Systemic Blood Pressure Is Associated with Anemia and Placenta Growth Factor In Sickle Cell Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2644-2644 ◽  
Author(s):  
Payal C. Desai ◽  
Julia Brittain ◽  
Allison Deal ◽  
Susan Jones ◽  
Alan Hinderliter ◽  
...  

Abstract Abstract 2644 Introduction: The seventh report of the Joint National Committee (JNC 7) defines hypertension as blood pressure (BP) ≥ 140/90 and pre-hypertension as BP ≥ 120/80. Data from the National Health and Nutrition Examination Survey (NHANES) shows that 42% of African American patients over the age of 20 are classified as hypertensive. Previous studies in patients with sickle cell disease (SCD) have reported that systemic blood pressures (BP) are lower than age- and race-matched controls. The purpose of this study was to evaluate the clinical and laboratory factors associated with systolic and diastolic blood pressures in SCD. Methods: The data for this study was obtained from an ongoing study to determine the natural history of pulmonary hypertension in SCD. The first available systemic BP measurement for each patient was recorded, along with clinical and laboratory parameters. We evaluated associations between systolic and diastolic BP and 25 clinical and laboratory covariates using Spearman's correlation coefficient, and Wilcoxon Rank Sum tests for categorical covariates. Patients were stratified based on age and SCD genotype (SS, Sb0, SD vs. SC, Sb+). Blood pressures from our SCD patients were compared to median values obtained from the Cooperative Study of Sickle Cell Disease (CSSCD) using Wilcoxon Signed Rank tests. Results: Blood pressures were evaluated in 153 separate patients (SS = 115, SC = 18, Sb0 = 10, Sb+ = 9, SD =1), with a median age of 37 years (range 18 – 71 years). Thirty two (21%) patients had a known history of hypertension and 38 (25%) patients were on at least one antihypertensive medication for either hypertension or proteinuria. The mean (STD) systolic and diastolic BP for the patients with SS, Sb0 thalassemia, and SD (N=126) were 122 mm Hg (±15) and 69 mm Hg (±10), respectively; and the median systolic and diastolic BP for patients with SC and Sb+ thalassemia (N=27) were 131 mm Hg (±12) and 75 mm Hg (±13), respectively. We observed significant correlations between systolic BP and age (r=0.36, p=<.0001) and body mass index (BMI) (r=0.42, p=<.0001). We also observed significant correlations between SBP and hemoglobin (r=0.20, p=0.01); reticulocyte count (r=-0.29, p=0.0003); lactate dehydrogenase (r= −0.18, p=0.02); total bilirubin (r=−0.28, p=0.0008); indirect bilirubin (r=−0.28, p=0.001); white blood count (WBC) (r=−0.24, p=0.0023); absolute neutrophil count (r=−0.24, p=0.005); and placenta growth factor (PIGF) (r=−0.36, p=0.02). When compared to patients from the CSSCD, systolic BP was significantly higher in females ages 25–34 and 35–44, and in males ages 25–34 and 35–44 (Table 1). Conclusion: The low systemic BP in SCD patients may be related to their lower BMI, combined with biologic factors such as anemia, hemolysis as well as increased levels of the vascular endothelial growth factor (VEGF) family member, placenta growth factor. The higher BP in our patient population compared to values in the CSSCD may be related to differences in BMI, degree of anemia, and levels of PlGF. With the increasing survival of SCD patients, studies are required to determine the appropriate BP levels to initiate anti-hypertensive therapy. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Kaitlin Strumph ◽  
Michael Hafeman ◽  
Saritha Ranabothu ◽  
William Gomes ◽  
Steven Benitez ◽  
...  

