Plasma Biomarkers of Iron Regulation, Overload, and Inflammation in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1380-1380
Author(s):  
Abhishek Mangaonkar ◽  
Niren Patel ◽  
Hongyan Xu ◽  
Kavita Natrajan ◽  
Betsy Clair ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Transferrin Saturation ◽  
Iron Regulation ◽  
Cell Disease ◽  
Transfusion History

Abstract Transfusional iron overload has been increasingly recognized among patients with sickle cell disease (SCD) over the past two decades. We recently reported on the prevalence of iron overload among 635 adult SCD patients followed at our center and found that 80 patients (12%) had developed iron overload as a result of repeated blood transfusions. Fifty six (70%) of these subjects developed iron overload as a result of episodic, mostly unnecessary transfusions at outlying hospitals. There have been reports of association of increased morbidity and mortality among iron overloaded SCD patients; it has also been hypothesized that SCD patients tend to develop fewer complications of iron overload, compared to transfusion dependent beta thalassemia, primarily due to the chronic inflammatory state with resultant upregulation of hepcidin, and lower extra-hepatic iron loading. We studied biomarkers of iron metabolism, iron regulation, and inflammatory markers in 22 patients with SCD (SS) and iron overload (two consecutive ferritin levels of >1000 ng/ml and significant transfusion history) and compared these with 14 SCD patients without iron overload (ferritin <1000 ng/ml, and no significant transfusion history). Serum Fe, ferritin, %transferrin saturation (Tf) and total iron binding capacity, as well as high sensitivity C reactive protein (hsCRP) were performed by routine laboratory methods. Plasma concentrations of soluble transferrin receptor (sTfR), interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF-15) were measured using commercially available ELISA kits (R&D Systems, Minneapolis, USA). Plasma hepcidin was measured using a commercially available kit from DRG Diagnostics (Marburg, Germany). The results are summarized below: Abstract 1380. TableAgeyearsFerritin ng/ml% sathsCRPmg/dLHepcidinng/mlsTfRnmol/LGDF-15pg/mlIL-6pg/mlCases (n=22)33.42083.560.40.8829.872.21201.55.2Controls (n=14)29.0401.840.40.9512.477.11115.34.1p-value0.236.14E-050.020.80.0020.20.550.24 As expected, ferritin and % Tf saturation were significantly higher in the iron overloaded group. Hepcidin levels were also significantly higher in cases vs. controls, indicative of appropriate upregulation of hepcidin in Fe overload. sTfR and GDF-15 levels, as well as the inflammatory markers (hsCRP and IL-6) did not differ significantly between Fe overloaded and non-iron overloaded SCD patients. The two groups did not differ significantly in terms of the measures of disease severity (number of pain crises/year and number of hospitalizations/year). We further looked at the ratio of hepcidin/ferritin, sTfR/log ferritin, GDF-15/hepcidin, and tested the correlation between GDF-15 and hepcidin levels and ferritin and hepcidin levels; the ratio of hepcidin to ferritin was not different between cases and controls (0.019 and 0.021, respectively, p=0.73). sTfR to log ferritin ratio was significantly lower in cases compared to controls (22.3 vs 33.24, p=0.0004). GDF-15/hepcidin ratio was also found to be significantly lower in cases (262.1 vs 1896.7, p=0.01). Additionally, GDF-15 and hepcidin levels correlated significantly in controls but not iron overloaded SCD patients (p=0.04 vs p=0.7). Similarly, hepcidin and ferritin levels were significantly correlated in controls (p=0.03) but not in cases (p=0.8). Our results suggest that i) hepcidin levels are appropriately upregulated in iron overloaded SCD patients, ii) inflammatory markers (hsCRP and IL-6) were not significantly different between iron overloaded and non-iron overloaded patients, suggesting that systemic inflammation is not the driving factor behind hepcidin upregulation in iron overloaded SCD patients; however, a local/paracrine effect of IL-6 on hepatocytes secondary to Fe related inflammation in the liver cannot be excluded; and iii) GDF-15 and sTfR levels are not different between cases and controls, indicating that erythropoiesis does not differ between Fe overloaded and non-iron overloaded SCD patients. The observation that the correlation between GDF-15 and hepcidin levels is lost in iron overloaded SCD patients suggests that erythropoiesis does not contribute to hepcidin regulation in these subjects. This can further be clarified by studying the role of the newly described erythroid regulator of hepcidin, erythroferrone in SCD with and without iron overload. Disclosures No relevant conflicts of interest to declare.

scholarly journals American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support

2020 ◽  
Vol 4 (2) ◽  
pp. 327-355 ◽  
Author(s):  
Stella T. Chou ◽  
Mouaz Alsawas ◽  
Ross M. Fasano ◽  
Joshua J. Field ◽  
Jeanne E. Hendrickson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Guideline Development ◽  
Practice Research ◽  
Evidence Based ◽  
Red Cell ◽  
Cell Disease ◽  
American Society

Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

scholarly journals Iron Overload in the Face of Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-38-SCI-38
Author(s):  
Yatrik Shah
Keyword(s):  
Transcription Factors ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Absorption ◽  
Conflicts Of Interest ◽  
Iron Accumulation ◽  
Cell Disease ◽  
Divalent Metal Transporter 1 ◽  
Tissue Iron

Abstract Several distinct congenital disorders can lead to tissue-iron overload with anemia including β-thalassemia and sickle cell disease. We show that intestinal absorption of iron is highly increased and significantly contributes to tissue iron accumulation in these disorders. The present work describes a novel pathway by which oxygen sensing transcription factors are highly upregulated in iron overload anemias and are subsequently essential for the increase intestinal iron absorption. Oxygen signaling is mediated through well-conserved hypoxia driven transcription factors, hypoxia-inducible factor (HIF)1a and HIF2a. In the intestine, HIF2a directly activates divalent metal transporter 1 (DMT1), duodenal ferric reductase (DcytB), and Fpn1, which are iron transporters critical for adaptive changes in iron absorption. We demonstrate that HIF2a and its downstream target gene, DMT1 are essential for iron accumulation in mouse models of β-thalassemia and sickle cell disease. Furthermore, studies of thalassemic mouse model with established iron overload demonstrated that loss of intestinal HIF2a and DMT1 signaling led to decreased tissue iron accumulation in the livers. Interestingly, disrupting intestinal HIF2a not only improves tissue iron accumulation, but a marked improvement of anemia was also observed. These novel findings suggests that inhibition of HIF2a signaling pathway could be a novel and robust treatment strategy for several conditions that cause iron overload with anemia. Disclosures No relevant conflicts of interest to declare.

Cardiac Iron Overload In Sickle-Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1013-1013
Author(s):  
Antonella Meloni ◽  
Mammen Puliyel ◽  
Alessia Pepe ◽  
Massimo Lombardi ◽  
Vasilios Berdoukas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Clinical Characteristics ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Cell Disease ◽  
Cardiac Iron ◽  
Cardiac Iron Overload

Abstract Introduction Chronically transfused sickle cell disease (SCD) patients have lower risk of endocrine and cardiac iron overload load than comparably transfused thalassemia major patients. The mechanisms for this protection remain controversial but likely reflects lower transferrin saturation and circulating labile iron pools because of chronic inflammation and regeneration of apotransferrin through erythropoiesis. However, cardioprotection is incomplete; we have identified 6 patients out of the 201 patients (3%) followed at our Institution who have prospectively developed cardiac iron. We present the clinical characteristics of these patients to identify potential risk factors for cardiac iron accumulation. Methods Cardiac, hepatic, and pancreatic iron overload were assessed by R2* Magnetic Resonance Imaging (MRI) techniques as extensively described by our laboratory. The medical records of the selected patients were reviewed for demographic data, for transfusion and chelation history and for hematologic and biochemical parameters. Results Table 1 describes clinical characteristics of the six patients at the time they developed detectable cardiac iron (R2* ≥ 50 ms). Patient 6 was included because he showed a R2* of 49 Hz that was increasing rapidly. Five of the six patients were managed on simple transfusions. Five patients had been on chronic transfusion for more than 11 years. The three patients who developed cardiac iron the earliest (3.7 – 14 years of transfusions) had more efficient suppression of endogenous red cell production (HbS levels 2-5%) compared with patients who required longer transfusional exposure (HbS levels 13.3 – 41%). All patients had qualitatively poor chelation compliance (<50%), based upon their prescription refill rate. All patients had serum ferritin levels exceeding 4600 and liver iron concentration (LIC) greater than 22 mg/g. Pancreatic R2* was greater than 100 Hz in every patient studied (5/6). Figure 1 shows the longitudinal relationship between iron overload in the heart and in the other organs for each patient; initial iron levels are shown in black. Cardiac R2* appears increase dramatically once a critical LIC “threshold” is reached, qualitatively similar to the 18 mg/g threshold observed in thalassemia major patients. Cardiac R2* rose proportionally to pancreas R2*, similar to thalassemia major patients, with all of the patients having pancreas R2* > 100 Hz at the time cardiac iron was detected. Conclusions Cardiac iron overload occurs in a small percentage of chronically transfused SCD patients and is only associated with exceptionally poor control of total body iron stores. Duration of chronic transfusion is clearly important but other factors, such as levels of effective erythropoiesis, may also contribute to cardiac risk. The relationship between cardiac iron and pancreas R2* suggests that pancreas R2* can serve as a valuable screening tool for cardiac iron in SCD patients. Disclosures: Berdoukas: ApoPharma inc: Consultancy. Coates:ApoPharma inc, Novartis, Shire: Consultancy. Wood:Novartis: Consultancy, Honoraria; Shire: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria, Use of deferiprone in myocardial infarction, Use of deferiprone in myocardial infarction Patents & Royalties.

