Статті в журналах: "Sickle cell disease, Cardiomyopathy"

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Niss, Omar, Charles T. Quinn, Adam Lane, Joshua Daily, Philip R. Khoury, Nihal Bakeer, Thomas R. Kimball, Jeffrey A. Towbin, Punam Malik, and Michael D. Taylor. "Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease." JACC: Cardiovascular Imaging 9, no. 3 (March 2016): 243–52. http://dx.doi.org/10.1016/j.jcmg.2015.05.013.

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Palomarez, Alexis, Manisha Jha, Ximena Medina Romero, and Renita E. Horton. "Cardiovascular consequences of sickle cell disease." Biophysics Reviews 3, no. 3 (September 2022): 031302. http://dx.doi.org/10.1063/5.0094650.

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Sickle cell disease (SCD) is an inherited blood disorder caused by a single point mutation within the beta globin gene. As a result of this mutation, hemoglobin polymerizes under low oxygen conditions causing red blood cells to deform, become more adhesive, and increase in rigidity, which affects blood flow dynamics. This process leads to enhanced red blood cell interactions with the endothelium and contributes to vaso-occlusion formation. Although traditionally defined as a red blood cell disorder, individuals with SCD are affected by numerous clinical consequences including stroke, painful crisis episodes, bone infarctions, and several organ-specific complications. Elevated cardiac output, endothelium activation along with the sickling process, and the vaso-occlusion events pose strains on the cardiovascular system. We will present a review of the cardiovascular consequences of sickle cell disease and show connections with the vasculopathy related to SCD. We will also highlight biophysical properties and engineering tools that have been used to characterize the disease. Finally, we will discuss therapies for SCD and potential implications on SCD cardiomyopathy.

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Hammoudi, Nadjib, François Lionnet, Alban Redheuil, and Gilles Montalescot. "Cardiovascular manifestations of sickle cell disease." European Heart Journal 41, no. 13 (April 21, 2019): 1365–73. http://dx.doi.org/10.1093/eurheartj/ehz217.

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Abstract Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.

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Desai, Ankit A., Amit R. Patel, Homaa Ahmad, John V. Groth, Thejasvi Thiruvoipati, Kristen Turner, Chattanong Yodwut, et al. "Mechanistic Insights and Characterization of Sickle Cell Disease–Associated Cardiomyopathy." Circulation: Cardiovascular Imaging 7, no. 3 (May 2014): 430–37. http://dx.doi.org/10.1161/circimaging.113.001420.

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Sachdev, Vandana, Matthew Hsieh, Neal Jeffries, Anna Noreuil, Wen Li, Stanislav Sidenko, Hwaida Hannoush, et al. "Reversal of a rheologic cardiomyopathy following hematopoietic stem cell transplantation for sickle cell disease." Blood Advances 3, no. 19 (October 2, 2019): 2816–24. http://dx.doi.org/10.1182/bloodadvances.2019000387.

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Key Points Cardiac morphology improves significantly as early as 3 months after HSCT for SCD; these changes are maintained up to 1 year. Diastolic dysfunction is associated with mortality, and this study shows improvements in diastolic measures and other functional parameters.

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Ginwalla, Mahazarin, Abdullah AlMasoud, David Tofovic, Tara Alin, Sadeer Al-Kindi, Guilherme Oliveira, Sanjay Rajagopalan, Robert Schilz, and Jane Little. "Cardiovascular evaluation and management of iron overload cardiomyopathy in sickle cell disease." American Journal of Hematology 93, no. 1 (October 23, 2017): E7—E9. http://dx.doi.org/10.1002/ajh.24924.

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Federti, Enrica, Iana Iatcenko, Alessandra Ghigo, Alessandro Mattè, Veronica Riccardi, Immacolata Andolfo, Angela Siciliano, et al. "Colchicine Protects Against Cardiomyopathy in Humanized Mouse Model for Sickle Cell Disease." Blood 140, Supplement 1 (November 15, 2022): 2513–14. http://dx.doi.org/10.1182/blood-2022-163037.

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Blinder, Morey A., Francis Vekeman, Alex Trahey, Medha Sasane, Carole S. Paley, and Mei Sheng Duh. "Age-Related Blood Transfusion Patterns in Patients with Sickle Cell Disease (SCD) and the Association with Sickle Cell Complications." Blood 118, no. 21 (November 18, 2011): 12. http://dx.doi.org/10.1182/blood.v118.21.12.12.

