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

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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Normal Pulmonary Artery Pressure in Sickle Cell Patient with Severe Iron Deficiency Anemia.

Blood ◽

10.1182/blood.v108.11.3785.3785 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3785-3785

Author(s):

Oswaldo Castro ◽

Adriana Medina ◽

Peter Gaskin

Keyword(s):

Sickle Cell Disease ◽

Iron Deficiency ◽

Pulmonary Artery ◽

Sickle Cell ◽

Serum Bilirubin ◽

Systolic Pressure ◽

Deficiency Anemia ◽

Pulmonary Artery Systolic Pressure ◽

Cell Disease ◽

Iron Deficient

Abstract One-third of adults with sickle cell disease (SCD) have echocardiographic (ECHO) evidence of pulmonary hypertension (PHTN), a complication associated with early mortality. Because the pulmonary artery pressures in most SCD patients with PHTN are only mildly elevated, the question arises whether such increases are primarily a reflection of the high cardiac output state that accompanies the anemia. Recently we treated a 45 year-old woman with homozygous sickle-cell disease and profound iron deficiency due to heavy menstrual flow. Two ECHOs were done while she was severely iron deficient (Hb 5 g/dl, MCV 57 fl, reticulocytes 72,407/mm3, serum bilirubin 0.5 mg/dl, iron 29 mcg/dl, transferrin 376 mg/dl, and ferritin 3.6 ng/ml). Her pulmonary artery systolic pressure (PAs) was calculated from the tricuspid regurgitant jet velocity (TRV) using the Bernoullie equation: 4(TRV3) + central venous pressure (assumed at 10 mm Hg). The PAs was normal, 24 mm Hg, even though the patient also had M-mode evidence of left ventricular diastolic dysfunction and a small pericardial effusion. Treatment with intravenous iron and red cell transfusion partially improved her iron deficiency and anemia (Hb 7 g/dl, MCV 67 fl, serum bilirubin 0.7 mg/dl, iron 54 mcg/dl, transferrin 322 mg/dl, and ferritin 33.9 ng/ml) but also increased her hemolytic rate: though LDH data are unavailable, the reticulocyte count rose to 117,900/mm3. Repeat ECHO exams at this time showed that her pulmonary artery systolic pressures increased to 35–36 mm Hg. These values are at or near the lower range of pulmonary artery systolic pressures (36–70 mm Hg) measured in SCD patients in whom PHTN was diagnosed at cardiac catheterization. The figure compares hematologic values, and pulmonary artery systolic pressure in our iron deficient SS patient at baseline and during treatment. This experience, though anecdotal, suggests that the PHTN in SCD is unrelated to the anemia per se and, by implication, also unrelated to the high cardiac output. The patient’s mild pulmonary systolic hypertension actually developed with improvement of her anemia. Our hypothesis is that when the patient’s iron deficiency was most severe, the low MCHC decreased Hb S polymerization and decreased hemolysis, as in other iron deficient SCD patients. Her relatively low hemolytic rate may have prevented the mild PHTN, which developed once treatment improved her iron deficiency but increased hemolysis. Our hypothesis is consistent also with an emerging new paradigm in sickle cell disease pathophysiology: a strong link between hemolysis-related nitric oxide system (NO) dysfunction and risks for pulmonary hypertension, leg ulcers, priapism, and death. In this context it is interesting that iron deficiency anemia up-regulates vascular nitric oxide synthase in animals. In humans iron deficiency increases NO production even in the absence of anemia. Hence, this patient’s iron depletion may have contributed to the maintenance of her low pulmonary pressures also by a direct NO-mediated vascular effect. Figure Figure

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Diastolic Dysfunction Is an Independent Risk Factor for Death in Patients with Sickle Cell Disease.

Blood ◽

10.1182/blood.v106.11.206.206 ◽

2005 ◽

Vol 106 (11) ◽

pp. 206-206 ◽

Cited By ~ 1

Author(s):

Vandana Sachdev ◽

Roberto F. Machado ◽

Yukitaka Shizukudu ◽

Yesoda Rao ◽

Stanislav Sidenko ◽

...