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.

scholarly journals Average Monthly Cost of Iron Chelator Treatment in Adult Patients with Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4858-4858
Author(s):  
Samip Master ◽  
Richard Preston Mansour
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Retrospective Analysis ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Private Insurance ◽  
Iron Chelator ◽  
Adult Patients ◽  
Cell Disease ◽  
Monthly Cost

Introduction: Iron overload in adult patients with sickle cell disease (SCD) can lead to variety of complications like liver dysfunction/cirrhosis, cardiac enlargement, diabetes mellitus, hypogonadism and arthropathy. These complication can be prevented by iron chelation therapy .We did retrospective analysis to find incidence of iron over load in this population and also did a survey to find the insurance status in this population. Methods: We take care of approximately 300 adult patients with SCD at out hematology clinic. We did retrospective analysis to investigate the prevalence of iron overload in this population. We also did survey on 100 adult patients with SCD to find out about the insurance converge for them. Web search was done to find out the average monthly cost of iron chelators. Results: On retrospective analysis of 458 adult patients with SCD, we found that 117/458(25.58%) had iron over load. Majority of them, 93/117 were SS type of SCD. Results of survey done on 100 adult patients with SCD showed that 61 had Medicaid, 2 were free care, 25 had Medicare and 12 had private insurance. The average monthly cost of Deferiprone is $ 18762, while that of Deferasirox is $ 13,082. Conclusions: Iron over load is a common complication affecting a quarter of the adult patients with SCD. The treatment of iron overload is expensive, as just the iron-chelator therapy costs approximately 160 to 220 K per year. In an attempt to minimize additional iron accumulation in our chronically transfused patient population we encourage the schedule of exchange of 1 unit phlebotomy and 1 unit of red cell infusion every two weeks. Disclosures No relevant conflicts of interest to declare.

Growth differentiation factor-15 in young sickle cell disease patients: Relation to hemolysis, iron overload and vascular complications

2014 ◽  
Vol 53 (4) ◽  
pp. 189-193 ◽  
Author(s):  
Azza Abdel Gawad Tantawy ◽  
Amira Abdel Moneam Adly ◽  
Eman Abdel Rahman Ismail ◽  
Yasser Wagih Darwish ◽  
Marwa Ali Zedan
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Vascular Complications ◽  
Cell Disease ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Serum ferritin and total units transfused for assessing iron overload in adults with sickle cell disease

2012 ◽  
Vol 157 (5) ◽  
pp. 645-647 ◽  
Author(s):  
Emma Drasar ◽  
Nisha Vasavda ◽  
Norris Igbineweka ◽  
Moji Awogbade ◽  
Marlene Allman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Cell Disease

scholarly journals Case Report: Acute Stroke in Young Adult Patient with Moyamoya Syndrome Secondary to Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Oladipo Cole ◽  
Asia Filatov ◽  
Javed Khanni ◽  
Patricio Espinosa
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Moyamoya Disease ◽  
Conflicts Of Interest ◽  
Acute Chest Syndrome ◽  
African American Female ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Radiographic Findings

Moyamoya disease, well described in literature, is a chronic cerebrovascular occlusive disorder. It is characterized by progressive stenosis/occlusion of the terminal portions of the internal carotid arteries (ICA) and the proximal portions of the middle cerebral arteries (MCA). Less frequently described is Moyamoya syndrome, the name given to radiographic findings consistent with Moyamoya disease, but with an identifiable cause. The diseases associated with Moyamoya Syndrome include Sickle Cell Disease (SCD), Thalassemias, and Down's Syndrome to name a few. Common complications of Moyamoya include both ischemic and hemorrhagic strokes. Upon literature review, Moyamoya syndrome caused by SCD is not well described. When it is, the discussion is centered around the pediatric patient population and surgical management. Our case report describes a 22-year-old African American female with SCD who initially presented with Acute Chest Syndrome. Her hospital course was complicated by development of overt debilitating neurologic deficits. Subsequently, she was found to have Moyamoya Syndrome on neuroimaging. She was successfully treated with medical management without any surgical intervention. This case highlights the necessity of thorough examination, differential diagnosis, imaging findings, and consideration of predisposing syndromes in the work-up for Moyamoya syndrome; especially individuals with Sickle Cell Disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Satish Maharaj ◽  
Simone Chang ◽  
Karan Seegobin ◽  
Marwan Shaikh ◽  
Kamila I. Cisak
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Acute Chest Syndrome ◽  
Adult Males ◽  
Cell Disease ◽  
Unequal Variances ◽  
Recorded Data

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT&gt;0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

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