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Abstract Abstract 12 Background: For patients with SCD, blood transfusion (tf) is the mainstay of treatment to prevent and alleviate SCD complications. Though the majority of patients in pediatric care often receive optimal preventive care, discrepancies are seen in care management of patients transitioning from pediatric to adult care as well as in adult patients. The study objectives were to evaluate blood transfusions patterns and incidence of SCD complications in pediatric and adult patients with a focus on those transitioning from pediatric to adult care. Methods: State Medicaid data from the FL (1998–2009), NJ (1996–2009), MO (1997–2010), IA (1998–2010), and KS (2001–2009) were used for this study. Patients with ≥2 SCD diagnoses (ICD-9 282.6x) and ≥1 tf following the 2nd SCD diagnosis were included in the analysis. Patients were followed for as long as they were enrolled in Medicaid. Quarterly rates of tf events, SCD complications, and prescriptions of hydroxyurea were calculated. Each tf event was defined as a unique day when at least one procedure code for packed RBCs, whole blood, or exchange tf was recorded. SCD complications included pain, infection, stroke, cardiomyopathy, renal disease, and Moyamoya disease. A logistic regression was used to assess associations between tf and transition age (<18 vs ≥18 yrs), population density of living area (urban, suburban, rural), state of residence, and SCD complications. An interaction term of transition age and SCD complications was also included to isolate the impact of SCD complications on tf between the pediatric and adult periods. Other covariates included prescription of hydroxyurea, tf during the previous quarter, other relevant medications (e.g.: pain medication, diuretics, anticoagulants), comorbidities (e.g.: hypertension, myocardial infarction, liver disease), and, serving as proxies for overall health status, the frequency of hospitalizations, emergency, and outpatient visits during the previous quarter. Results: A total of 3,208 patients were included (FL: 1,550, NJ: 992, MO: 489, KS: 121, IA: 56) in the study. Each patient was observed for an average (SD) of 6.0 (3.1) years. About 73% of patients lived in an urban area, 23% lived in suburban area, and 4% lived in a rural area. The rate of tf had a distinct bimodal pattern over ages. The rate of blood tf increased from 0.25 tf/pt/quarter at 1 year of age to a maximum of 0.54 tf/pt/quarter at 16 years old (Figure 1). After age 16, the tf rate decreased sharply to 0.29 tf/pt/quarter at age 26, and remained relatively stable thereafter. In contrast, the frequency of diagnoses for SCD complications increased markedly after age 16, reaching 2.92 diagnoses/pt/quarter at 28 years old and 3.50 diagnoses/pt/quarter at 40 years old (Figure 2). Pain was the most common complication, followed by infection, and renal disease. The frequency of diagnoses for cardiomyopathy slowly increased between 18 and 42 years old from 0.05 to 0.36 diagnoses/pt/quarter and then more than doubled to reach 0.80 diagnoses/pt/quarter at age 45 (Figure 2). Hydroxyurea use increased steadily up until age 18 and declined thereafter (Figure 1). Prescriptions for pain medications rose in a linear fashion from age 15 to 35 years from an average of 0.61 prescription/pt/quarter to 3.05 prescriptions/pt/quarter, and stayed high until the end of follow up. Results from the logistic regression showed that patients were less likely to receive blood tf post transition age (odds ratio [OR], ≥18 years old: 0.85, p=.014) and when receiving hydroxyurea (OR: 0.82, p<.001). In contrast, patients were more likely to receive tf if they lived in urban or suburban areas compared to rural areas (OR, urban: 3.65; suburban: 3.40; p<.001 for both) and experienced SCD complications (OR: 2.66, p<.001). The positive association between SCD complication and tf was stronger post transition age (OR, interaction between SCD complication and older age: 1.39, p<.001). Conclusions: Patients transitioning to adult care are transfused less frequently than pediatric patients and suffer from more frequent SCD related complications. These findings highlight the changes in treatment patterns corresponding to transition to adult care. While age related increases in SCD complications may be anticipated, the dramatic increase in complications along with the decline in tf frequency are likely to be due at least in part to inadequate transition to adult providers. Disclosures: Blinder: Novartis: Honoraria. Vekeman:Analysis Group: Analysis group received research grant from Novartis pharmaceuticals, Employment. Trahey:Analysis Group: Analysis Group received research grant from Novartis Pharmaceuticals, Employment. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment. Duh:Analysis Group: Analysis Group received research grant from Novartis Pharmaceuticals, Employment.

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Neumayr, Lynne, Ellen Fung, Paul Harmatz, Ellen Butensky, John Wood, Claudia Morris, Shanda Robertson, Meredith Milet, and Elliott Vichinsky. "Left Ventricular Dysfunction in Chronically Transused Patients with Sickle Cell Anemia and Thalassemia." Blood 108, no. 11 (November 16, 2006): 3745. http://dx.doi.org/10.1182/blood.v108.11.3745.3745.

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Abstract BACKGROUND: Iron-induced cardiomyopathy has been extensively described in thalassemia (THAL) patients. Left ventricular (LV) dysfunction is the leading cause of death in THAL, with prevalence estimates ranging from 6% to 23%. Recent MRI techniques confirmed that T2* measurements consistent with elevated cardiac iron are associated with LV dysfunction and early mortality. Transfusion therapy is being increasingly used for the treatment and prevention of complications in sickle cell disease (SCD). By adulthood, the majority of SCD patients will have received multiple transfusions and nearly 1/3 will be iron-overloaded. However, cardiomyopathy, its prevalence, and the role of iron toxicity have not been studied in SCD. The Multicenter Study of Iron Overload, a 5-year prospective natural history study, enrolled 152 transfusion dependent THAL, 204 chronically transfused SCD (txSCD) and 64 control SCD in order to compare the effects of iron toxicity in these two diseases. We compared the prevalence of LV dysfunction and its relationship to iron-toxicity in THAL, txSCD and control SCD. METHODS AND RESULTS: Baseline or year 1 echocardiograms (ECHOs) were available in 45% of the patients (80 THAL, 94 txSCD and 16 SCD controls) and reviewed for evidence of LV dysfunction, defined as an ejection fraction ≤ 55% or shortening fraction ≤ 28%. Pulmonary hypertension (PHT) was defined as a tricuspid regurgitant jet velocity (TRV) ≥ 2.5 m/s or pulmonary artery pressure (PAP) ≥ 35 mmHg. ECHOs reported as normal, even without TRV or PAP recorded, were assumed to be negative for PHT. At study entry, THAL and txSCD patients were severely iron over-loaded and their average ferritin and liver iron concentrations were not significantly different: 3506 g/dl and 20 mg/g dry weight. (Serum ferritin in the control SCD was 120 g/dl.) The average age of the patients was 30.3 ± 12 yrs, and did not differ across the three groups. LV dysfunction was found in 22% THAL; THAL patients with LV dysfunction had been transfused longer than those with normal ECHOs (26.5 vs. 21.1 yrs, p=. 03). A subgroup of THAL was screened with cardiac MRI: 11/21 (52%) had evidence of cardiac iron deposition, 4 of these patients (36%) had LV dysfunction. In THAL screened with MRI, all patients with LV dysfunction had cardiac iron deposition. LV dysfunction was seen in 14% of txSCD but in 0% of the control SCD. txSCD patients with LV dysfunction were older (43.7 vs. 28.5, p <. 0001) and more likely to have PHT (75% vs. 22%, p < .001). PHT was more common in txSCD than THAL (29% vs. 15%, p=. 03) and found in 13% of the control SCD group. No txSCD patients were screened with MRI. CONCLUSIONS: LV dysfunction is common in transfusion dependent THAL and associated with duration of transfusion and iron deposition. In SCD, patients with cardiomyopathy were chronically transfused, older, and more likely to have PHT. SCD patients are developing iron overload similar to THAL; cardiac MRI studies are essential for the evaluation of iron deposition and its relationship to cardiomyopathy.

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Kamdar, Manali K., and Darla K. Liles. "Sudden Death in Adult Sickle Cell Patients: A Single Institutional Experience." Blood 118, no. 21 (November 18, 2011): 1061. http://dx.doi.org/10.1182/blood.v118.21.1061.1061.