Keyword(s):

Risk Factors ◽

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Pulmonary Artery ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Sickle Cell ◽

Systolic Pressure ◽

Pulmonary Artery Systolic Pressure ◽

Cell Disease

Abstract Background. Pulmonary hypertension, defined by an elevated pulmonary artery systolic pressure measured by Doppler-echocardiogram, has been identified as the major predictor of death in the adult sickle cell disease population. While diastolic dysfunction is also observed in this population, the prevalence in unselected patients, the association with high pulmonary artery systolic pressure, and the attributable mortality remain unknown. Methods. Diastolic function parameters, pulmonary artery systolic pressures and right and left ventricular size and function were measured prospectively in 215 subjects with sickle cell disease. Associations between these parameters, lab and echocardiographic variables and prospective mortality were determined. Results. Diastolic dysfunction, measured by conventional and tissue-Doppler echocardiography, was present in 19% of patients with sickle cell disease. Diastolic dysfunction and pulmonary hypertension were both present in approximately 11% of patients and diastolic dysfunction accounted for approximately 10–20% of the variability in tricuspid regurgitant jet velocity. Importantly, Cox Proportional Hazards analysis revealed that diastolic dysfunction, as reflected by low E/A ratio, was associated with prospective mortality with a risk ratio of 1.9 (95%CI 1.0 to 3.7; p=0.028), even after adjustment for tricuspid regurgitant jet velocity. While pulmonary hypertension remained the dominant determinant of mortality risk, even after adjustment for measures of diastolic function (adjusted rate ratio of 5.3; 95% CI= 1.9 to15.0; p<0.001), the risk was additive such that patients with both risk factors had an odds ratio for death of 10.1 (95% CI= 3.2 to 31.9; p<0.001). Conclusions. Diastolic dysfunction and pulmonary hypertension due to other causes each contribute independently to prospective mortality in patients with sickle cell disease. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of Doppler-echocardiographic screening of adult patients with sickle cell disease to identify individuals at high risk of death for intensified therapy. Figure Figure

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Efficacy of Allogeneic Hematopoietic Cell Transplantation (HCT) in Sickle Cell Disease: Results of a Systematic Review/Meta-Analysis

Blood ◽

10.1182/blood-2019-124955 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2106-2106

Author(s):

Madiha Iqbal ◽

Tea Reljic ◽

Ernesto Ayala ◽

Hemant S. Murthy ◽

Ambuj Kumar ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Clinical Outcomes ◽

Sickle Cell ◽

Pediatric Patients ◽

Medical Literature ◽

Meta Analysis ◽

Adult Patients ◽

Cell Disease ◽

Allogeneic Hct

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy which affects over 300,000 children born each year worldwide. In spite of improvement in supportive care in recent years, there is still a lack of effective treatment options. SCD leads to debilitating and cyclic episodes of erythrocyte sickling with progressive organ injury, contributing to lifetime morbidity and shortened life expectancy. Allogeneic HCT (allo-HCT) is a potentially curative therapy for SCD because engraftment is associated with resolution of the clinical phenotype of the disease and abrogation of its complications. Medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated the efficacy of allo-HCT in the adult population. Here, we conduct a systematic review/meta-analysis to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in children and adults. Materials and methods: We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane library on July 3rd, 2019. We extracted data on clinical outcomes related to benefits (overall [OS] and disease free/event free survival [EFS/DFS]) and harms (non-relapse mortality [NRM] and graft failure [GF]), independently by two authors. Our search strategy identified 1001 references but only 30 studies (n= 1995 patients) were included in this systematic review/meta-analysis. We also performed a sub analysis on clinical outcomes for studies that included only pediatric patients (defined as <18 years) and those in patients ≥18 years of age. Results: Median age for patients enrolled in all the studies was at 10 years. Recurrent veno-occlusive crises represented the most common indication for allo-HCT followed by acute chest syndrome and stroke; nevertheless, most patients had more than one indication. Matched related donors (MRD) were the most common donor source (93%). Bone marrow was the most common source of hematopoietic stem cells (77%). Majority of patients underwent conditioning with myeloablative regimens (77%). Pooled OS rates (n=29 studies, 1681 patients) after allogeneic HCT was 95% (95%CI=93-96%) with low heterogeneity (I2=6.4%) among included studies (Figure 1). Pooled EFS/DFS rates (n=29 studies, 1894 patients) post-allografting was 90% (95%CI=87-93%) with moderate heterogeneity (I2=54%). Pooled NRM rates from 30 studies (1995 patients) was 4% (95%CI=2-6%) with low heterogeneity (I2=29.4%). Pooled GF rates from 28 studies (1851 patients) was 4% (95%CI=2-6%) with moderate heterogeneity (I2=55%). A subset analysis specifically for pediatric patients (n= 11 studies, 1009 patients, median age at 9.7 years) showed a pooled OS rate of 96% (95%CI=94-97%) with low heterogeneity (I2=0%); and for adult patients (n=3 studies, 51 patients, median age at 33.4 years) the pooled OS was 94% (95%CI=80-100%) with moderate heterogeneity (I2=52%). Pooled EFS/DFS for pediatric patients (n= 11 studies, 1009 patients) was at 89 %( 95%CI=84-93%) with moderate heterogeneity (I2=55.1%); and for adult patients (n=2 studies, 30 patients) was at 95% (95%CI=83-100%) with high heterogeneity (I2=96.5%). Pooled NRM from 10 studies with pediatric patients (281 patients) was at 6 % (95%CI=3-10%) with low heterogeneity (I2=0%); and from 3 studies with adult patients (51 patients) was at 1% (95%CI=0-7%) with low heterogeneity (I2=15.1%). Pooled GF from 10 studies with pediatric patients (281 patients) was at 3 % (95%CI=1-7%) with moderate heterogeneity (I2=40%); and from 2 studies with adult patients (30 patients) was at 5% (95%CI=0-17%) with high heterogeneity (I2=95.4%). Conclusions: The results of our systematic review/meta-analysis show excellent OS, EFS/DFS in children and adults undergoing allo-HCT with pooled OS rates exceeding 90%. The main limitation to offering an allo-HCT in SCD remains the availability of a suitable donor as 85% of patients meeting criteria do not have a MRD. We anticipate that with emergence of haploidentical transplantation the number of allo-HCT will increase in the future. GF remains a significant concern in this population and future studies should focus on novel immune suppression strategies to help reduce GF. Disclosures Kharfan-Dabaja: Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy.

