scholarly journals EXPRESS: Murine models of sickle cell disease and beta-thalassemia demonstrate pulmonary hypertension with distinctive features.

2021 ◽  
pp. 204589402110559
Author(s):  
Paul W Buehler ◽  
Delaney Swindle ◽  
David Pak ◽  
Mehdi A Fini ◽  
Kathryn Hassell ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell ◽  
Transferrin Saturation ◽  
Cardiac Mechanics ◽  
Beta Thalassemia ◽  
Murine Models ◽  
Thalassemia Intermedia ◽  
Cellular Iron ◽  
And Function ◽  
Genetically Determined

Sickle cell anemia (SCA) and β-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension (PH). The etiologies responsible for the associated development of PH in both diseases are multi-factorial with extensive mechanistic contributors described. Both SCA and β-thalassemia intermedia present with intra and extravascular hemolysis, and because SCA and β-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the PH phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of SCA PH patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study we hypothesized that a common pathophysiology would characterize the PH phenotype in SCA and β-thalassemia intermedia murine models, but because unlike SCA, β-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, there may be differences as well. Herein we describe common and divergent features of PH in aged Berk-ss (SCA) and Hbbth/3+ (intermediate β-thalassemia) mice and suggest translational utility as proof-of-concept models to study PH therapeutics specific to genetic anemias.

In Vitro and In Vivo Antioxidant Effect of Fermented Papaya Preparation (FPP) on Blood Cells of Beta-Thalassaemia Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1766-1766
Author(s):  
Eitan Fibach ◽  
Johnny Amer ◽  
Ada Goldfarb ◽  
Eliezer Rachmilewitz
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Peripheral Blood ◽  
Thalassemia Major ◽  
Oxidative Status ◽  
Beta Thalassemia ◽  
Thalassemia Intermedia

Abstract In sickle cell anemia (SCD) and thalassemia, although the basic lesions are mutations in the globin genes, the pathophysiology involves oxidative stress-mediated cell damage in the bone marrow (ineffective erythropoiesis due to apoptosis of early erythroid precursors) and in the peripheral blood (chronic hemolysis of mature RBC). In addition, some patients develop thromboembolic complications and recurrent bacterial infections, the etiology of which is related at least in part, to documented oxidative stress in platelets and neutrophils (PMN), respectively. To study the presence and the role of oxidative stress in thalassemia and SCD, we adapted flow cytometry techniques for measuring the generation of Reactive Oxygen Species (ROS), the content of reduced glutathione (GSH), membrane lipid peroxidation and externalization of phosphatidylserine (PS) moieties in RBC, platelets and PMN. Cells derived from the peripheral blood of patients with beta-thalassemia major, intermedia or SCD showed increased oxidative status (increased ROS, lipid peroxidation and PS externalization, and decreased GSH) compared with their normal counterparts. Incubating fresh blood samples from patients with thalassemia major and thalassemia intermedia with 10 mg/ml FPP for 16 hours at 37oC reduced the oxidative status of RBC as well as platelets and PMN. Experiments carried out in normal and thalassemic mice (Th3/+, a mouse model of human beta-thalassemia intermedia demonstrated that mice treated for one week with 10 mg/ml FPP (dissolved in the drinking water) had reduced oxidative stress compared to control mice. The in-vivo effect of FPP was tested on 9 patients with beta-thalassemia (6 - major and 3 - intermedia) treated with 3 gr FPP per os three times a day for 12–15 weeks. Following the treatment, the ROS in RBC, platelets and PMN decreased and the GSH increased in all patients (see table). Six of these patients responded by a modest increase in RBC, reticulocytes and hemoglobin levels. These results suggest that FPP may have an important clinical efficacy as an antioxidant in thalassemia and sickle cell anemia. The in vivo effect of FPP treatment of beta-thalassemia patients Baseline After treatment n Mean ± SE Mean ± SE P-value* * Paired samples t-test RBC 9 324.07 ± 29.19 209.55 ± 23.65 0.001 ROS Platelets 9 223.73 ± 26.49 109.11 ± 8.71 0.001 PMN 9 222.72 ± 46.42 117.61 ± 8.98 0.045 RBC 9 55.37 ± 5.37 94.88 ± 3.71 0.001 GSH Platelets 9 59.41 ± 4.98 97.55 ± 5.26 <0.0001 PMN 9 58.29 ± 5.35 90.06 ± 5.87 0.005