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Abstract Abstract 1061 In 1994 Platt et al published the Cooperative Study of Sickle cell Disease (CSSCD) which evaluated the course of nearly 4,000 children and adults with sickle cell disease. This study was one of the largest studies to look at survival in sickle cell disease and suggested a median survival of 42 years for males and 48 years for females with homozygous SS disease. In the past 20 years numerous supportive care measures have been implemented and the impact of these on survival of our adult sickle cell patients is unclear. We undertook a retrospective review of charts and autopsies for all patients in our adult sickle cell clinic that died from the time of inception until 2010 to determine if there was any impact on cause of death We performed a retrospective chart review study of all deaths of our adult sickle cell patients since inception of the clinic in 1998. Of the 260 patients actively enrolled in our clinic, 36 died during the time period of 1998 to 2010. Thirty four patients had sickle cell disease, 2 patients had sickle beta thalassemia, and no patient had Hemoglobin SC disease. Data regarding cause of death was determined from autopsy reports and from hospital charts at the time of death. The median age at death was 40 yrs. Despite most patients dying at or before age 40, only 9 of the 36 (25%) patients had autopsies. The cause of death in the autopsies obtained included liver infarct(1), drug overdose (2), cardiomyopathy (3), pulmonary emboli(1), coronary artery dissection(1) and chest syndrome(1). Of the patients who did not undergo autopsy, cause of death was evident in the hospital chart in 9 of the remaining 27 patients. In this group of patients cause of death was noted to be intracranial hemorrhage (2), sepsis (3), small bowel obstruction (1), cancer (1), chest syndrome (1) and heart failure (1). The remainder of the 18 patients died unexpectantly of sudden cardio respiratory arrest of undetermined etiology. Five of these patients died at home and 13 patients died within 48 hours of being hospitalized for acute pain crisis. In chart review of these 18 patients 7 patients had hypertension and 9 patients had renal failure. Of these 18 patients prior echocardiographic data was available in 14 patients. Interestingly, 7 of the 14 patients had TR jet velocity >2.5 m/second. The incidence of TR jet velocity >2.5 m/sec is higher than the 25–30% cited by Gladwin et al in a general sickle cell population. In summary despite numerous advances in supportive care over the past 15 years since the CSSCD the mean age of death in our small group of patients was still in the fourth decade. As in the CSSCD the majority of patients still died of cardiac and pulmonary complications many of which were not evident at the time of hospitalization. This retrospective data suggests close monitoring of these patients during the first two days of hospitalization given the high incidence of sudden cardiac death in this population. This retrospective review also suggests the necessity for improved screening and treatment modalities to prevent cardiopulmonary complications such as pulmonary hypertension in this population. Disclosures: No relevant conflicts of interest to declare.

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Jain, Shivi, Adam Rock, Caitlin Lopes, Santosh L. Saraf, Xu Zhang, Michel Gowhari, Robert E. Molokie, Victor R. Gordeuk, and Sally Campbell-lee. "Role of Automated Red Cell Exchange in Acute and Chronic Complications of Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 3674. http://dx.doi.org/10.1182/blood-2018-99-115677.

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Abstract Background. Automated red cell exchange transfusion (ARCET) is commonly used in patients with sickle cell disease, but objective data on its impact on acute and chronic complications are limited. Methods. Fifty-two sickle cell disease patients at the University of Illinois at Chicago underwent exchange transfusion from January 2011 to January 2016. Six patients were excluded due to incomplete data leaving 46 patients available for analysis. We collected data from the year before, year after and the year of ARCET to study the impact of red cell exchange on clinical, biological and hematological parameters. Results. There were 435 procedures with average of 9.45 per patient (range 4-14). The mean age of our cohort was 58.2 years. There were 22 (47.8%) males and 24 (52.2%) females. Genotypes include 42 (91.3%) HbSS, 1 (2.2%) HbSC, 1 (2.2%) HbSBeta+thalassemia and 2 (4.3%) HbSBeta0thalassemia. The most common indication for ARCET in our cohort was prior stroke in 32 patients (69.6%) and prevention of stroke in 7 patients (15.2%), followed by frequent vaso-occlusive crisis (VOC) 8 patients (17.4%), multiple acute chest syndrome 6 patients (13%), pulmonary hypertension 6 patients (13%) and chronic kidney disease 5 patients (8.9%). Iron overload, sickle hepatopathy, cardiomyopathy and seizure were some of the other indications. Twenty-five patients (54.3%) had more than one indication to undergo the ARCET. Thirty-one patients (67.4%) are still continuing the treatment. Thirty patients (65.2%) were on hydroxyurea (HU) prior to ARCET and 8 patients (17.4%) were still on HU while on ARCET. The mean frequency of ARCET was every 6 weeks. The mean pre and post ARCET values for hemoglobin(Hb), hematocrit (Hct), Hemoglobin S %(HbS), white cell count (wbc) and platelets(plt) are shown in Table 1. Paired t-test and Wilcoxon signed-rank test were used to analyze the clinical and hematological parameters. Analysis shows increase in mean Hb and Hct post ARCET and decrease in mean wbc, plt and HbS % post ARCET and the difference is statistically significant. (Table 3). Post ARCET body mass index (BMI) and weight are increased and the difference is statistically significant with p value 0.002 for BMI and 0.003 for weight. (Table 3). Ten (21.7%) patients showed decrease in the ferritin level post exchange. Thirty patients (65%) had VORTEX port whereas 29 patients (63%) had central venous access for procedures prior to Vortex placement (17/29, 59%). Nine patients (20%) had peripheral access mostly power port (for access) with one peripheral vein for return (6/9 67%). There were 10 access related complications and there were 3 port replacements due to septum damage and infection. There were 10 procedure related complications and 10 transfusion reactions as described in Table 2. ED admissions were decreased in 13(28.3%) patients from mean 7.69 to 2.92 admissions. The annual inpatient admissions showed a decrease in 18(39.2%) patients from mean 4.6 days pre ARCET to 1.6 admissions post ARCET. The acute care admissions showed an increase due to program expansion of our acute care center during this study period. Discussion. Our study shows that red cell exchange is an effective treatment modality for patients with sickle cell disease. It contributes to improvement in weight, increase in Hb and Hct and decrease in wbc, plt, HbS% and iron overload. It also decreases inpatient and ED admissions. The procedure is safe and tolerable with minimal complications. Long term studies are needed study the efficacy of this treatment modality and its contribution to improvement of quality of life and life expectancy in sickle cell disease patients. Disclosures No relevant conflicts of interest to declare.

