Abnormal right ventricular to pulmonary artery coupling in sickle cell disease

Abstract Despite the high prevalence of PHTN in adults with SCD, the prevalence in the pediatric population with SCD is not known. We hypothesized that elevated pulmonary artery pressures may be found in SCD adolescents with history of pulmonary complications, such as acute chest syndrome (ACS), obstructive sleep apnea (OSA), asthma, and reactive airway disease. Thirty such sickle cell disease adolescents were screened at Howard University or University of Michigan for PHTN with Doppler echocardiography. We defined PHTN as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/sec (corresponding to a pulmonary artery systolic pressure greater than 35 mm Hg). PHTN was found in 16 SCD patients (53.3%) and 5 (16.7%) had TRV > 3.0 m/sec. Clinical findings according to the presences or absence of PHTN are shown in the table. Potential factors contributing to PHTN in patients with SCD include chronic hemolysis and chronic hypoxia. Our results suggest that PHTN is common among SCD adolescents with a history of pulmonary complications. Consideration should be given to screening such patients for PHTN and exploring treatment options. Further studies are urgently needed to clarify the prevalence and mechanisms of PHTN in adolescents with SCD. Clinical and demographic data of 30 SCD adolescents with pulmonary findings who underwent echocardiography at Howard University Hospital or University of Michigan PHTN (N = 16) No PHTN (N = 14) P Age in years (mean +/− SD) 15.9 +/− 3.2 17.4 +/− 2.3 0.17 Females (no. and %) 5 (31.3) 7 (50) 0.5 Hemoglobin SS Phenotype (no and %) 14 (87.5 11 (78.6) 0.5 Hemoglobin concentration (mean +/− SD) 8.0 +/− 2.1 9.3 +/−1.9 0.11 White blood cells (mean +/− SD) 10.9 +/− 2.9 9.7 +/− 3.7 0.4 Platelet (mean +/− SD) 475 +/− 172 364 +/− 240 0.17 Hemoglobin F percent (mean +/− SD) 5.1 +/− 3.5 6.4 +/− 5.5 0.6 Lactate dehydrogenase (mean +/− SD) 505 +/− 162 264 +/− 50 0.002 Total bilirubin (mean +/− SD) 4.1 +/− 2.6 3.4 +/− 2.6 0.5 Creatinine concentration (mean +/− SD) 0.6 +/− 0.2 0.7 +/− 0.2 0.18 Aspartate transaminase (mean +/− SD) 48 +/− 27 36 +/− 16 0.18 Alanine transaminase (mean +/− SD) 51 +/− 37 39 +/− 20 0.3

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Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood.v112.11.4819.4819 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4819-4819

Author(s):

Rodolfo D Cancado ◽

Maria Cristina A Olivato ◽

Newton Nunes Lima Filho ◽

Orlando Campos ◽

Carlos Chiattone

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Systolic Pressure ◽

Pulmonary Artery Systolic Pressure ◽

Cell Disease ◽

Risk Of Death ◽

Hydroxyurea Therapy

Abstract Pulmonary hypertension develops in most forms of hereditary and chronic hemolytic anemia, including sickle cell disease, thalassemia, hereditary spherocytosis, and paroxysmal nocturnal hemoglobinuria, suggesting that there is a clinical syndrome of hemolysis-associated pulmonary hypertension. Retrospective studies from tertiary care referral centers suggest a prevalence of pulmonary hypertension in adults with sickle cell disease ranging from 20 to 40%. Despite the fact the elevations in pulmonary artery pressures are slight, morbidity and mortality are high. In adult sickle cell anemia patients, pulmonary hypertension is emerging as a major risk factor for death. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 80 consecutive patients (20 men and 60 women; mean [±SD] age, 30 ± 10.8 years) between 1/20/2006 and 1/20/2008. The genotype on the basis of hematologic and hemoglobin characteristics was hemoglobin SS in all patients. Pulmonary hypertension was prospectively defined as a tricuspid regurgitant Jet velocity (TFJV) of at least 2.5 m per second. Patients were followed for a mean of 18 months (6–24 months), and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 37.5 percent of patients (30/80). Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified age, female sex, deferasirox therapy, left ventricular mass index, pulmonary artery systolic pressure, reticulocytes, white-cell count, platelet count, lactate dehydrogenase (a marker of hemolysis), blood urea nitrogen, creatinine, uric acid and self-reported history of cardiovascular complication, billiary stones, retinopathy and acute chest syndrome, as significant independent correlates of pulmonary hypertension. The hemoglobin level, fetal hemoglobin level, hydroxyurea therapy and serum ferritin level were unrelated to pulmonary hypertension. Hazard rate for death according to the TFJV of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was associated with an increased risk of death (0.00 versus 2.54; P=0.998). Mortality rate in 24 months was 6.7% (2/30) for patients with TRJ velocity ≥ 2.5 m/sec versus 0.0% (0/50) for patients without pulmonary hypertension. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Large trials evaluating the effects of treatment for pulmonary hypertension in the sickle cell anemia population are indicated.