Association of Pulmonary Hypertension with Sickle Cell Disease Subtypes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4824-4824
Author(s):  
Alice J. Cohen ◽  
Chaim Tuckman-Vernon
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Doppler Echocardiography ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Hemoglobin C ◽  
Baseline Hemoglobin

Abstract Pulmonary hypertension (PH) is a common complication of sickle cell disease (SD) and a significant cause of morbidity and mortality. PH, measured by Doppler echocardiography and defined as a tricuspid regurgitant jet velocity (TRV) &gt; 2.5 m per second (m/s), is hypothesized to be related to the chronic hemolytic anemia of SD, but causality is unproven. If so, the presence of hemoglobin C, which reduces hemolysis, would be expected to have a reduced likelihood of PH. This study reviewed the prevalence of PH in 3 categories of patients with SD: homozygous S (SS), sickle-beta thalassemia (SB), and SC. Methods: Sickle cell disease patients registered at a state funded community comprehensive care adult sickle cell center were routinely screened for PH by Doppler echocardiography. The presence of PH, the incidence of a related complication, acute chest syndrome (ACS), and baseline hemoglobin (hgb) were reviewed. Results: 16 patients with SC type, 30 with SS and 39 with SB disease underwent screening. The prevalence of PH, ACS and hgb are listed in the table below. Conclusion: SC patients have PH and ACS similar to patients with SS and SB patients. These patients have higher baseline hemoglobin and may have hyperviscosity as a cause of PH and ACS as opposed to hemolytic anemia. Further study of PH and ACS in SC patients is warranted. SC SS SB p value PH 6/16 (38%) 12/40 (40%) 11/39 (28%) p= NS ACS 7/16 (44%) 10/30 (33%) 19/39 (49%) p=NS PH + ACS 4/16 (25%) 5/30 (17%) 4/39 (10%) p=NS ACS in PH patients 4/6 (67%) 5/12 (42%) 4/11 (36%) p-=NS Hgb 10.8 7.89 8.57 p=0.000

Placental Growth Factor Is Elevated in Patients with Sickle Cell Disease and Associated with Pulmonary Hypertension, Hemolysis, Inflammation, Iron Overload, and Hepatic Dysfunction.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1531-1531
Author(s):  
Laurel Mendelsohn ◽  
Anitaben Tailor ◽  
Gregory J Kato
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Hepatic Dysfunction ◽  
Transferrin Saturation ◽  
Placental Growth Factor ◽  
Cell Disease ◽  
Pulmonary Pressure