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Morin, Cara, Akshay Sharma, Gary Beasley, Jane S. Hankins, Stacy High, Amanda Kennedy, Richard Lovins, Parul Rai, Brandon M. Triplett, and Jason Johnson. "Assessment of Cardiac Abnormalities in Sickle Cell Disease Patients Using Cardiac Magnetic Resonance Imaging (CMR)." Blood 138, Supplement 1 (November 5, 2021): 3110. http://dx.doi.org/10.1182/blood-2021-149227.

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Abstract Introduction Sickle cell disease (SCD) is characterized by chronic hemolytic anemia which predisposes patients to high output heart failure. Recently it has been recognized that repetitive microvascular ischemic insults and reperfusion injury result in diffuse myocardial fibrosis and cardiac remodeling that eventually leads to irreparable myocardial injury. Superimposed on these cardiac insults, patients with SCD often have iron overload related to chronic transfusions. Together, these insults produce a unique SCD-related cardiomyopathy characterized by restrictive physiology with LV dilation. Cardiac Magnetic Resonance Imaging (CMR) is the only non-invasive technique for assessing and quantifying diffuse myocardial fibrosis with simultaneous highly accurate assessment of heart size and systolic and diastolic function. Diffuse myocardial fibrosis is measured by a CMR technique called T1 mapping and calculated as extracellular volume (ECV), which may serve as an early marker of sickle cell related cardiomyopathy. An early marker for SCD-related cardiomyopathy would allow for efficient screening, prevention, and institution of treatment strategies. We describe utilization of CMR to evaluate cardiac pathology in a cohort of pediatric SCD patients. Methods Twenty-six children with SCD underwent CMR, as clinically indicated, between January 2020 and July 2021 at our institution. We analyzed cardiac chamber size (left atrium [LA], left ventricle [LV], right ventricle [RV]), systolic and diastolic function parameters, and quantitative myocardial parametric mapping values (T1 pre- and post-contrast and T2*) for these patients. ECV was calculated for all patients using T1 pre- and post-contrast values in conjunction with current hemoglobin values. Four patients underwent an allogeneic hematopoietic cell transplant (HCT) for SCD and had serial CMR performed before and 1 month after HCT. Results Median age of patients was 17 years; 12 (70%) were female; 22 (84%) had HbSS, 3 (12%) had HbSC and 1 (4%) had Hb S beta thalassemia. 15 (58%) patients had LA enlargement and only a few had ventricular enlargement (LV, 11 [42%]; RV, 9 [35%]). Patients rarely had had LV (4 [15%]) or RV (1 [4%]) systolic dysfunction. Twenty-five (96%) patients had increased ECV; median 30.5% (IQR 28-34%, reference normal 20.8% +/- 2.4). All patients had normal myocardial T2* values indicating no myocardial iron deposition. Additional details are provided in Table. Among those who underwent HCT, all 4 had elevated ECV at baseline, which improved in 1 patient 1-month post-HCT (27% [pre] to 21% [post]). One patient had a dilated LA at baseline with the other 3 developing LA dilation at 1-month post HCT. Conclusion CMR provides accurate and reproducible measurements of chamber sizes/ventricular volumes, myocardial mass, and ventricular function. Multiparametric mapping enabled quantitative evaluation of myocardial fibrosis in patients with SCD. We found that diffuse myocardial fibrosis is often present in children with SCD, even those with apparently normal cardiac function. This indicates damage to the myocardium occurs before symptoms or measurable changes on echocardiography, calling into question our current screening procedures. T1 mapping to monitor the progression of fibrosis could help evaluate response to current therapies including SCD directed therapies, cardioprotective medications, and curative options such as HCT and gene therapy. Hence, we believe that cardiac MRI is complementary to echocardiography and provides additional clinically relevant information that will help guide treatment in patients with SCD. Additionally, it has been shown that patients with SCD who undergo successful HCT exhibit significant improvements in cardiac size, function, and diastolic filling parameters as early as 3 months after the procedure, with improvements continuing slowly up to 1 year after HCT. Early post-HCT evaluation in our cohort did show moderate improvement in ECV in one HCT recipient. Further follow up with serial monitoring is ongoing to evaluate long term changes in these patients. Data on additional patients who have undergone serial CMR monitoring after HCT will be presented at the ASH annual meeting. Figure 1 Figure 1. Disclosures Sharma: CRISPR Therapeutics: Other, Research Funding; Medexus Inc: Consultancy; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Vindico Medical Education: Honoraria. Hankins: UpToDate: Consultancy; Global Blood Therapeutics: Consultancy; Vindico Medical Education: Consultancy; Bluebird Bio: Consultancy. Triplett: Miltenyi: Other: Travel, meeting registration.

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Mechal, H., M. Haboub, Z. Qechchar, H. Bendahou, M. Benouna, A. Drighil, L. Azzouzi, and R. Habbal. "Sickle cell disease and thalassemia: Significant causes of dilated cardiomyopathy, experience of Ibn Rochd university hospital-Casablanca." Archives of Cardiovascular Diseases Supplements 13, no. 1 (January 2021): 40–41. http://dx.doi.org/10.1016/j.acvdsp.2020.10.116.

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Mburu, Maureen, Samit Ghosh, Xucai Chen, Solomon Fiifi Ofori-Acquah, and Flordeliza S. Villanueva. "Nonhematopoietic Nrf2 Deficiency Worsens Chronic Intravascular Hemolysis but Not Cardiomyopathy in Transgenic Sickle Cell Mice." Blood 136, Supplement 1 (November 5, 2020): 18. http://dx.doi.org/10.1182/blood-2020-142783.

