these data. The PGS is significantly associated with TRV, which was internally validated using TSIR approach. Our genomic findings further support the role of TSP1 in the pathophysiology of the pulmonary vasculopathy seen in SCA. [Display omitted] DisclosuresAtaga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees. Hankins: Global Blood Therapeutics: Consultancy; Vindico Medical Education: Consultancy; Bluebird Bio: Consultancy; UpToDate: Consultancy. Estepp: Global Blood Therapeutics: Consultancy, Research Funding.

Targeted Proteomics of Pulmonary Hypertension in Sickle Cell Disease

BACKGROUND AND AIMHemolysis, inflammation and coagulopathy associated with sickle cell disease (SCD) can lead to pulmonary hypertension. More than 15% of adult patients with SCD are affected by pulmonary hypertension as measured by a tricuspid regurgitation velocity (TRV) ≥ 2.9 m/sec (Nouraie, M. et al., Validation of a composite vascular high-risk profile for adult patients with sickle cell disease. American Journal of Hematology, 94:E312-E314. 2019). Moreover, sickle cell disease patients with pulmonary hypertension have a much higher mortality risk than those without pulmonary hypertension. There is little knowledge on the proteomic profile of pulmonary hypertension in SCD. Our aim was to conduct a proof-of-concept study to explore targeted serum protein biomarkers that are differentially expressed in SCD patients with elevated tricuspid regurgitation velocities and explore their corresponding pathways. MATERIAL AND METHODSData from the Walk-PHaSST study was used for this study. The Walk-PHaSST was a multicenter study to assess the effect of sildenafil for SCD patients with pulmonary hypertension (Gladwin, M. T. et al., Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS One, 9:e99489. 2014). In the screening phase of the study, 720 patients with SCD were recruited. Study participants underwent clinical and lab examinations, as well as an echocardiography. We selected two groups of patients: one group of patients with a TRV≤2.6 m/sec and another with TRV≥2.9 m/sec (N =35 in each). The serum concentration of 92 protein biomarkers was measured using an OLINK cardiovascular panel. This panel assess a range of biological process including inflammatory response, angiogenesis, cell adhesion, coagulation, and response to hypoxia. T-tests were performed between the aforementioned groups for each of the serum biomarkers. The Hochberg method was used to calculate the false discovery rate. A volcano plot was created using the Bonferroni correction. Finally, we tested the correlation of the differentially expressed biomarkers with clinical variables measured in blood samples of the participants. These variables include white blood cell (WBC), neutrophil count, thrombospondin-1 (TSP as measure of coagulation), PIGF and VEGF (growth factors involved in angiogenesis), and NT-proBNP (elevated in pulmonary hypertension). RESULTSUsing a false discovery rate of 0.01, we discovered 14 significantly expressed proteins. Six of them passed a Bonferroni corrected overall critical p value < 0.00054 (Figure 1). These included T-cell surface glycoprotein (CD4), lymphotactin (XCL1), SLAM family member 7 (SLAMF7), galectin-9 (GAL9), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2), and tumor necrosis factor receptor superfamily member 11A (TNFRSF11A). We observed up to a 1.2-fold increase in these 6 protein biomarker levels in the high TRV groups.The correlogram (Figure 2) indicated that there is a slightly positive correlation between WBC and CD4, GAL9, TRAILR2, and TNFRSF11A (r > 0.20). For neutrophil count, we observed significantly negative correlation with selected markers including TNFRSF11A levels (r = -0.51), GAL9 (r = -0.35), XCL1 (r = -0.27), SLAMF7 (r = - 0.21), and CD4 (r < - 0.24). A significantly negative correlation between TSP and GAL9 levels (r = -0.31) was also observed. Finally, we observed a strong, positive correlation between all proteins and serum NT-proBNP levels (r > 0.44). CONCLUSIONCirculatory protein markers of immune response and coagulation are highly expressed in SCD patients with elevated TRV. This provides evidence that these protein biomarkers have potential to be utilized as prognostic markers for pulmonary hypertension in patients with SCD. [Display omitted] DisclosuresLittle: Biochip Labs: Patents & Royalties; Hemex Health, Inc.: Patents & Royalties. Gibbs: Acceleron Pharma: Consultancy, Other: lecture fees; Actelion: Consultancy, Other: lecture fees; Aerovate: Consultancy, Other: lecture fees; Bayer: Consultancy, Other: lecture fees; Compexia: Consultancy, Other: lecture fees; Janssen: Consultancy, Other: lecture fees; MSD: Consultancy, Other: lecture fees ; Pfizer: Consultancy, Other: lecture fees; United Therapeutics: Consultancy, Other: lecture fees. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Nouraie: Phoenicia BioScience Inc.: Consultancy.