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TSP1-CD47 Signaling Modulates the Severity of Pulmonary Hypertension in a Mouse Model of Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.898.898 ◽

2011 ◽

Vol 118 (21) ◽

pp. 898-898

Author(s):

Enrico M Novelli ◽

Mingyi Yao ◽

Xiaojun Huang ◽

Jeffrey Baust ◽

Hunter Champion ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Right Ventricle ◽

Right Ventricular ◽

Sickle Cell ◽

Systolic Pressure ◽

Cell Disease ◽

C57bl Mice ◽

No Signaling

Abstract Abstract 898 In sickle cell disease (SCD), mutant hemoglobin S polymerizes when deoxygenated, driving red blood cell (RBC)-dependent vaso-occlusion and hemolysis. These processes lead to platelet and hemostatic activation, pulmonary hypertension (PH) and vascular disease. Transgenic-knockout sickle (BERK) mice that express exclusively human α- and βS-globins mimic SCD in humans by displaying reduced nitric oxide (NO) bioavailability, impaired NO-mediated vascular reactivity and PH. Recently, the platelet α-granule protein thrombospondin-1 (TSP1) was found to be elevated in the plasma of patients with SCD and to potently inhibit physiologic NO signaling, via binding to the cell surface receptor CD47. We hypothesized that blocking the TSP1-CD47 interaction may restore NO signaling and prevent PH in BERK mice. To test this hypothesis we conducted a transplantation experiment to explore the repopulating potential of BERK bone marrow (BM) in lethally myeloablated CD47KO recipients and the impact of the CD47 null milieu on the PH phenotype. We harvested the BM from 5–6 months old BERK mice and transplanted it into irradiated (10 Gy) 8–9 weeks old CD47KO mice (n=9). All recipients survived transplantation and were terminally evaluated 4 months post transplantation. Mice underwent blood sampling for determination of engraftment by hemoglobin electrophoresis, evaluation of endothelial dependent arterial vasodilation by myography, full pulmonary hemodynamic assessment and measurement of right ventricular hypertrophy (RVH) using the Fulton Index (ratio of ventricular weights (right ventricle/left ventricle including septum). The chimeras had 98.3% (SD 0.6%) hemoglobin S, thereby demonstrating full donor chimerism. Segments of thoracic aortas from the chimeras were mounted on a myograph system and exposed to acetylcholine, a physiologic vasodilator that stimulates endothelial nitric oxide synthase (eNOS) activation. Concentration-response curves showed that the arterial segments from chimeras that lacked tissue CD47 had improved endothelial-dependent vasodilation, as evaluated by % relaxation in response to acetylcholine, as compared to arterial segments from BERK mice (P < 0.05). Hemodynamic data showed that the tissue CD47KO chimeras had lower right ventricular end systolic pressure (RV ESP) as compared to BERK mice (22 vs. 31 mm Hg, p<0.05). Conversely, their RV ESP did not significantly differ from historical control C57BL/6 mice (22 vs. 20 mm Hg, NS, panel A). Measurement of RVH (Fulton Index) similarly revealed that the chimeras were protected from RVH (p<0.05, panel B). Thus, despite the presence of sickle RBC, the absence of the TSP1-CD47 signaling axis improved endothelial-eNOS-NO signaling and reduced pulmonary pressures and RVH responses. These data demonstrate that BM from BERK mice successfully engrafts CD47KO mice, and that in the absence of the TSP1-CD47 axis endothelial and vascular function improves and PH is ameliorated. We now plan to validate these results in controlled experiments where BM from BERK mice is transplanted in CD47KO and C57BL mice as controls. We expect that unlike C57BL mice transplanted with BERK BM, CD47KO mice will be protected from the vascular complications of SCD, including PH.Figurelegend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure.Figure. legend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure. Disclosures: Isenberg: Vasculox, Inc.: Equity Ownership.