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Background: Cardiopulmonary complications are the leading causes of death in sickle cell disease (SCD). Cardiac complications in SCD include left ventricular (LV) hypertrophy and LV systolic or diastolic dysfunction. In SCD, intravascular hemolysis (IVH) contributes to multiorgan damage, but its role in cardiac injury is unknown. We previously reported that nonhematopoietic deficiency of nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor that controls antioxidative and anti-inflammatory genes, worsens the severity of IVH in SCD mice. Here, we first sought to determine if Townes transgenic SCD mice develop an abnormal cardiac phenotype, utilizing a cross-sectional study of varying-aged mice to test the hypothesis that these mice develop an age-related cardiomyopathy. Second, we determined whether IVH associated with absence of Nrf2 in the nonhematopoietic system worsens SCD cardiomyopathy. Methods: To identify a SCD cardiac phenotype, we performed echocardiography in a cross sectional cohort of Townes transgenic sickle cell mice (SS) and matched AA controls of varying ages (1-10 months). LV echocardiography dimensions were normalized to body weight. To determine the role of IVH and Nrf2 on the SCD cardiac phenotype, we transplanted whole bone marrow cells from SS mice to irradiated Nrf2-/- mice or C57BL/6 (Nrf2+/+) mice, to generate bone marrow chimeric sickle mice with Nrf2 deficiency in nonhematopoietic tissues (SSNHNrf2-/-) or chimeric sickle controls (SSNrf2+/+), respectively. Serial echocardiography was performed for up to 10 months, and hearts were harvested post-mortem for histology and molecular studies. Results: Cross-sectional study: Echocardiography showed cardiac abnormalities, most pronounced by 10 months, in the SS (n=8-9) compared to AA mice (n=9-13), respectively: LV hypertrophy was evidenced by a larger LV internal diameter (0.16 ± 0.01 vs. 0.13 ± 0.10 mm/g, p=0.005), higher LV mass index (5.2 ± 0.5 vs. 4.0 ±0.2 mg/g, p=0.02) and higher post-mortem heart weight (7.8 ± 0.3 vs. 5.2 ± 0.2 mg/g, p<0.0001) in SS mice. Compared to AA mice, SS mice had a lower ejection fraction (52 ± 4% vs 69 ± 2%, p=0.006) and fractional shortening (27 ± 2% vs. 39 ± 2%, p=0.001), consistent with impaired systolic function in SCD. Trichome-stained histological heart sections revealed myocardial fibrosis in SS but not in AA mice. Longitudinal study: Ten months after bone marrow transplant engraftment, SSNHNrf2-/- mice (n=6) had a significantly higher total plasma heme (p=0.008), lactate dehydrogenase (p=0.038), and plasma hemoglobin (p=0.008), confirming an exacerbation of IVH compared to SSNrf2+/+ controls (n=3). Surprisingly, compared to SSNrf2+/+ mice, SSNHNrf2-/- mice had a higher hematocrit (27.0 ± 1.0 vs. 23.1 ± 0.2%, p=0.035), lower reticulocyte count (57.5 ± 2.2% vs. 68.6 ± 4.8%, p=0.04), and a trend towards higher RBC count (p=0.05). Serial echo revealed that SSNHNrf2-/- mice, compared to SSNrf2+/+ controls, had a lower LV internal diameter (0.17 ± 0.01 vs 0.21 ± 0.01 mm/g, p=0.001) and LV mass index (4.7 ± 0.2 vs. 6.8 ± 0.2 mg/g, p=0.0004), consistent with less LV hypertrophy in the SSNHNrf2-/- mice. These findings were confirmed postmortem, where SSNHNrf2-/- mice had lower heart weight (p=0.0002) and cardiac mRNA expression of BNP (p=0.045) compared to SSNrf2+/+ controls. There were no significant differences in systolic or diastolic function parameters between SSNrf2+/+ controls and SSNHNrf2-/- mice. There was, however, a trend towards less myocardial fibrosis in SSNHNrf2-/- mice based on cardiac mRNA expression of Collagens 1 and 3. Conclusions: Townes transgenic sickle mice exhibit an age-dependent cardiomyopathy, with LV eccentric hypertrophy, systolic dysfunction, and myocardial fibrosis by 10 months of age. We reaffirm that Nrf2 deficiency in non-hematopoietic tissue worsens markers of IVH in SCD mice and unveil an unexpected decoupling phenomenon whereby despite increasing IVH in SSNHNrf2-/- mice, anemia improves. The amelioration of the SCD cardiac phenotype in SSNHNrf2-/- mice suggests that chronic IVH conferred by Nrf2 deficiency does not principally drive SCD-associated cardiomyopathy. While the improvement in anemia that we observed with Nrf2 deficiency may have played a role in amelioration of cardiomyopathy, further study is warranted to explore a possible cardiac protective effect of Nrf2 deficiency in SCD mice. Disclosures No relevant conflicts of interest to declare.

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Brucato, Martha, Xiaobin Wang, and Sophie Lanzkron. "Developmental Outcomes of Children Exposed to Maternal Sickle Cell Disease (SCD)." Blood 130, Suppl_1 (December 7, 2017): 983. http://dx.doi.org/10.1182/blood.v130.suppl_1.983.983.

