Splenectomy Is Not Associated With Higher Tricuspid Regurgitant Jet Velocity In Patients With Sickle Cell Disease

Abstract Introduction An elevated tricuspid regurgitant jet velocity (TRV) has been associated with hemolysis and increased mortality in sickle cell disease (SCD). An elevated TRV is also associated with decreased exercise capacity as measured with the six minute walk distance (6MWD). Vascular complications including pulmonary arterial hypertension (PAH) and thrombosis have been reported to occur at an increased rate following splenectomy in various disorders, including chronic hemolytic anemias or those associated with ineffective erythropoiesis, such as thalassemia. The risk of elevated TRV, already high in patients with thalassemia (33%), is significantly increased with splenectomy (unadjusted O.R 5.3, 95% CI 2.1-13.5). We wanted to evaluate the independent association of splenectomy with TRV in a cohort of patients with homozygous SS disease (HbSS). Methods We performed a retrospective cross sectional analysis of the association between splenectomy and an elevated TRV. 41 splenectomized HbSS patients were identified within the 482 HbSS patients ≥12 years of age from the multi-centered Walk-PHASTT study of pulmonary hypertension; this study incorporated a cardiovascular phenotype, including echocardiogram and 6-minute walk distance (6MWD) as part of the observational phase of the study. This sample size achieved > 99% power to detect a 15% difference in TRV in the 2 groups at a significance level of 0.05 using a 2 sided two sample t-test. Other parameters compared between groups included 6MWD, age, blood pressure, body surface area, urine albumin, blood urea nitrogen, ferritin, creatinine, white blood cell count, platelet count, hematocrit, hemoglobin, bilirubin, lactate dehydrogenase, aspartate aminotransferase, absolute reticulocyte count (ARC), absolute neutrophil count and hydroxyurea use. Continuous variables were analyzed with linear regression and 2-sided t-tests and categorical variables were analyzed with Chi-square test. Multivariable linear regression models were constructed using variables significantly associated with TRV in bivariate analyses. Results There were no significant differences in mean± SD TRV (2.62± 0.42 vs 2.62± 0.43, p=0.99) or 6MWD (446± 84 vs 440± 97, p=0.74) between the 2 groups. A history of splenectomy was associated with significantly higher ARC, hemoglobin and hematocrit. When adjusted for hemoglobin and ARC an association of TRV with splenectomy was still not observed (p=0.82). Conclusion Surgical asplenia is not associated with higher TRV compared with presumed auto-infarction of the spleen in a large cohort of adult patients with HbSS. Platelet and WBC counts were also not higher in the splenectomized patients, making it less likely that the thrombotic risk is greater in splenectomized patients compared to the high baseline risk in HbSS patients. The overall greater risk of elevated TRV with asplenia in HbSS cannot be addressed here, because most patients are functionally asplenic even absent surgical resection. However, these results suggest that, distinct from thalassemia, surgical asplenia does seem to not confer additional risk for elevated TRV in HbSS, an important consideration when weighing the risks and benefits of splenectomy. Disclosures: No relevant conflicts of interest to declare.

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Pulmonary Hypertension in Sickle Cell Disease: Cardiopulmonary Evaluation and Response to Chronic Phosphodiesterase 5 Inhibitor Therapy.

Blood ◽

10.1182/blood.v104.11.235.235 ◽

2004 ◽

Vol 104 (11) ◽

pp. 235-235 ◽

Cited By ~ 7

Author(s):

Roberto F. Machado ◽

Sabrina E. Martyr ◽

Anastasia Anthi ◽

Gregory J. Kato ◽

Lori A. Hunter ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Functional Capacity ◽