Risk Factors for Adverse Maternal and Fetal Outcomes in Pregnant Patients with Sickle Cell Disease

BackgroundApproximately 100,000 Americans are affected by sickle cell disease (SCD), an inherited hematologic disorder. In women with sickle cell disease, pregnancy is associated with increased maternal and fetal adverse outcomes (Elenga et al). However, there is a paucity of data on risk factors for adverse events in this population. This retrospective study seeks to add to the deficient repertoire of information regarding maternal and fetal outcomes in patients with sickle cell disease and their children.MethodsWe retrospectively evaluated pregnancy outcomes of women with SCD who had previously undergone echocardiography from the year 2000-2021. The associations between clinical variables and adverse hematologic (AHE), cardiac (ACE), obstetric (AOE) and fetal/neonatal (ANE) events were evaluated by the Generalized Linear Model (GLM). The adverse hematologic events were vaso-occlusive crisis (VOC) antepartum and postpartum, acute chest syndrome, venous thromboembolism antepartum and postpartum, and transfusion antepartum.ResultsWe identified 43 women/59 pregnancies with a median maternal age 27 years old (interquartile range [IQR] 20), pre-pregnancy BMI 25 kg/m2 (IQR 16). Maternal sickle cell genotype was SS in 31 (72%) women/37 (63%) pregnancies, SC in 8 (18%) women/18 (31%) pregnancies, and other genotype in 4 (9%) women/4 (7%) pregnancies. Prior venous thromboembolism was present in 12 (27%) women/15 (25%) pregnancies and prior acute chest syndrome (ACS) in 33 (80%) women/41 (75%) pregnancies. In the year before pregnancy, 24 (56%) women were admitted at least once for VOC. There were no maternal deaths during pregnancy or up to 1 year postpartum. AHE (n = 171) occurred in 43 (73%) pregnancies (Figure A), with a median of 2 (range 0-13) AHE per pregnancy. AHE were more common with genotype SS, history of ACS, history of ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, tricuspid regurgitation velocity (TRV) >2.5 m/s on echocardiogram, and increased maternal age, and less common with increased hemoglobin (Figure B). ACE were rare (n = 3) (Figure A) and weakly associated with increased maternal age (Figure C). AOE (n = 37) occurred in 27 (45%) pregnancies (Figure A) and were associated with lower pre-pregnancy maternal BMI (Figure D). ANE (n = 54) occurred in 27 (46%) of pregnancies, and were associated with maternal hypertensive disorders of pregnancy (Figure E).ConclusionsWe found that AHE during pregnancy in women with SCD were associated with genotype SS, history of ACS, ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, higher maternal age, and inversely related to hemoglobin. In addition, AHE during pregnancy were associated with TRV >2.5 m/s on echocardiogram, which has not been previously shown in women with SCD. These data may be useful to identify women at increased risk during pregnancy. Data show that patients with sickle cell disease who have more disease-related complications including history of acute chest syndrome, frequent pain crisis, elevated TRV on echocardiogram, and lower hemoglobin are at greater risk for AHE. This suggests that disease severity is directly related to outcomes. The association between increased maternal age and ACE has been demonstrated in the past in women without SCD (DeViti et al). The same can be noted for the association of AOE with lower maternal BMI (Verma et al), and ANE being associated with maternal hypertensive disorders of pregnancy (Lugobe et al). In the future, prevention of these complications will be key. Future directions include determining the effect of disease-modifying therapy on these outcomes, though safety during pregnancy has not yet been demonstrated for more novel agents such as voxelotor and crizanlizumab. With more information on these risk factors, we hope that modification and treatment can result in better outcomes. [Display omitted] DisclosuresDesai: Pfizer: Other: Publication Fee, Research Funding; Foundation for Sickle Cell Research: Honoraria; Forma: Consultancy; Novartis: Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding.

Pulmonary hypertension after bone marrow transplantation in children.