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Abstract BACKGROUND: Pregnant women with SCD have an increased risk of both maternal and fetal complications, including preeclampsia, venous thromboembolism, and cardiomyopathy, as well as an increased risk of intrauterine growth restriction, preterm birth, low birth weight, and fetal demise. While in general children with a history of intrauterine growth restriction are at risk for abnormal neurodevelopment as well as later obesity and metabolic syndrome, the long-term developmental outcomes of children without SCD but exposed to maternal SCD are unknown. Better data about the long-term developmental outcome for children of mothers with SCD will provide guidance about the utility of disease modifying therapy during pregnancy. The objective of this study is to explore outcomes for children born to mothers with SCD using data from the Boston Birth Cohort (BBC). METHODS: The BBC is a prospective birth cohort established in 1998 at the Boston Medical Center (BMC) that recruits preterm cases (born at less than 37 weeks gestation) and full term controls. The BBC enrolls predominantly urban, low-income minority mothers and their children 24-72 hours after delivery at the BMC and follows the children from birth up to age 21 years. Data is collected on maternal preconception medical conditions, pregnancy complications, and pregnancy exposures through structured interviews at the time of enrollment and medical record extraction. Data on child development is collected from medical records and structured interviews performed by trained study staff at their scheduled pediatric appointments. Approximately 38% of study participants self-identify as black/African American, 22% as Hispanic, 19% as Haitian, and 8.5% as white. From maternal electronic medical record data capturing 147,827 emergency room and outpatient visits contributed by 5,972 subjects, we identified all women with ICD-9-CM codes for sickle cell disease (282.60-64, 282.68, 282.69, 282.41, 282.42) and probable (two or more 282.62 codes) sickle cell anemia. We then linked maternal and child data on the basis of a unique family-level study ID. Information on child development was obtained from electronic medical record data, based on the presence of relevant ICD-9-CM hospital diagnosis codes from pediatric outpatient, inpatient, and emergency room visits. RESULTS: We identified 93 women who had at least one of the ICD-9 codes for SCD. For this report we have included only those forty-one women who were coded at least twice with a 282.62 diagnosis (Hemoglobin SS disease with crisis). Six (15%) had poor fetal growth during their pregnancy, while eight (20%) were diagnosed with preeclampsia or antepartum hypertension. Among these mothers with available questionnaire and medical record extraction data (n = 38), 7 (18%) delivered their children before 37 weeks gestation, and 6 (16%) had children weighing less than 2500 grams at birth. Twenty mothers had children who received pediatric care at the Boston Medical Center, with ages ranging from 2 to 9 years of age; one was diagnosed with SCA, while 19 are unaffected carriers. Among the 19 children without SCD with available follow-up data, 5 (26%) carried a diagnosis code of overweight/obesity; their mothers were seen for an average of 73 medical visits (SD 50) during their pregnancy. Five children, without any overlap with the children diagnosed with obesity, were diagnosed with failure to thrive; while not statistically significantly different, their mothers had fewer medical encounters (mean 55, SD 37). Five children were diagnosed with delayed milestones, two of whom were late preterm (35 and 33 weeks gestation); two of these children were diagnosed with obesity and two with failure to thrive. DISCUSSION: This exploratory, descriptive study represents the first data on long-term outcomes of children without SCD who were exposed to maternal SCD in utero . While we are limited by small sample size, finding that 26% of children born to mothers with SCD have developmental delay is a significant concern. This compares to the overall cohort where 12% of control children and 39% of preterm cases have been found to have developmental delay. Future studies will include medical record review of mothers to identify additional mothers with confirmed SCD in the cohort and exploration of additional predictors of these concerning outcomes. Figure Figure. Disclosures Lanzkron: Prolong: Research Funding; HRSA: Research Funding; Bayer: Research Funding; Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; PCORI: Research Funding.

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Tolu, Seda S., Morayma Reyes Gil, Ugochi Olivia Ogu, Jui Choudhuri, Roger Fecher, Gracy Sebastian, and Caterina P. Minniti. "High Hemoglobin F in Sickle Cell Disease: Waning Protection with Age." Blood 134, Supplement_1 (November 13, 2019): 3576. http://dx.doi.org/10.1182/blood-2019-122387.

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Background: Sickle cell disease (SCD) is a monogenetic inherited red cell disorder with pleomorphic clinical manifestations. Hemoglobin F (HbF) concentration is the major genetic modifier of clinical expression and levels between 10% and 20% have been found to improve survival and decrease vaso-occlusive complications (VOCs). As survival for patients with SCD has increased dramatically in the past 20 years, we hypothesized that SCD-related complications may increase with age, even in "high F" individuals. Recent data suggest that individuals with the Arab-Indian haplotype and/or HbS-δβ thalassemia, who have HbF of 15% to 25%, still suffer from VOCs. SCD patients with HBS and deletional hereditary persistence of fetal hemoglobin (HPFH) have high levels of HbF (>30%) in a pancellular distribution, and absence of symptoms as suggested by prior studies. Here, we report on a cohort of patients with HbSS/Sβ0, with HbF >14%, either hydroxyurea naïve or treated for ≤ 6 months. Methods: We report on a cohort of 11 adults with SCD and HbF levels > 14%, who had never been on hydroxyurea, or were treated for ≤6 months. Charts were reviewed for VOCs, opioid therapy, acute chest syndrome (ACS), avascular necrosis (AVN), retinopathy, pneumonia, leg ulcers, splenomegaly/infarction, stroke, pulmonary hypertension, cardiomyopathy/infarction, chronic kidney disease, priapism and miscarriage. All events were confirmed by supportive laboratory or imaging data. HbF levels for each patient are represented as lifetime average values. In 10/11 patients, cellular distribution of HbF by flow cytometry (CytoFlex, Beckman Coulter, CA) was performed following fixation, permeabilization, and incubation of red blood cells with a monoclonal antibody against Hb-F, directly conjugated with FITC (Cat # MHFH01, Life Technologies, MD). Beta globin dosage genetic analysis was performed on a subset of patients (8/11) which used multiplex-polymerase chain amplification of fragments specific for portions of the epsilon, gammaG, gammaA, delta, and beta globin genes, which is commonly associated with deletional variant of HPFH (Quest Diagnostics, VA). Results: Our cohort consisted of 11 patients, 3 males, age range 23 -72 years, one of which (age 72) is deceased. Genotypes included 10 HbSS, four with alpha thalassemia trait, and one HbS/β0. Mean HbF levels ranged from 14 % to 29.50%, SD ± 4.76. Table 1 shows patients ordered in ascending age with clinical complications for each patient. Notably, all patients experienced VOCs regardless of age or HbF level, 91% were prescribed opioids, 46% of whom were on chronic opioid therapy, 40 % had leg ulcers 36% had AVN and 27% had ACS . The number of complications per patient increased with age, despite maintenance of high HbF. Available flow cytometry and genetic data revealed heterocellular distribution of HbF in 8 patients, and pancellular distribution in 2 patients: patient (#2) and patient (#10). Patient (#2) is positive for deletional HPFH with genetic confirmation of heterozygous positive deletion in the beta globin gene cluster. Genetic data is not available for patient (#10) at this time. Interestingly, both patients still exhibited VOCs, complicated by yearly hospitalizations, required intermittent opioid therapy and with age, developed AVN. Laboratory data are notable for minimal levels of hemolysis. Discussion: Most individuals with SCD living in high resources countries now reach adulthood. Therefore the disease profile that was previously studied and reported mostly in the pediatric population is evolving. High levels of HbF appear to delay the onset of complications, but do not completely prevent them, perhaps due to a heterocellular distribution of HbF or non-deletional HPFH. In our cohort, two patients with confirmed pancellular distribution of HbF, one of which with confirmed deletional HPFH, were not fully protected from the clinical complications of SCD, suggesting alternative pathogenic mechanisms for VOCs may be at play. Therefore, individuals with HbF concentrations of as high as ~30 % may still suffer from pain, hospitalizations for VOC's, and vasculopathic changes, such as leg ulcers. The number of complications increases with age despite maintenance of high HbF. Therefore, additional therapy and close vigilance is necessary when treating sickle cell patients with high levels of HbF, especially with increasing age. Disclosures Reyes Gil: Albert Einstein College of Medicine: Patents & Royalties: Patent application pending for NETs AI software. Ogu:Vertex Pharmaceuticals: Consultancy. Minniti:Doris Duke Foundation: Research Funding.