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Effect of Hydroxyurea on Elevated Pulmonary Artery Pressures in Children with Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.4841.4841 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4841-4841

Author(s):

Farzana Pashankar ◽

Deepa Manwani ◽

Margaret Lee ◽

Nancy S. Green

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Laboratory Data ◽

Fetal Hemoglobin ◽

Total Daily Dose ◽

Cell Disease ◽

Biomarker Analysis ◽

Significant Change

Abstract Abstract 4841 Background: Pulmonary hypertension (PHT) is a significant complication of sickle cell disease. Studies in children report a 16–30% prevalence of elevated pulmonary artery pressures, as estimated by measurement of tricuspid regurgitant jet velocity (TRV) on echocardiography. The pathogenesis of elevated pulmonary artery pressures is multifactorial, with hemolysis induced endothelial dysfunction playing a major role. More recent studies highlight the role of inflammation in the pathogenesis. Hydroxyurea is a well established treatment for sickle cell disease. It acts primarily by induction of fetal hemoglobin, thereby reducing hemolysis, with possible additional effects on vascular and endothelial function. The aim of this study was to determine if early detection and treatment with hydroxyurea will decrease elevated pulmonary artery pressures in children with sickle cell disease. Methods: The study was conducted at 3 centers. Children with Hb SS and Hb Sb0 thalassemia between the ages of 5–21 years, with a screening echocardiogram showing a TRV ≥ 2.5 m/sec were identified. An echocardiogram was repeated to confirm elevated TRV. Subjects with persistent elevation of TRV ≥ 2.5 m/sec on repeat echocardiogram, were consented and started on hydroxyurea at 20 mg/kg/d with escalation to a maximum tolerated dose or a total daily dose of 30 mg/kg/d. Laboratory data and echocardiograms were repeated at 6 and 12 months to measure effect of hydroxyurea on TRV. Additionally blood and urine samples were also collected pre treatment, at 6 and 12 months post treatment for biomarker analysis, which will be performed later. Baseline and 6 month laboratory and echocardiogram data were compared using paired t test. Results: Twelve patients were enrolled. Mean age was 12.25 years (range 6–19 years) with a M:F ratio of 2:1. Average follow up is 11 months. Patients tolerated hydroxyurea well, and in 90% of patients the dose was escalated to 30 mg/kg/d. 1 patient achieved MTD at 20 mg/kg/d. Two patients went off study at 4 and 5 months respectively. As shown in Table 1, six months after starting hydroxyurea there was a significant increase in mean oxygen saturation, hemoglobin, mean corpuscular volume and fetal hemoglobin. There was a significant decrease in mean reticulocyte count, LDH and white blood cell count. There was no significant change in TRV six months after treatment with hydroxyurea. Conclusion: Hydroxyurea significantly decreased measures of hemolysis in children with sickle cell disease. Six months after treatment with hydroxyurea, there was no significant change in estimated pulmonary artery pressures measured on echocardiography. The study is ongoing to see if hydroxyurea affects pulmonary artery pressures with a longer duration of treatment. Disclosures: No relevant conflicts of interest to declare.

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Pulmonary Artery Occlusion Pressure May Overdiagnose Pulmonary Artery Hypertension in Sickle Cell Disease

CHEST Journal ◽

10.1378/chest.1113813 ◽

2011 ◽

Vol 140 (4) ◽

pp. 881A

Author(s):

Sunil Sharma ◽

Renuka Kadali ◽

Ramesh Daggubati ◽

Jimmy Efird ◽

Hadi Chohan ◽

...