Background: Strokes and silent cerebral infarcts (SCIs) lead to significant morbidity and mortality in children with sickle cell disease (SCD). Discovering modifiable risk factors is paramount to decreasing the incidence and progression of these devastating cerebrovascular outcomes. Higher systolic blood pressures have previously been shown to increase risk for stroke and SCIs however patients with SCD often have lower clinic blood pressures than the general population. 24 hour ambulatory blood pressure monitoring (ABPM) allows for more robust examination of blood pressure values. Previous studies have investigated associations with abnormal ABPM parameters and end-organ dysfunction, mainly SCD nephropathy. Associations with cerebrovascular events have not yet been investigated. This study aimed to determine if there is an association between blood pressure abnormalities on ABPM with stroke and silent cerebral infarcts. Methods: A cross-sectional study was performed. Children with SCD were enrolled and completed a 24-hour ABPM. Of this cohort, children with HbSS or HbSβ0 with a documented MRI brain within a year of the ABPM were included in the analysis. SCIs were defined as discrete, infarct-like T2 hyperintense lesions measuring at least 3mm in diameter on two orthogonal imaging sequences. Bivariate analyses were performed to identify the association between ambulatory blood pressure parameters with cerebrovascular outcomes specifically SCI or history of stroke. Results: A final cohort of 42 children with a median age of 13 years (10, 17) was included in the analysis. Seven (17%) had a history of stroke, 7 (17%) had documented SCIs, and the remaining 28 (67%) had no history of stroke or SCIs. Masked hypertension was seen in 5% of subjects and nocturnal hypertension was seen in 25%. Abnormal overnight dipping noted in 85% of subjects. The presence of nocturnal hypertension was significantly higher in the SCI/stroke group (55% vs 12%, p = 0.01). Sensitivity analyses were performed to determine if blood pressure abnormalities continued to show an association with cerebrovascular findings when stroke patients were removed. Nocturnal hypertension remained significantly associated with the presence of SCIs (p = 0.006). The median systolic load (percentage of blood pressures above the 95th percentile on ABPM), while below the cutoff for hypertension in both cohorts, was higher in the stroke/SCI group (18.6) compared to the group without SCIs or stroke (6.1), but did not meet statistical significance (p = 0.07). Conclusions: This study reveals an association between nocturnal hypertension and a higher prevalence of SCI and stroke in children with SCD. Our findings also confirm the high prevalence of nocturnal hypertension and impairment of nocturnal dipping seen in this population. Adequately powered, prospective cohorts of ABPM in SCD patients are needed to further evaluate causation between nocturnal hypertension and cerebrovascular outcomes. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2014-2020 ◽  
Author(s):  
Julia E. Brittain ◽  
Ben Hulkower ◽  
Susan K. Jones ◽  
Dell Strayhorn ◽  
Laura De Castro ◽  
...  

Abstract Placenta growth factor (PlGF) is released by immature erythrocytes and is elevated in sickle cell disease (SCD). Previous data generated in vitro suggest that PlGF may play a role in the pathophysiology of SCD-associated pulmonary hypertension (PHT) by inducing the release of the vasoconstrictor, endothelin-1. In this cross-sectional study of 74 patients with SCD, we confirm that PlGF is significantly elevated in SCD compared with healthy control subjects. We found significantly higher levels of PlGF in SCD patients with PHT but observed no association of PlGF with the frequency of acute pain episodes or history of acute chest syndrome. The observed correlation between PlGF and various measures of red cell destruction suggests that hemolysis, and the resultant erythropoietic response, results in the up-regulation of PlGF. Although relatively specific, PlGF, as well as N-terminal pro-brain natriuretic peptide and soluble vascular cell adhesion molecule, has low predictive accuracy for the presence of PHT. Prospective studies are required to conclusively define the contribution of PlGF to the pathogenesis of PHT and other hemolytic complications in SCD.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3787-3787
Author(s):  
Ashley J. Duits ◽  
John B. Schnog

Abstract Angiogenesis plays a central role in neovascular processes. In sickle cell patients neovascularization is considered a common feature that is associated with complications such as retinopathy and cerebrovascular disease. Several studies have reported increased vascular growth factor levels such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in small groups of patients. Recently the angiopoietin/Tie2 system has been shown to be of major importance in vessel maturation. In order to thoroughly characterize vascular growth factor profiles in sickle cell patients we analyzed serum levels of VEGF, PlGF, Angiopoietin-1, Angiopoietin-2, Tie-2 and erythropoietin (EPO) during the asymptomatic phase as well as during painful crises in HbSS patients (n=42) and compared these to levels in HbAA controls (n=30). Also, levels were compared between patients with and without a history of acute vaso-occlusive complications the year prior to sample collection. Serum Angiopoietin-2, Tie-2 and EPO levels were significantly higher in sickle cell patients as compared to controls (p&lt;0.01, p=0.03 and p&lt;0.01 respectively), whereas PlGF and VEGF serum levels were similar between patients and controls (p= 0.21 and p=0.5). Only Angiopoietin-2 and EPO serum levels were significantly increased in sickle cell patients during acute vaso-occlusive crises as compared to levels in asymptomatic patients (p&lt;0.01 and p=0.03 respectively). No differences were detected in measured parameters between patients with a history of acute vaso-occlusive complications as compared to patients without acute vaso-occlusive complications in the preceding year. Our results show a specific pattern of angiopoietins in sickle cell patients. Considering the importance of endothelial cell activation in sickle cell disease and the regulation of endothelial cell survival and blood vessel maturation by the angiopoietin/Tie-2 system, further analysis of angiogenesis in sickle cell disease is warranted.