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De Castro, Laura M., Jude C. Jonassaint, and Marilyn J. Telen. "Left Sided Heart Dysfunction in Sickle Cell Disease: Echocardiographic and Genetic Studies." Blood 106, no. 11 (November 16, 2005): 78. http://dx.doi.org/10.1182/blood.v106.11.78.78.

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Abstract The moderate to severe anemia associated with sickle cell disease (SCD) causes a high output state that can lead to cardiomyopathy, decompensation and left heart failure. While at least one report suggested that chronic high output and volume overload are relatively well tolerated in SCD, other studies have suggested that congestive heart failure and other cardiac abnormalities may occur in more than 50% of adults. The incidence of sudden death is also increased and may be as high as 40% in adults with SCD. Several types of left ventricular (LV) dysfunction are associated with sudden death in other populations, although an association of LV disease and sudden death in SCD has not been studied. For these reasons, and also based on the clinical observation that SCD patients frequently experience transient episodes of clinical congestive heart failure (especially when receiving intravenous fluids during vaso-occlusive episodes), we sought to document the frequency with which left-sided cardiac dysfunction existed in our patient population. We performed a retrospective review of resting echocardiograms to quantitate multiple parameters of cardiac function in patients either homozygous for hemoglobin S or with Sβ0 thalassemia. 116 patients had had at least one echocardiogram performed (55 females, mean age 37, range 13–71; 61 males, mean age 32, range 16–62). 31% of these patients (mean age 41) had left ventricular hypertrophy (LVH), defined as a left ventricular mass index ≥134 and ≥110 g/m2 for men and women, respectively, and 22% (mean age 35) had left ventricular enlargement. Of the 36 patients with LVH, 27 had mild LVH, and 9 had moderate-severe LVH. Presence and severity of LVH were significantly related to mean arterial blood pressure (p=0.004), even though most patients were not hypertensive. Mean arterial pressures were also related to posterior LV wall thickness (p<0.0001), and baseline hemoglobin level was inversely associated with posterior wall thickness (p=0.0001). In addition, 53% had left atrial (LA) enlargement, 9% had mild-moderate aortic valve regurgitation, and 37% had mild-moderate mitral valve regurgitation (MR), with an additional 45% having trivial MR. Of all 116 patients studied, 61% (mean age 41, range 21–66) had pulmonary hypertension (pHTN), as indicated by a reported tricuspid regurgitant jet velocity of ≥2.5 m/s. In the patient group with LV enlargement, 75% of patients had pHTN, while of patients with LVH, 77% had pHTN. LA enlargement was also significantly more common in patients who had pHTN (p=0.002). While only 10% of patients had an ejection fraction below 55%, 37% (mean age 37) had fractional shortening (FS) less than 0.30. This suggests the presence of limited cardiac reserve in relatively young patients, as decreased FS is generally a finding that precedes a decrease in cardiac output. We have also begun to identify genetic polymorphisms that are associated with cardiac dysfunction. Two polymorphisms in the β2 adrenergic receptor gene were associated with either LA enlargement (rs1042713, p=0.02) and/or presence of LVH or LV enlargement (rs1042713, p=0.001; rs1042717, p=0.04). Polymorphisms of the adenylate cyclase 6 gene were also associated with LA enlargement (hcv1244841, p=0.02) and LV function as measured by FS (rs370070, p=0.01). In summary, these data demonstrate the significant prevalence of left-sided cardiac dysfunction in SCD. We hypothesize that these abnormalities contribute to progressive physical limitations, as well as sudden death. The pathophysiology of high output heart failure in this setting therefore merits considerable further study.

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Christakopoulos, Georgios E., Satheesh Chonat, Inigo Valiente-Alandi, Diamantis G. Konstantinidis, Amanda Schleper, Nihal Bakeer, Anastacia Loberg, et al. "Reactive Oxygen Species Produced by NADPH Oxidase Contribute to Cardiac Pathology in a Mouse Model of Sickle Cell Disease." Blood 128, no. 22 (December 2, 2016): 853. http://dx.doi.org/10.1182/blood.v128.22.853.853.