Cell Disease ◽

Walk Distance ◽

Jet Velocity ◽

Minute Walk Distance ◽

Minute Walk ◽

Tricuspid Regurgitant Jet Velocity

Abstract Pulmonary hypertension (PH) is a risk factor for mortality in Sickle Cell Disease, but it is unclear whether pulmonary hypertension is a marker or a direct cause of mortality. To better understand the pathophysiology of pulmonary hypertension in patients with sickle cell disease we performed evaluations of cardiopulmonary function in sickle cell disease patients with pulmonary hypertension (n= 15, mean age = 41 ± 2.4 years, males = 7, HbSS = 15, mean Hb = 8.3 ± 0.2 g/dl, mean tricuspid regurgitant jet velocity = 3.2 ± 0.11 m/s) compared to matched controls with sickle cell disease without pulmonary hypertension (n=11, mean age=40.2 ± 2.5 years, males=4, HbSS=11, mean Hb=8.5 ± 0.3 g/dl, mean tricuspid regurgitant jet velocity = 2.28 ± 0.07 m/s). To evaluate if specific therapy for pulmonary hypertension has any impact on systolic pulmonary artery pressure (PAP), estimated by tricuspid regurgitant jet velocity (TRJ), and functional capacity, measured by six-minute walk test (a well validated surrogate of functional capacity and response to therapy in patients with other causes of pulmonary hypertension), we treated 14 patients with sickle cell disease and pulmonary hypertension (mean age = 40 ± 2.5 years, males = 3, HbSS = 14, mean Hb = 8.8 ± 0.6 g/dl, mean TRJ = 3.4 ± 0.1 m/s) with sildenafil for at least three months. When compared to controls pulmonary hypertension patients had lower maximal oxygen consumption (VO2 max (% predicted), +PH: 44 ± 4, −PH: 55 ± 4; P=0.41), walked shorter six-minute walk distance (meters, +PH: 308.5 ± 53.8, −PH: 427.1 ± 44.6; P=0.03), demonstrated greater degree of interstitial lung disease by chest CT (P < 0.05), and more perfusion impairments measured by ventilation perfusion scan (P < 0.05). Six-minute walk distance correlated directly with maximal oxygen consumption (R=0.6; P=0.01), and inversely with mean pulmonary arterial pressure (R= −0.5; P=0.03) and tricuspid regurgitant jet velocity (R= −0.6;P=0.002), suggesting that the test is an adequate surrogate of functional capacity and response to therapy in pulmonary hypertension patients with sickle cell disease. Chronic treatment with sildenafil (up to 100 mg TID) decreased pulmonary arterial pressure (PAP mmHg, baseline: 50 ± 4.4, sildenafil: 41 ± 2.5; P=0.04) and increased six-minute walk distance (meters, baseline: 394 ± 31, sildenafil: 476 ± 26: P= 0.02). Sildenafil was well tolerated with only 2 patients stopping the drug due to headaches. We also observed 3 episodes of transient eyelid edema not requiring discontinuation of drug. Priapism was not observed in the 3 males treated (2 on exchange transfusion therapy, 1 with erectile dysfunction). In conclusion, we find that in patients with sickle cell disease, 1) pulmonary hypertension, though relatively mild, is associated with severe impairments in cardiopulmonary function, 2) traditional markers of functional capacity such as six-minute walk test can be utilized in this population as a therapeutic endpoint for clinical trials, 3) and therapy with sildenafil seems to have a favorable impact on pulmonary pressures and functional capacity.

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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

PLoS ONE ◽

10.1371/journal.pone.0108922 ◽

2014 ◽

Vol 9 (10) ◽

pp. e108922 ◽

Cited By ~ 7

Author(s):

Laurence Dedeken ◽

Rudy Chapusette ◽

Phu Quoc Lê ◽

Catherine Heijmans ◽

Christine Devalck ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Single Center ◽

Cell Disease ◽

Walk Distance ◽

Cross Sectional ◽

Minute Walk Distance ◽

Minute Walk

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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.

Blood ◽

10.1182/blood.v120.21.2107.2107 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2107-2107

Author(s):

Rudy Chapusette ◽

Laurence Dedeken ◽

Phu-Quoc Le ◽

Catherine Heijmans ◽

Christine Devalck ◽

...

Keyword(s):

Sickle Cell Disease ◽

Exercise Capacity ◽

Sickle Cell ◽

P Value ◽

Cell Disease ◽

Walk Distance ◽

Cross Sectional ◽

History Of ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 2107 The 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 1. 6-minute walk distance (6MWD) in 46 SCD children according to their biological values and clinical complications Mean 6MWD in meters (SD) p value Mean Age in years (SD) p value Hemoglobin (g/dl) · ≥ 9 (N = 24) 531.5 (95.4) 0.173 11.2 (2.8) <0.001 · < 9 (N = 22) 569.8 (92.2) 14.5 (2.7) MCV (fL) · ≥ 90 (N = 24) 536.1 (100.7) 0.251 12.6 (3.5) 0.518 · < 90 (N = 22) 568.3 (86.8) 13.2 (2.8) HbF (%)* · ≥ 10% (N = 30) 544.0 (101.7) 0.360 13.2 (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) 0.229 11.8 (3.0) 0.105 · < 1000 (N = 32) 562.3 (97.4) 13.4 (3.1) Previous ACS* · Yes (N = 38) 548.6 (98.3) 0.625 13.5 (3.1) 0.453 · No (N = 7) 566.9 (85.5) 12.5 (4.2) Silent Infarct · Yes (N = 12) 502.5 (113.9) 0.035 12.1 (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.

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Non-Cardiopulmonary Factors Affecting the Six-Minute Walk Distance in Patients with Sickle Cell Disease: Results From the Walk-PHaSST Study

Blood ◽

10.1182/blood.v118.21.1074.1074 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1074-1074 ◽

Cited By ~ 1

Author(s):

Ruchika Goel ◽

Kathryn L. Hassell ◽

Roberto F Machado ◽

Robyn J. Barst ◽

Nancy Yovetich ◽

...