Pulmonary hypertension is a rare but important cause of mortality after haematopoietic stem cell transplantation (HSCT) in children. This complication is poorly characterised in the literature. We report here a series of children who developed pulmonary hypertension after HSCT. Between January 2008 and December 2015, we retrospectively analysed 366 children who underwent HSCT (age range 0.5-252 months; median 20.3 months). During the post-HSCT course, echocardiography scans motivated by respiratory symptoms identified 31 patients with elevated tricuspid regurgitation velocity (>2.8 m·s-1), confirmed when possible by right heart catheterisation (RHC). 22 patients had confirmed pulmonary hypertension with mean±sd pulmonary arterial pressure 40.1±10 mmHg (range 28-62 mmHg) and pulmonary vascular resistance 17.3±9.2 Wood Units (range 8-42 Wood Units). Among the 13 responders at reactivity test, only one patient responded to calcium channel blockers. Seven patients (32%) died. 15 pulmonary hypertension patients were alive after a mean±sd follow-up of 6.5±2.3 years (range 2-10 years). All survivors could be weaned off pulmonary hypertension treatment after a median follow-up of 5 months (range 3-16). The delay between clinical symptoms and initiation of pulmonary hypertension therapy was significantly longer in patients who subsequently died (mean±sd 33.5±23 days; median 30 days) than in survivors (mean±sd 7±3 days) (p<0.001). Pulmonary hypertension is a severe complication of HSCT with an underestimated incidence and high mortality. Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.

Screening for pulmonary arterial hypertension in systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a dreaded complication of systemic sclerosis (SSc) that occurs in ∼10% of patients. Most individuals present with severe symptoms, significant functional impairment and severe haemodynamics at diagnosis, and survival after PAH diagnosis is poor. Therefore, early diagnosis through systematic screening of asymptomatic patients has the potential to identify PAH at an early stage. Current evidence suggests that early diagnosis and treatment of PAH in patients with SSc may lead to better clinical outcomes. Annual screening may include echocardiography, but this can miss some patients due to suboptimal visualisation or insufficient tricuspid regurgitation. Other options for screening include the DETECT algorithm or the use of a combination of pulmonary function testing (forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio) and N-terminal-pro-brain natriuretic peptide levels. Symptomatic patients, those with an elevated tricuspid regurgitation velocity on echocardiogram with or without secondary echocardiographic features of PAH, and those who screen positive on the DETECT or other pulmonary function test algorithms should undergo right heart catheterisation. Exercise echocardiography or cardiopulmonary exercise testing, nailfold capillaroscopy and molecular biomarkers are promising but, as yet, unproven potential options. Future screening studies should employ systematic catheterisation to define the true predictive values forPAH.

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 High Output State of Sickle Cell Patients: Associations with Anemia-Related Organ Damage

Introduction:As longevity of sickle cell disease (SCD) patients increases, chronic organ damage becomes more prevalent. Tricuspid regurgitation velocity (TRV) ≥2.5 m/sec) has long been considered a reliable indicator of pulmonary hypertension (PH). However, studies using right heart catherization confirmed PH in only 25% of patients with TRV elevation, despite the independent association of an elevated TRV with mortality. Since TRV elevation is also associated with anemia and cardiac remodeling on trans-thoracic echocardiography (TTE), we hypothesized that an elevated TRV may also identify SCD patients with a hyperdynamic circulation due to severe anemia, putting them at higher risk for anemia-related organ damage and early mortality.We aimed to determine the associations between TRV elevation and other high output parameters on TTE with anemia-related organ damage and to assess what echocardiographic parameters predict anemia-related organ damage and mortality.Methods:In this retrospective, longitudinal study, SCD patients were followed from the oldest TTE onwards. At baseline and after follow-up, TTE parameters of cardiac function (including TRV and signs of volume and pressure overload), anemia-related organ damage (microalbuminuria, renal failure, stroke, leg ulcers, priapism, diastolic dysfunction) and mortality were assessed. Logistic and cox regression analyses were applied to analyze associations between baseline echocardiographic findings and laboratory results with development of anemia-related organ damage during follow-up to identify predictors of organ damage.Results:In total 254 patients were included in the study cohort. The mean follow-up was 6.0 years (4.0-8.0 yr). Elevated TRV was found at baseline in 58/254 (22.8%) patients versus 196/254 (77.2%) patients with a normal TRV. Patients with an elevated TRV had an increased cardiac output (59 dL/min vs. 52 dL/min; P <0.01), E-wave velocity (104 cm/sec vs. 94 cm/sec; P=.03), septal E/e‘-ratio (9.2 vs. 7.9; P=.02), left ventricular (LV) mass index (111 g/m2 vs. 94 g/m2; P <0.01) and left atrial (LA) volume index (50 g/m2 vs. 39 g/m2; P <0.01) compared to patients with a normal TRV, which remained unchanged during follow-up. At baseline and upon follow up microalbuminuria (28% vs. 15%; P 0.03) and renal failure (7% vs. 0%; P <0.01) were more prevalent in patients with TRV elevation as compared to patients without TRV elevation. The composite incidence of new forms of anemia-related organ damage after follow-up was higher in patients with an elevated TRV (45% vs. 27%; P 0.02). An elevated LV mass index (representing pressure overload) and septal E/e‘-ratio (representing volume overload) were associated with TRV and a higher prevalence of anemia-related organ damage at baseline, but not with new organ damage upon follow-up or mortality. Predictors of organ damage after follow-up were hemoglobin level (OR 0.7 [0.5 - 0.9]; P <0.01) and age (OR 3.1 [1.7 - 5.5]; P <0.01) and new organ damage was predicted by lactate dehydrogenase (LDH) (OR 1.5 [1.1-2.0]; P=.02) and age (OR 2.0 [1.3 - 3.0]; P <0.01).Conclusion:A high output state in SCD patients is associated with an elevated TRV and anemia-related organ damage, in particular nephropathy, mainly as a consequence of severe anemia and increasing age. These associations may better explain early mortality in these patients despite the fact that only a limited part of these patients do have pulmonary hypertension. Patients with an elevated TRV or other signs of a high output state are at risk of anemia-related organ damage (in particular nephropathy) and should be monitored closely. Early administration of available treatment modalities should be considered. DisclosuresNo relevant conflicts of interest to declare.