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Sickle cell disease, sickle trait and the risk for venous thromboembolism: a systematic review and meta-analysis

Thrombosis Journal ◽

10.1186/s12959-018-0179-z ◽

2018 ◽

Vol 16 (1) ◽

Cited By ~ 13

Author(s):

Jean Jacques Noubiap ◽

Mazou N. Temgoua ◽

Ronni Tankeu ◽

Joel Noutakdie Tochie ◽

Ambroise Wonkam ◽

...

Keyword(s):

Systematic Review ◽

Venous Thromboembolism ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Meta Analysis ◽

Cell Disease

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Iron stores in pregnant women with sickle cell disease: a protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2018-026497 ◽

2019 ◽

Vol 9 (9) ◽

pp. e026497 ◽

Cited By ~ 2

Author(s):

Desmond Aroke ◽

Benjamin Momo Kadia ◽

Tsi Njim

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Iron Deficiency ◽

Pregnant Women ◽

Sickle Cell ◽

Iron Deficiency Anaemia ◽

Meta Analysis ◽

Cochrane Library ◽

Cell Disease ◽

Deficiency Anaemia

IntroductionSickle cell disease (SCD) is the most common inherited disease worldwide. The greatest disease burden is seen in sub-Saharan Africa. Early diagnosis and improved care of people living with SCD have led to an increase in the number of women with SCD reaching the reproductive age. Iron deficiency anaemia remains the most common cause of anaemia in pregnancy, affecting 51%–63% of pregnancies in Africa. However, the unavailability of guidelines on supplementation of iron in this pregnant subpopulation often leaves clinicians in a fix. We propose to conduct the first systematic review and possibly a meta-analysis on the prevalence, associated factors and maternal/fetal outcomes of iron deficiency anaemia among pregnant women with SCD.Methods and analysisWe will search the following electronic databases for studies on the iron status of pregnant women with SCD: PubMed, MEDLINE, EMBASE, Google Scholar, African Journals Online, African Index Medicus, Popline and the Cochrane Library. After the selection of eligible studies from the search output, review of full text, data extraction and data synthesis will be performed. Studies obtained from the review shall be evaluated for quality, risk of bias and heterogeneity. Appropriate statistical methods shall be used to pool prevalence estimates for matching studies globally and in subpopulations. This protocol has been reported as per the 2015 guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.Ethics and disseminationThere is no requirement for ethical approval as the proposed study will use published data. The findings of this study will be published in a peer-reviewed journal and will be presented at conferences.Trial registration numberCRD42018109803.