Blood ◽  
2010 ◽  
Vol 116 (1) ◽  
pp. 109-112 ◽  
Author(s):  
Nambirajan Sundaram ◽  
Anitaben Tailor ◽  
Laurel Mendelsohn ◽  
Janaka Wansapura ◽  
Xunde Wang ◽  
...  

Abstract Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial. This trial was registered at http://clinicaltrials.gov as #NCT00011648.


Blood Reviews ◽  
2018 ◽  
Vol 32 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Vijay K. Kalra ◽  
Shuxiao Zhang ◽  
Punam Malik ◽  
Stanley M. Tahara

2012 ◽  
Vol 87 (10) ◽  
pp. E65-E68 ◽  
Author(s):  
Payal C. Desai ◽  
Allison M. Deal ◽  
Julia E. Brittain ◽  
Susan Jones ◽  
Alan Hinderliter ◽  
...  

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1129-1138 ◽  
Author(s):  
Nitin Patel ◽  
Caryn S. Gonsalves ◽  
Minyang Yang ◽  
Punam Malik ◽  
Vijay K. Kalra

Abstract Individuals with sickle cell disease (SCD) have increased inflammation, a high incidence of airway hyperreactivity (AH), and increased circulating leukotrienes (LT). We show that expression of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP), key catalytic molecules in the LT pathway, were significantly increased in peripheral blood mononuclear cells (MNCs) in patients with SCD, compared with healthy controls. Placenta growth factor (PlGF), elaborated from erythroid cells, activated MNC and THP-1 monocytic cells to induce LT production. PlGF-mediated increased FLAP mRNA expression occurred via activation of phosphoinositide-3 (PI-3) kinase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and hypoxia inducible factor-1α (HIF-1α). HIF-1α small interfering RNA (siRNA) reduced PlGF-induced FLAP expression. FLAP promoter-driven luciferase constructs demonstrated that PlGF-mediated luciferase induction was abrogated upon mutation of HIF-1α response element (HRE), but not the nuclear factor-κB (NF-κB) site in the FLAP promoter; a finding confirmed by chromatin immunoprecipitation (ChIP) analysis. PlGF also increased HIF-1α binding to the HRE in the FLAP promoter. Therefore, it is likely that the intrinsically elevated levels of PlGF in SCD subjects contribute to increased LT, which in turn, mediate both inflammation and AH. Herein, we identify a mechanism of increased LT in SCD and show HIF-1α as a hypoxia-independent target of PlGF. These studies provide new avenues to ameliorate these complications.


Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1506-1514 ◽  
Author(s):  
Natalya Perelman ◽  
Suresh K. Selvaraj ◽  
Sandeep Batra ◽  
Lori R. Luck ◽  
Anat Erdreich-Epstein ◽  
...  

Abstract Sickle cell disease (SCD) results in chronic hypoxia and secondarily increased erythropoietin concentrations. Leukocytosis and activated monocytes are also observed in SCD in absence of infection or vaso-occlusion (steady state), the reasons for which are unknown. We found that erythroid cells produced placenta growth factor (PlGF), an angiogenic growth factor belonging to the vascular endothelial growth factor (VEGF) family, and its expression was induced in bone marrow CD34+ progenitor cells in the presence of erythropoietin. Furthermore, the steady state circulating PlGF levels in subjects with severe SCD (at least 3 vaso-occlusive crises [VOCs] per year) were 18.5 ± 1.2 pg/mL (n = 9) compared with 15.5 ± 1.2 pg/mL (n = 13) in those with mild SCD (fewer than 3 VOCs per year) and 11.3 ± 0.7 pg/mL (n = 9) in healthy controls (P &lt; .05), suggesting a correlation between PlGF levels and SCD severity. In addition, PlGF significantly increased mRNA levels of the proinflammatory cytochemokines interleukin-1β, interleukin-8, monocyte chemoattractant protein-1, and VEGF in peripheral blood mononuclear cells (MNCs) of healthy subjects (n = 4; P &lt; .05). Expression of these same cytochemokines was significantly increased in MNCs from subjects with SCD at steady state (n = 14), compared with healthy controls. Of the leukocyte subfractions, PlGF stimulated monocyte chemotaxis (P &lt; .05, n = 3). Taken together, these data show for the first time that erythroid cells intrinsically release a factor that can directly activate monocytes to increase inflammation. The baseline inflammation seen in SCD has always been attributed to sequelae secondary to the sickling phenomenon. We show that PlGF contributes to the inflammation observed in SCD and increases the incidence of vaso-occlusive events.


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