Predictive Value of Gradual Change in Renal Function on Vasculopathy Related Complications and Mortality in Patients with Sickle Cell Disease

▪Introduction:For a long time sickle cell disease (SCD) was mainly prevalent in children and young adults, but due to improved prevention of (fatal) complication in early life, SCD patients become older. However, with the rising age of these patients more complications are observed including cumulating organ damage, which plays an important role in the limited life expectancy of adult sickle cell patients. In the general population, change in renal function over time is related to cardiovascular mortality and is considered to be a reflection of general microvascular damage. By the use reciprocal serum creatinine values over time the subclinical decline in renal function is linear in time. Given the fact that most forms of organ damage in SCD are related to vasculopathy, the gradual change in renal function in the SCD population may have a predictive value for developing organ damage. In this study, we assessed the relation between the slope in renal deterioration (plotted by linear regression) with organ damage and several laboratory values in a cohort of sickle cell patients in a single tertiary hospital.Methods:All SCD patients (HbSS, HbSC and HbSβ-thalassemia) at the out-patient clinicin the period from 2006 until 2016 were included and their gradual change in renal function over this period was determined and the slope of renal deterioration was plotted. Only creatinine values assessed in steady state conditions were included in the analysis. Patients with less than 3 creatinine measurements over this period or missed their regular outpatient appointments in the last three years were excluded. Patients were divided into three tertiles according to the slope of renal decline and the development of organ damage (i.e., microalbuminuria, chronic kidney disease (CKD; eGFR<60 ml/min/1.73m2), retinopathy, avascular necrosis (AVN), CVA and elevated tricuspid regurgitation velocity (TRV)), mortality rate, various laboratory values (i.e., Hb, LDH, reticulocyte count, leukocyte count, HbF, NT-proBNP, creatinine and eGFR) and patient characteristics (i.e., age, gender, genotype groups) were related to these tertiles.Results:In total 167 patients were included in the study and divided in tertiles according to the slope of renal function (ie. Tertile 1 representing the fastets detertioration in renal function over time and tertile 3 the slowest decline in renal function). Patients with the more severe genotype (HbSS/HbSβ0) were significantly more present in tertile 1 as compared to the other tertiles (83.9%, 55.4% and 52.7%, respectively (p=0.001)) indicating that the decline in renal function was significantly faster in patients with HbSS/HbSβ0. The slope of renal function decline was also significantly associated with occurrence of microalbuminuria (59.3% , 32.1% and 15.1% for tertile 1-3, respectively (p<0.001)). Mortality (10.7%, 3.6% and 1.8% , respectively) and CKD (7.1%, 1.8% and 0.0%, respectively) showed the same trend but did not reach statistical significance. Other forms of organ damage, i.e., retinopathy, AVN, CVA and increased TRV were not associated with the slope in renal deterioration. (Table 1) Hemolysis (LDH, Hb, reticulocytes) was significantly more prevalent in tertile 1 as compared to the other tertiles whereas leukocyte count, HbF or NT-proBNP were not related to the decline in renal function.Conclusion:This study demonstrates that long-term subclinical renal deterioration determined in a population of patients with SCD is faster in patients with the severe genotype (HbSS/HbSβ0) and is associated with microalbuminuria while a trend towards correlation with mortality and renal failure was observed. The slope in renal decline appeared to be related with hemolytic rate while no association with other forms of organ damage or laboratory values was found. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relationship between ventilation heterogeneity and exercise intolerance in adults with sickle cell anemia.