Abstract Abstract 1531 Poster Board I-554 Placental Growth Factor (PlGF) is a functional cytokine in the vascular endothelial growth factor (VEGF) family that generally promotes angiogenesis, depending on the specific context, and can also promote atherogenesis. Produced in erythroid cells, its level in patients with sickle cell disease (SCD) has been previously related to the rate of erythropoiesis. We evaluated PlGF plasma levels in SCD patients by ELISA, and related it to biomarkers of pulmonary hypertension (PH), an emerging and serious complication of SCD linked to early mortality. We find that PlGF levels are significantly higher in SCD (n=95) than healthy African American control subjects (n=19) (median 16.6 vs. 2.1 pg/mL, p<0.001). PlGF levels were higher in SCD patients with elevated pulmonary pressure (normal pulmonary pressure vs. mildly elevated vs. highly elevated: medians 13.7 vs. 16.7 vs. 19.8 pg/mL, p<0.0001). Supporting a linkage to rate of hemolysis, PlGF correlated with LDH (p=0.001) and inversely with hemoglobin level (p<0.0001). Suggesting a link to inflammation, PlGF correlated significantly with C-reactive protein (p=0.001) and erythrocyte sedimentation rate (p<0.001). PlGF correlated with markers of iron overload, including ferritin, transferrin saturation and inversely with transferrin (all p<0.001). Finally, PlGF correlated with markers of hepatic dysfunction, including low albumin and high direct bilirubin (p<0.001). We found significantly higher PlGF levels in SCD patients taking hydroxyurea compared to those not taking it (median 17.4 vs. 14.0 pg/ml, p<0.01). Confirming that hydroxyurea increases PlGF levels, in a separate cohort of seven patients, PlGF levels rose significantly from their baseline values after initiating hydroxyurea (median approx 22 vs. 27, p<0.05). Our data suggest that elevated PlGF level is associated with PH in patients with SCD, and PlGF is correlated with severity of hemolysis, inflammation, iron overload and hepatic dysfunction. Considering the variable evidence in the literature for either stimulating or inhibiting angiogenesis, it is not clear whether pathologic elevation of PlGF may be mediating pulmonary hypertension, or perhaps conversely providing an adaptive response to vascular damage. It has been suggested by Perelman et al. that PlGF may mediate leukocyte activation that might promote disease severity in SCD. However, hydroxyurea, which tends to ameliorate SCD complications, stimulates PlGF level in an unexpected manner, possibly related to the ability of hydroxyurea to stimulate erythropoietin production, which might in turn induce PlGF. Further research is needed to reconcile the role of PlGF in PH in SCD. Disclosures Tailor: Mesoscale: Employment.

Plasma ‘Free’ HB Is Related to Red Cell Derived Vesicle Numbers in Sickle Cell Anemia and Thalassemia Intermedia: Implications for Nitric Oxide (NO) Scavenging and Pulmonary Hypertension.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1671-1671 ◽  
Author(s):  
Maxwell Westerman ◽  
Arnold Pizzey ◽  
Jocelyn Hirschman ◽  
Mario Cerino ◽  
Ada Eze ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Healthy Adult ◽  
Thalassemia Intermedia ◽  
Plasma Hemoglobin ◽  
Increased Risk ◽  
The Relationship ◽  
Normal Controls

Abstract Plasma hemoglobin (Hb) is a scavenger of nitric oxide (NO), which is a likely contributor to the pathogenesis and treatment of clinical abnormalities such as pulmonary hypertension and vasocclusive episodes in sickle cell anemia (SCA) and possibly in thalassemia syndromes, where pulmonary hypertension has been described most frequently in splenectomised patients with thalassemia intermedia (TI). Since plasma Hb consists of both free Hb and RBC-derived microvesicle Hb (Greenwalt. Vox Sang1991;61:14), the relationship between plasma Hb and circulating vesicles may be significant. We have measured plasma Hb and plasma vesicle levels in adults with SCA and thalassemia intermedia (TI). Patients with SCA were all untransfused and TI patients had no transfusions during the previous 3 months. Plasma Hb values in healthy adult controls (1.77±0.2, n=7) were significantly lower than in SCA (11.21±2.08mg/dl, n=15, p=0.003) or in splenectomised TI patients (48.46 ±3.66mg/dl, n=5, p=0.0038). Plasma Hb levels were significantly greater in TI as compared to levels in SCA (p=0.001). Vesicle numbers in SCA were 12.59±3.65 x103/ul (n=21, p< 0.001, SCA v control) and in TI were 24.19 ±12.23 (n=7, p< 0.001, TI v control). Thus both plasma Hb and circulating vesicle levels in SCA and TI were significantly greater than healthy controls. Plasma Hb was significantly greater in TI than in SCA and circulating vesicles markedly greater in TI than in SCA. Furthermore there was a significant correlation between plasma Hb and vesicle numbers in SCA, TI and normal controls (n=26, R2=0.59, p=0.0015). An analysis of splenectomised versus non-splenectomised TI patients revealed a further trend; both plasma Hb and vesicle numbers were significantly higher in splenectomised (n=5, n=7 respectively) than in non-splenectomised patients (n=4, n=4 respectively). Plasma Hb and vesicle numbers were respectively 48.5±3.6 and 24.19±12.2 in splenectomised patients compared to 17.18±5.58 (p=0.014) and 4.36±0.81 (p=0.008) in non-splenectomized TI patients. These findings show that raised plasma Hb levels are related to increments in vesicle numbers in TI and SCA. Splenectomy in TI, which is associated with increased risk of pulmonary hypertension and thrombosis, is associated with increased vesicle numbers and plasma Hb. We suggest that the scavenger characteristics of Hb containing vesicles for NO may differ from the scavenger characteristics of free Hb and thus require detailed study..