Keyword(s):

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Pulmonary Artery Occlusion Pressure ◽

Artery Occlusion ◽

Pulmonary Artery Hypertension ◽

Occlusion Pressure ◽

Cell Disease

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Estimated pulmonary artery systolic pressure and sickle cell disease: a meta-analysis and systematic review

British Journal of Haematology ◽

10.1111/bjh.13447 ◽

2015 ◽

Vol 170 (3) ◽

pp. 416-424 ◽

Cited By ~ 21

Author(s):

Melissa C. Caughey ◽

Charles Poole ◽

Kenneth I. Ataga ◽

Alan L. Hinderliter

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Meta Analysis ◽

Systolic Pressure ◽

Pulmonary Artery Systolic Pressure ◽

Cell Disease

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Comparison between Automated Erythrocytopharesis (AECP) and Manual Exchange Transfusion (M-Ex)) in Reducing Hb-S and in Recovery of Acute Chest Syndrome and Other Acute Presentations of Sickle Cell Disease Patients

Blood ◽

10.1182/blood-2018-99-119785 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4928-4928

Author(s):

Said Yousuf Ahmed ◽

Sameh M. Saleh ◽

Mohamed Shefan Hameed ◽

Ahmed M. Ragheb ◽

Telal M. Abbas ◽

...

Keyword(s):

Saudi Arabia ◽

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Exchange Transfusion ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Hemoglobin S ◽

Artery Thrombosis ◽

Hb S

Abstract Background: Sickle Cell Disease represents a national health problem in Saudi Arabia with close to 150 thousands of the population are afflicted with the disease. Patients are frequently admitted with life threatening complications like Acute chest syndrome (ACS), Hyperhemolysis (HH), pneumonia, thromboembolism including pulmonary Artery Thrombosis (PAT) or severe protracted painful vasoocclusive crises (VOC). Rapid lowering of Hemoglobin S helps in reducing sickling and in alleviating such complications and allowing rapid recovery. Exchange transfusion is the fastest way to remove pathogenetic sickling red blood cells and reducing Hb S level to a safe level. It can be done manually (Mex) or via Automated Erythrocytopharesis machine (AECP). In this study we compared manual exchange to AECP in achieving the targeted lowering of Hb S and in accelerating clinical recovery. Patients and Methods: Patients included are sickle cell disease patients (HbSS, HbSC, Hb S/thal) admitted to the ER of a central Hospital. Indications of exchange were: acute chest syndrome, acute severe painful vaso-occlusive crises refractory to standard ER protocol of analgesia, stroke, priapism, Hyperhemolysis, and acute pulmonary embolism. P value of significance was calculated using student t-test comparing between median Hb S achieved after manual exchange vs AECP. To assess the rapidity of reversal of desaturation in acute chest syndrome patients, the cumulative incidence of reversal of desaturation and normalization of Oxygen saturation on room air were plotted against time at 0 time of the start of exchange, 2 hours,4 , 12, 24, 48 and 72 hours/discharge (D/C) Results: Table 1 shows clinic-biological characteristics of patients who underwent exchange transfusion. A total of 230 patients-admissions were registered between Dec 1. 2017 to July 27, 2018 for painful VOC to ER; 51 (32%) had clinical indications for exchange (ACS 25, Stroke / fits 1, priapism 1, pulmonary artery thrombosis 1, Hyperhemolysis with VOC (n:7) , VOC with HLH (n:1), and the remaining with "refractory" painful VOC with or without infection. One patient died immediately at the time of arrival to ER before starting any standard resuscitative measures . Exchange transfusion was indicated and done for 53 (23%); 12 (22,6%) AECP and the remaining (77.4%) had Manual Exchange. The median Hb S after manual exchange was 44 % (range 31-74%) which was unsatisfactory and way higher than the targeted level while Automated ECP reached down satisfactorily to a median of 31%(range 8%-50%) ; 67% of whom achieved it with only one session. No mortalities or major procedure related complication reported with manual or automated ECP. Procedurally, 3 patients needed 2 automated sessions and 1 patient used 2 kits for one session. Manual exchange could not achieve the target Hemoglobin S level below or around 30% due to logistic and technical difficulties and sometimes patients' refusal while Automated ECP reached to a mean Hb s level of 28%( range 8%-50%) and nearly two thirds (67%) reached to as low as 31% Hb S level with only one session of Automated ECP and was associated with rapid improvement of the oxygenation within the first 2 hours of the procedure. Conclusions: Erythrocytopharesis (Automated RBC exchange) is effective, quick and safe procedure that is life saving for many patients with ACS and is associated with less difficulties and complications if compared with the manual exchange. Because SCA is a national problem in Saudi Arabia and acute chest syndrome and other acute major complications comprehensively kill SCD patients, Automated Erythocytopharesis should be available nation-wide like dialysis machines at all large hospitals in all cities and should be distributed according to the prevalence of SCA in the area or location. Disclosures No relevant conflicts of interest to declare.

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