Sickle cell anemia (SCA) causes dysfunction of multiple organs, with pulmonary involvement as a major cause of mortality. Recently, there has been growing interest in the nitrogen single-breath washout (N2SBW) test, which is able to detect ventilation heterogeneity and small airway disease when the results of other pulmonary function tests (PFTs) are still normal. Thus, the objectives of the present study were to assess the heterogeneity in the ventilation distribution in adults with SCA and to determine the association between the ventilation distribution and the clinical, cardiovascular, and radiological findings. This cross-sectional study included 38 adults with SCA who underwent PFTs, echocardiography, computed tomography (CT), and 6-min walk test. To evaluate the ventilation heterogeneity, the patients were categorized according to the phase III slope of the N2SBW (SIIIN2). Compared with adults with lower SIIIN2 values, adults with higher SIIIN2 values showed lower hemoglobin levels (P=0.048), a history of acute chest syndrome (P=0.001), an elevated tricuspid regurgitation velocity (P=0.039), predominance of a reticular pattern in the CT (P=0.002), a shorter 6-min walking distance (6MWD) (P=0.002), and lower peripheral oxygen saturation (SpO2) after exercise (P=0.03). SIIIN2 values correlated significantly with hemoglobin (rs=-0.344; P=0.034), forced vital capacity (rs=-0.671; P<0.0001), diffusing capacity for carbon monoxide (rs=-0.376; P=0.019), 6MWD (rs=-0.554; P=0.0003), and SpO2 after exercise (P=0.040). Heterogeneity in the ventilation distribution is one of the most common pulmonary dysfunctions in adults with SCA. Moreover, relationships exist between ventilation heterogeneity, worsening of pulmonary structural damage, and reduced tolerance for exercise.

Echocardiographic predictors of outcome in patients with chronic obstructive pulmonary disease.

We aimed to assess the relationship between echocardiographic characteristics and mortality in patients with chronic obstructive pulmonary disease (COPD). We prospectively studied 154 patients (mean age 71 ± 10 years, 71% male) with COPD. All patients underwent transthoracic Doppler echocardiography within 48 hours of hospital admission. Primary endpoint was all-cause mortality during a median period of 22 months. Mildly elevated tricuspid regurgitation pressure and mitral E/e' ratio were the most commonly encountered echocardiographic abnormalities, observed in 60% and 56% of patients, respectively. In Kaplan-Meier analysis of survival, left atrial enlargement, E/e' ratio > 8, right atrial enlargement, right ventricular dilation, decreased tricuspid annular plane systolic excursion, decreased tricuspid annular systolic velocity, and elevated tricuspid regurgitation velocity were associated with all-cause mortality (p < 0.05 for all). In the Cox proportional hazards analysis, the mitral E/e' ratio (hazard ratio 1.048; 95% confidence interval 1.001-1.096) remained an independent echocardiographic predictor of survival after adjustment for age, COPD severity, and other baseline echocardiographic parameters. Among patients with COPD, an abnormal mitral E/e' ratio was an independent echocardiographic predictor of all-cause mortality. Echocardiographic evaluation of structural and functional cardiac abnormalities provides important prognostic information and should be used routinely in the assessment of patients with COPD. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:211-221, 2017.