The Serum Levels of N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) Is a Strong Indicator of Pulmonary Hypertension in Patients with Sickle Cell/Beta Thalassemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1207-1207
Author(s):  
Ersi Voskaridou ◽  
Antonios Tsoutsias ◽  
George Tsetsos ◽  
Evgenia Spyropoulou ◽  
Evangelos Terpos
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Natriuretic Peptide ◽  
Sickle Cell ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Right Atrial ◽  
Beta Thalassemia ◽  
Amino Terminal ◽  
Strong Indicator

Abstract Echocardiography studies have reported that approximately 30% of screened adult patients with sickle cell disease (SCD) have pulmonary hypertension (PH) defined as systolic pulmonary artery pressures of ≥ 35 mm Hg or regurgitant jet velocity value (TRV) of ≥ 2.5 m/sec. PH is increasingly observed in SCD and thalassemia. B-type natriuretic peptide (BNP) and the putatively inactive amino-terminal fragment of proBNP (NT-proBNP) are produced by the cleavage of proBNP, which is secreted from the ventricles during pressure strain. The serum concentration of NT-proBNP is considered as one of the strongest independent predictors for survival in patients with left ventricular dysfunction. The aim of this study was to evaluate the prevalence of PH in correlation with hemolytic findings and NT-proBNP levels in 73 patients with HbS/beta-thalassemia (HbS/β-thal; thal 0: 44 pts and thal +: 29 pts). The presence of PH was evaluated by using Doppler echocardiography and applying the modified Bernoulli equation (pulmonary artery systolic pressure=4V2 +right atrial pressure). Exclusion criteria of this study include: evidence of left ventricular failure, vaso-occlussive crisis during the last 15 days, atrial fibrillation or ventricular tachycardia, mitral value regurtitation (MVR) &gt;2/4+ or mitral value stenosis, and severe pericardial perfusion. In all pts we measured Hb, leukocyte, platelet, and reticulocyte counts, LDH, bilirubin, ferritin, creatinine, and Hb F. NT-proBNP levels were evaluated using an electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). Thirty-six patients (49%) were on hydroxyurea administration for a median time of 9 years. Nineteen patients (26%) had PH and experienced mild symptoms, such as fatigue or dyspnea on slight exertion. The administration of hydroxyurea did not affect the presence of PH. Patients with PH had elevated values of NT-pro BNP, reticulocyte counts and serum ferritin and a borderline increase of HbF compared with non PH patients (table). Even patients without PH had elevated concentrations of NT-proBNP compared with 20 controls of similar age and gender (mean±SD for controls: 48.1±22.1 pg/mL; p&lt;0.0001). The results of this ongoing study have shown that the frequency of PH in our cohort of HbS/beta-thal patients is similar with that observed in patients with SCD. Serum NT-proBNP is a strong indicator of PH in this cohort of hemoglobinopathy patients. Furthermore, the correlation between PH with reticulocyte counts and ferritin suggests that the degree of hemolysis and iron overload is implicated in the pathogenesis of PH in HbS/beta-thal. Parameter Patients with PH (n=19) Patients without PH (n=54) p-value Age (median; range) 40 ± 10.4 38 ± 12.6 Gender (n) 11M/8F 17M/37F On hydroxyurea (n) 12 (33.3%) 24 (66.6%) 0.23 NT-proBNP (pg/mL; mean ± SD) 486.8 ± 126.8 261.7 ± 139.6 &lt;0.01 Hb (g/dL; mean ± SD) 9.0 ± 1.5 8.9 ± 1.6 0.31 Retics (x1000/mm3) (mean ± SD) 239 ± 88 170 ± 61 0.01 LDH (U/L; mean ± SD) 779.6 ± 378.1 780.7 ± 352.9 0.76 Bilirubin (mg/dL; mean ± SD) 2.3 ± 1.8 2.4 ± 1.6 0.51 Creatinine (mg/dL; mean ± SD) 0.8 ± 0.1 0.8 ± 0.3 0.37 Ferritin (μg/L; mean ± SD) 1204.5 ± 1159.7 508.7 ± 599.1 0.02 HbF (%) 16.2 ± 8.0 13.5 ± 10.1 0.07