Keyword(s):

Chronic Pain ◽

Sickle Cell Disease ◽

Sickle Cell ◽

P Value ◽

Cell Disease ◽

Walk Distance ◽

Factors Affecting ◽

History Of ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 1074 Non-Cardiopulmonary Factors Affecting the Six-Minute Walk Distance in Patients with Sickle Cell Disease: Results from the Walk-PHaSST Study. INTRODUCTION: The six-minute walk (6MW) test is frequently used to assess exercise capacity. Patients with sickle cell disease (SCD) can have decreased 6MW distance (6MWD) compared to controls. The 6MWD in conjunction with the TR-jet velocity (TRV) and NT-proBNP have recently been proposed to have a greater predictive value for screening SCD patients suspected of having pulmonary hypertension (PH) than TRV alone. (Parent et al, NEJM, 365; 1, 2011 365 (1):44–53). The American Thoracic Society guidelines recommend caution in controlling for sources of variability in the 6MWD (Am J Respir Crit Care Med 166. 111–117, 2002). Age and height are known confounders of the 6MWD. However, non-cardiopulmonary factors including skeletal-mechanics and pain may also impact the 6MWD. AIM: This study explores whether non-cardiopulmonary factors affect the 6MWD in SCD patients. METHODS: We analyzed data from subjects screened for the walk-PHaSST trial. Walk-PHaSST was a multi-center, placebo-controlled, double-blind, 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (TRV '2.7m/s) in subjects with SCD aged >12 years. The primary endpoint in the trial was change in 6MWD. During screening, subjects were evaluated by self-reported medical history, physical examination, blood sampling, echocardiography and 6MWD. Univariate and multivariable linear regression was performed. A two sided p value <0.05 was considered significant. RESULTS: Of the 673 subjects screened, 671 had a 6MW test. The median (inter-quartile range) of 6MWD was 438m (503 – 381m = 122 m). On univariate analysis, there was no statistically significant effect of the SCD genotype on the 6MWD (p=0.26). Further, when combining the severe genotypes (HbSS and HbSβ0 thalassemia) vs the less severe genotypes, there was no significant difference in the 6MWD (p=0.22). By multivariable linear regression (Table 1), after adjusting for age, gender and TRV, the presence of the following (self-reported by subjects) were independently associated with an estimated decrease in the 6MWD: a) chronic pain (n = 260/671, 38.9%) by 24.3m (95% CI: 9.1–39.4m, p-value <0.01), b) history of avascular necrosis (AVN) of the hip (N =127/671, 18.9%) by 27.8m (95% CI: 9.2–46.4m, p-value <0.01), and c) osteopenia (N = 46/671,6.9% ) by 31.2m (95% CI: 2.7.-59.6m, p-value <0.05) There were no significant two-way interactions between chronic pain, AVN of the hip and/or osteopenia. History of leg ulcers, osteomyelitis and rheumatoid arthritis were not significant predictors of the 6MWD. DISCUSSION: In this multi-center study of patients with SCD, history of self-reported: 1) chronic pain 2) AVN of the hip and 3) osteopenia were independently associated with decreased functional capacity (as assessed by the 6MW test), after adjusting for age, gender, and TRV. While the 6MWD in patients with SCD is significantly related to cardiac function (i.e., PH and LV diastolic dysfunction), the potential effects of pain, osteonecrosis and osteopenia on 6MWD suggest that if using the 6MW test as the primary endpoint in future trials, one should consider documentation of the presence of these factors and use a stratified randomization based on a composite of these non-cardiopulmonary variables. Disclosures: Hassell: NIH:. Gladwin:Patents filed related to treating hemolysis.: Patents & Royalties.

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Hemolysis-Associated Elevation in Tricuspid Regurgitation Velocity Predicts Reduction in Six-Minute Walk Distance After Two Years of Follow up in Children and Adolescents with Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.574.574 ◽

2009 ◽

Vol 114 (22) ◽

pp. 574-574

Author(s):

Victor R. Gordeuk ◽

Lori Luchtman-Jones ◽

Andrew D. Campbell ◽

Sohail R Rana ◽

Mehdi Nouraie ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Children And Adolescents ◽