Atteintes pulmonaires au cours de la drépanocytose chez l’enfant

Acute and chronic pulmonary complications are frequent in sickle cell disease (SCD), with different spectrum and characteristics in children and adults. Chronic hypoxia is frequent and plays a role in several respiratory complications in SCD. Furthermore, hypoxia has been associated with a higher risk of cerebral ischemia. Despite differing oxygen affinity between hemoglobin A and S, standard pulse oximetry was shown to be accurate in diagnosing hypoxia in SCD patients. Whereas acute hypoxia management is similar to non-SCD patients, chronic hypoxia treatment is mainly based on a transfusion program rather than long-term oxygen therapy. Acute chest syndrome (ACS) is the foremost reason for admission to the intensive care unit and the leading cause of premature death. Guidelines on its management have recently been published. Asthma appears to be a different comorbidity and may increase the risk of vaso-occlusive crisis, ACS, and early death. Its management is not specific in SCD, but systemic steroids must be used carefully. Pulmonary hypertension (PH) is a major risk factor of death in adult patients. In children, no association between PH and death has been shown. Elevated tricuspid regurgitant velocity was associated with lower performance on the 6-min walk test (6MWT) but its long-term consequences are still unknown. These differences could be due to different pathophysiology mechanisms. Systematic screening is recommended in children. Regarding lung functions, although obstructive syndrome appears to be rare, restrictive pattern prevalence increases with age in SCD patients. Adaptation to physical exercise is altered in SCD children: they have a lower walking distance at the 6MWT than controls and can experience desaturation during effort, but muscular blood flow regulation maintains normal muscular strength. Sleeping disorders are frequent in SCD children, notably Obstructive sleep apnea syndrome (OSAS). Because of the neurological burden of nocturnal hypoxia, OSAS care is primordial and mainly based on adenotonsillectomy, which has been shown to reduce ischemic events. The high morbidity and mortality related to pulmonary impairments in SCD require a careful pulmonary assessment and follow-up. Mainly based on clinical examination, follow-up aims to the diagnosis of SCD-related respiratory complications early in these children.

Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients.

ObjectiveTo evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases.MethodsFifty-nine adults were included in this cross-sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography.ResultsAbnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p-value < 0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value = 0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p-value = 0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p-value = 0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography.ConclusionA significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases.

Elevated tricuspid regurgitant velocity as a marker for pulmonary hypertension in children with sickle cell disease: less prevalent and predictive than previously thought?

Although elevated tricuspid regurgitant velocity (TRV), an echocardiographic marker for pulmonary hypertension, has previously been tied to mortality in adult patients with sickle cell disease, recent data demonstrated that it correlates poorly with catheterization findings. We describe the largest echocardiographic evaluation of pediatric patients with sickle cell disease to date, specifically the results of a protocol whereby a TRV≥250 cm/s prompted further evaluation. We investigated if elevated TRV would independently identify patients at risk for increased morbidity. A clinical echocardiographic database containing 630 patients with sickle cell disease was retrospectively reviewed; 120 patients (19%) met inclusion criteria and were compared 1:1 to randomly selected age-matched controls from the same database. By multivariate analysis, the elevated TRV cohort did not differ from controls in likelihood of acute chest episodes, hospitalization, or stroke. The study cohort's mean TRV in fact decreased to 242±33 cm/s at follow-up without a discernible and comprehensive intervention to explain the improvement. Three patients had catheterization-proven pulmonary hypertension. In conclusion, elevated TRV in children with sickle cell disease is less prevalent than previously thought and is not independently associated with increased short-term morbidity.

Platelet hyperactivity in thalassemia patients with elevated tricuspid regurgitant velocity and the association with hemolysis

IntroductionPulmonary arterial hypertension is a life-threatening complication in thalassemia characterized by elevated pulmonary arterial pressure. Increased platelet activation is associated with this complication; however, its role remains unclear. MethodsPlatelet activation in splenectomized β-thalassemia/hemoglobin E (Hb E) patients was measured using flow cytometric determination of P-selectin and activated glycoprotein (aGP) IIb/IIIa expression, and platelet-leukocyte aggregates (platelet-neutrophil, platelet-monocyte and platelet-lymphocyte aggregates). Tricuspid regurgitant velocity (TRV) was measured and used as an indicator of pulmonary arterial pressure. Plasma hemoglobin served as markers of hemolysis. ResultsFifteen of 27 patients had elevated TRV (>2.5m/s). Platelet expression of P-selectin and aGPIIb/IIIa, and platelet-leukocyte aggregates were higher in thalassemia patients with elevated TRV than healthy control. Platelet-neutrophil aggregates increased in thalassemia patients with elevated TRV compared to patients with normal TRV. The increase in P-selectin and aGPIIb/IIIa expression induced by adenosine diphosphate (ADP) was higher in patients with elevated TRV than those with normal TRV. Platelet P-selectin expression and platelet-neutrophil aggregates correlated positively with TRV. Plasma hemoglobin levels in patients with elevated TRV were higher than those of the control subjects, and correlated with TRV. ConclusionThalassemia patients with elevated TRV have a further increase in platelet activation that correlates with hemolysis.