scholarly journals Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension

2011 ◽  
Vol 24 (11) ◽  
pp. 1285-1290 ◽  
Author(s):  
Jessica E. Knight-Perry ◽  
Lisa de las Fuentes ◽  
Alan D. Waggoner ◽  
Raymond G. Hoffmann ◽  
Morey A. Blinder ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Structure And Function ◽  
Cardiac Structure ◽  
Cell Disease ◽  
Cardiac Structure And Function ◽  
And Function

Identification of Oxidative Post-Translational Modifications on Plasma Albumin in Patients with Pulmonary Hypertension of Sickle Cell Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1215-1215
Author(s):  
Elizabeth S. Klings ◽  
Adam Odhiambo ◽  
David Perlman ◽  
Hua Huang ◽  
Catherine Costello ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Post Translational Modification ◽  
Dot Blot ◽  
Plasma Albumin ◽  
Post Translational Modifications ◽  
And Function ◽  
Dot Blot Analysis

Abstract Pulmonary hypertension (PH) in sickle cell anemia (SCA) is characterized by decreased nitric oxide bioavailability; which may, in part, be related to increased oxidative stress. It is possible that via protein post-translational modifications, oxidants are able to affect both protein structure and function. We hypothesized that, in patients with SCA and PH, oxidative post-translational modifications occur on plasma proteins and are important in disease pathogenesis. To examine this hypothesis, we chose to determine if oxidative post-translational modifications occur in a large-abundance protein, albumin, as a reflection of the presence of more widespread protein oxidative damage. Plasma was obtained from subjects with:SCA and PH (n=5);SCA steady-state without PH (n=4);Pulmonary Arterial Hypertension (PAH) (n=4);no evidence of cardiopulmonary disease (n=4). Platelet-poor plasma was separated into albumin-enriched and albumin-depleted fractions. The albumin-enriched fraction was subjected to proteolytic digestion by trypsin and studied by matrix assisted laser desorption ionization (MALDI) mass spectroscopy (MS) and liquid chromatography (LC)-MS/MS tandem mass spectrometry. Proteomics analyses were performed on all samples and post-translational modifications characterized by MS/MS. Results were confirmed by Western and dot-blot analysis using commercially available antibodies. In the albumin fraction, we identified peaks of differential post-translational modification on albumin peptide 146–159 only in PAH and SCA and PH samples; this PTM was identified to be a malondialdehyde adduct. The presence of a malondialdehyde adduct on albumin was confirmed by LC-MS/MS and Western analysis. We have identified a malondialdehyde adduct in plasma albumin that appears to be a common link between PH related to SCA and PAH. This finding supports the notion that oxidative stress modulates the pathogenesis of PH of SCA and suggests that this and other post-translational modifications may be important biomarkers of disease.

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