Sickle Cell ◽

Cell Disease ◽

Walk Distance ◽

Six Minute Walk Test ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 574 Background. Elevated tricuspid regurgitation velocity (TRV) as determined by echocardiography correlates with elevated systolic pulmonary artery pressure and is associated with increased morbidity and mortality in adults with sickle cell disease. The importance of elevated TRV in children and adolescents with sickle cell disease is not known. The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study is an ongoing, longitudinal and observational multicenter study of children with sickle cell disease. Methods. Baseline echocardiography and six-minute walk test were performed prospectively in 361 children and adolescents with sickle cell disease at steady state and then repeat studies were performed in 209 after a median of 22 months of follow up (range 10 months to 36 months), also at steady state. A hemolytic component was derived by principal component analysis of baseline values for reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and total bilirubin. Results. TRV or six-minute walk test were measured at both baseline and follow-up in 193 patients. Twenty-one of these 193 patients had elevated TRV of 2.60 m/sec or higher at baseline. Elevated baseline TRV was associated with high hemolytic rate in 15 patients, defined as hemolytic component above the median for the population studied, and with lower hemolytic rate in six patients. Elevated baseline TRV with high hemolytic rate predicted elevated TRV at follow up (odds ratio 7.7; 95% confidence interval [CI] 2.5 to 24.2; P <0.001) but elevated baseline TRV with lower hemolytic rate did not (odds ratio 1.6; 95% CI 0.2 to 14.1; P = 0.7). Elevated baseline TRV with high hemolytic rate also predicted a decline in the six-minute walk distance by 10% or more at follow-up (hazard ratio 3.9; 95% CI 1.4 to 10.7; P = 0.009). In contrast, higher cardiac output as measured by the left ventricular end diastolic dimension z-score was associated with reduced risk for a decline in the walk distance (hazard ratio 0.7; 95%CI 0.6 to 0.9; P = 0.006). Conclusion. Steady-state TRV elevation in association with a high hemolytic rate occurs on screening in about 8% of children and adolescents with sickle cell disease and is predictive of elevated TRV and reduced six-minute walk distance after approximately two years of follow. Such children may be at risk for adverse clinical consequences of pulmonary hypertension as young adults. Further studies are indicated to identify the molecular mechanisms and to develop appropriate medical management for children and adolescents with this complication. Disclosures: No relevant conflicts of interest to declare.

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Oxygen Desaturation at Rest and after Exercise in Pediatric Sickle Cell Disease Patients: Correlations with Hemolysis and Elevated Tricuspid Regurgitant Jet Velocity.

Blood ◽

10.1182/blood.v112.11.1423.1423 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1423-1423

Author(s):

Andrew D. Campbell ◽

Caterina Minniti ◽

Sohail R Rana ◽

Onyinye C. Onyekwere ◽

Mehdi Nouraie ◽

...

Keyword(s):

Sickle Cell Disease ◽

Oxygen Saturation ◽

Sickle Cell ◽

Left Ventricular ◽

Oxygen Desaturation ◽

Z Score ◽

Cell Disease ◽

Jet Velocity ◽

Minute Walk ◽

Tricuspid Regurgitant Jet Velocity

Abstract Background. As a part of a multicenter, observational study in determining the prevalence and risk factors of elevated tricuspid regurgitant jet velocity (TRV) in children, oxygen desaturation correlated with TRV. We further investigated the risk factors and clinical associations of oxygen desaturation at rest and after execrcise in children at steady state. Methods. 310 children and adolescents with sickle cell disease were studied under basal conditions. Pulse oximetry was determined at rest and after a six minute walk test. The relationships of oxygen saturation at rest and desaturation during exercise to the available clinical and laboratory variables were investigated. Results. Among 300 patients with available baseline oxygen saturations, 30 (10%) had saturation <95 percent, 129 (43%) had saturation of 95–98 percent, and 141 (47%) had saturation >98 percent. Twenty-three (9%) of 244 patients had >3 percentage point reduction in oxygen saturation during a six minute walk; the median (interquartile range) baseline saturation was 96 (95– 99) percent among these patients versus 98 (97–100) percent among those with less or no reduction in saturation during the walk (P = 0.0009). Hemoglobin (p<0.0001), creatinine (p=0.014) and total lung capacity (p=0.042) were also lower in patients with declines in saturations >3 percentage points during the walk while a hemolytic index (p<0.0001), tricuspid regurgitant jet velocity (p=0.030), pulmonary insufficiency end diastolic velocity (PIEDV) (p=0.019), left ventricular mass index (LVMI) (p=0.0006) and left ventricular internal diameter z score (LVIDD z score) (p=0.0001) were higher. In 3 separate logistic regression models (clinical variables, echocardiographic parameters, and pulmonary function testing), lower hemoglobin, hemolytic index, PIEDV, LVIDD z score, and low TLC were independent predictors of six-minute-walk desaturation of >3 percentage points. Conclusion. Markers of hemolysis, low hemoglobin, PIEDV, LVMI, LVIDD z score, lower TLC, and elevated TRV velocities are associated with ≥3% reduction in oxygen desaturation during six minute walk in children and adolescents with sickle cell disease. A high degree of oxygen desaturation during the six minute walk in sickle cell disease patients might serve as an early biomarker for pulmonary hypertension. Exercise induced changes in oxygen saturation in sickle cell disease children may provide insight into the development of pulmonary hypertension as adults.

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