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Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis

Blood ◽

10.1182/blood-2014-11-607317 ◽

2015 ◽

Vol 125 (21) ◽

pp. 3316-3325 ◽

Cited By ~ 84

Author(s):

E. Oteng-Ntim ◽

D. Meeks ◽

P. T. Seed ◽

L. Webster ◽

J. Howard ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Pregnant Women ◽

Sickle Cell ◽

Meta Analysis ◽

Perinatal Outcomes ◽

Cell Disease

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Pulmonary Artery Hypertension in Children with Sickle Cell Disease: Is Chronic Transfusion Protective?.

Blood ◽

10.1182/blood.v108.11.1210.1210 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1210-1210

Author(s):

Kristin Joyce ◽

Craig Sable ◽

Brenda Martin ◽

Caterina P. Minniti

Keyword(s):

Blood Pressure ◽

Sickle Cell Disease ◽

Pulmonary Artery ◽

Sickle Cell ◽

Vena Cava ◽

Systolic Pressure ◽

Pulmonary Artery Hypertension ◽

Right Atrial ◽

Cell Disease ◽

Systemic Pressure

Abstract Background Studies in adults with sickle cell disease (SCD) suggest an increased prevalence of pulmonary artery hypertension (PAHTN) with associated increased morbidity and mortality. These findings have not been validated in children. Methods The digital echocardiography (echo) database at Children’s National Medical Center was searched for echos performed on patients with SCD from 1999 to 2006. Patients on chronic transfusions undergo regularly scheduled studies; other patients are referred for a variety of indications including murmurs, cardiomegaly, hypoxia, chest pain, and respiratory distress. Echo reports and digital images were reviewed and the following information was recorded: Chronic transfusion, date of study, blood pressure, cardiac structure, ventricular function, presence of tricuspid regurgitation (TR), and velocity of TR. The estimated right ventricular (RV) pressure was calculated using modified Bernoulli equation (adding 5 mm Hg for estimated right atrial pressure if the inferior vena cava was not dilated). The ratio of RV systolic pressure to systemic systolic blood pressure was calculated. All studies with TR velocities of < 3 m/sec or a RV to systemic ratio of less than one third were considered to be normal. Results: The SCD database has 1060 patients ages 0 to 21 years; 166 echos were performed in 104 routine patients and 72 echos in 47 children while on chronic transfusions. TR could be measured in 56 routine and 20 transfusion studies. Comorbidities were present in 11 studies (7 patients) in the routine group: structural heart disease (4 ), constrictive pericarditis (1 ), significant obstructive airway disease (1 ), and pneumonia requiring mechanical ventilation (1 ). There were no comorbidities in the transfusion group. The mean TR velocity, estimated RV pressure, and RV to systemic pressure ratios were higher in the routine group; however when patients with comorbidities were removed, this difference was no longer statistically significant. Routine (n=55) Routine/no comorbidities (n=44) Transfused (n=20) 1p = 0.01 transfused vs. routine; p = 0.11 transfused vs. routine/no comorbidities 2p < 0.01 transfused vs. routine; p = 0.09 transfused vs. routine no comorbidities 3p = 0.01 transfused vs. routine; p = 0.13 transfused vs. routine/no comorbidities 1TR velocity (m/sec) 2.54 ± 0.48 2.30 ± 0.30 2.30 ± 0.30 Range 1.67–3.93 Range 1.67–3.19 Range 1.70–2.76 2RV pressure (mm Hg) 31.8 ±10.5 29.2 ± 6.6 26.5 ± 5.6 Range 16.2–67.8 Range 16.2–45.7 Range 16.6–36.4 3RV/systemic pressure ratio 0.29 ± 0.11 0.26 ± 0.064 0.23 ± 0.065 Range 0.16–0.78 Range 0.16–0.41 Range 0.14–0.38 There were 6 routine studies (2 when patients with comorbidities were removed) and no transfusion studies with a TR velocity above 3.0 m/sec. There were 23 routine studies (18 when patients with comorbidities removed) and 6 transfusion studies with a TR velocity between 2.5 and 3.0 m/sec. The ratio of RV to systemic pressure was greater than one third in 11 routine patients (5 when patients with comorbidities were removed) and 1 transfusion patient. Conclusions PAHTN is present in a small number of children with SCD and may be exacerbated by other medical problems. Chronic transfusion may be protective against PAHTN. Prospective analysis of this population is warranted.

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