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Abstract Cardiopulmonary complications are an important contributor to morbidity and mortality in patients with sickle cell anemia (SCA). We have recently discovered that patients with SCA develop cardiomyopathy with restrictive pattern, characterized by diastolic dysfunction with progressive left atrial dilation, superimposed on the anemia-associated hyperdynamic physiology causing hypertrophied, dilated ventricles (Niss et al, JACC: Cardiovascular Imaging, 2016). Using a longitudinal systematic analysis of mouse models of SCA versus mice with iron-deficiency anemia, we found that this unique cardiomyopathy is indeed not due to chronic anemia and is associated with upregulation of genes related to oxidative stress pathways (Bakeer et al, PNAS, in press). These findings along with the known fact of increased inflammation and oxidative stress in SCA led us to postulate that NADPH oxidase (Nox)-mediated reactive oxygen species (ROS) may be an important pathogenic mechanism underlying cardiomyopathy in SCA and consequently mice lacking Nox-mediated ROS might be relatively protected from cardiac dysfunction. To investigate the role of NADPH oxidase in SCA cardiovascular pathophysiology, we bred the knock-in humanized SCA murine model Hbbtm2(HBG1,HBB*)Tow (where mouse α- and β-globin genes have been replaced by the human α- and βS globin genes; commonly known as UAB mice and herein called SS mice) with mice knocked out for the p22phox subunit of NADPH oxidase (a common subunit for all mouse Nox isoforms). We evaluated the phenotype of SS;p22phox-/- mice in blood and determined their cardiac function as compared to SS (p22phox+/+) littermate control mice. Hemolysis and ensuing reticulocytosis did not appear significantly improved in the SS;p22phox-/- mice; red blood cell (RBC) ROS was also stable likely due to the major contribution of mitochondrial ROS in the reticulocytes. Baseline ROS levels in the neutrophils of SS;p22phox-/-mice were similar to the levels in SS mice, but inducible ROS was almost eliminated as expected with deficiency of the p22phox subunit and inactivation of all NADPH oxidase isoforms. Starting at 8 weeks of age, cardiac structure and function were assessed on age-matched SS and SS;p22phox-/- mice by serial echocardiography. We studied 3 timepoints: 8-15 weeks of age, 16-24 weeks, and 25-34 weeks. SS mice developed progressively increased left atrial dimension (LAd) starting at 16 weeks of age while SS;p22phox-/- mice had stable LAd, with values similar to WT (Figure 1A). This difference became more pronounced with aging (P=0.02 at 25-34 weeks). Isovolumic relaxation time (IVRT), the time interval between closure of the aortic valve and opening of the mitral valve, was prolonged in the SS mice older than 16 weeks of age, consistent with diastolic dysfunction. In contrast, SS;p22phox-/- mice had no change in IVRT (Figure 1B). Also consistent with diastolic dysfunction, the ratio of transmitral E and e-(MV IVS E/e-) was increased in the SS group vs SS;p22phox-/-. Finally, the SS mice showed elevated left ventricular (LV) mass and decreased LV shortening fraction by 22-34 weeks whereas these parameters were preserved in the SS;p22phox-/-mice. Histopathology studies were performed to evaluate changes in the cardiac tissue. In the SS mice, H&E, picrosirius red and Masson trichrome staining showed not only significant LV hypertrophy and dilation but also significant interstitial fibrosis. Immunostaining for the extracellular matrix proteins collagen and fibronectin, showed extensive deposition of these proteins in the SS mouse heart. In contrast, SS; p22phox-/-mouse hearts were relatively spared. In conclusion, our data show that SS;p22phox-/-mice demonstrate better preserved diastolic and systolic heart function compared to SS mice, and decreased heart tissue damage. These findings suggest that therapeutic manuevers aimed at decreasing oxidative stress in SCA may be an effective strategy to counter SCA cardiomyopathy. Figure 1 Echocardiographic parameters evaluating diastolic function of the heart of SS vs SS;p22phox-/-mice. A. Left atrial dimension (LAd). B. Isovolumic relaxation time (IVRT). SS: Hbbtm2(HBG1,HBB*)Tow (UAB) with wild-type p22phox; SS;p22phox-/-: UAB mice with targetted deletion of p22phox.(statistical analysis was performed using Wilcoxon rank-sum test; JMP 9.0 SAS Institute, Cary, North Carolina) Figure 1. Echocardiographic parameters evaluating diastolic function of the heart of SS vs SS;p22phox-/-mice. A. Left atrial dimension (LAd). B. Isovolumic relaxation time (IVRT). SS: Hbbtm2(HBG1,HBB*)Tow (UAB) with wild-type p22phox; SS;p22phox-/-: UAB mice with targetted deletion of p22phox.(statistical analysis was performed using Wilcoxon rank-sum test; JMP 9.0 SAS Institute, Cary, North Carolina) Disclosures No relevant conflicts of interest to declare.

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Son, James, Hongyan Xu, Nadine J. Barrett, Leigh G. Wells, Latanya Bowman, Betsy Clair, and Abdullah Kutlar. "Transfusional Iron Overload In An Adult Sickle Cell Disease Population: Epidemiology, Prevalence, and Management." Blood 122, no. 21 (November 15, 2013): 1005. http://dx.doi.org/10.1182/blood.v122.21.1005.1005.

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Abstract Transfusional iron (Fe) overload remains a significant problem among patients with chronic, transfusion dependent anemias, especially in transfusion dependent ß-thalassemia (Thal) syndromes. If not treated vigorously with chelation, Fe overload in Thal is associated with significant organ damage, especially with chronic liver disease and cardiac abnormalities which can contribute to morbidity and mortality. In recent decades, the significance of Fe overload in sickle cell disease (SCD) has also been recognized especially among pediatric patients on chronic transfusion regimens predominantly for primary and secondary prevention of stroke. The prevalence and significance of this problem among adult SCD patients is less clear, although it is widely believed that episodic, mostly unnecessary transfusion practices play a more prominent role in this patient population. There have been reports of an association between iron overload and increased morbidity and mortality among adult SCD patients; it has also been speculated that the chronic inflammatory state that exists in SCD affords some degree of protection against severe organ damage through upregulation of hepcidin and sequestration of Fe in these patients. We performed a retrospective review of 635 adult SCD patients followed at our Center to define and ascertain the epidemiology, prevalence, etiology, and clinical correlates of transfusional Fe overload. Fe overload was defined as two consecutive serum ferritin values of > 1000 ng/ml. 80 patients (12.6%) met this criterion. Of these, 38 were male and 42 were female. Genotype distribution was: 73 SS, 3 S-β+ thal, 2 S-β0 thal and 2 SC. The mean age was 35.9 (range 18-69). Out of the 80 patients with transfusional Fe overload, 24 (30%) were/had been on a chronic transfusion regimen (23 for secondary or primary stroke prevention and one for childhood cardiomyopathy). Seventy percent of the patients (n=56) developed Fe overload from episodic transfusions predominantly performed at outlying community hospitals. The mean highest ferritin value was 4991 ng/ml (range 1,052-16,500). There was no correlation between ferritin levels and the number of hospitalizations or painful episodes (p=0.9). Thirty seven patients (46.2%) had a history of chelation therapy (with desferoxamine, deferasirox, or both). In 25 patients who have been on deferasirox for a period of 6 months or more, serum ferritin levels decreased from 4452.3 to 3876.6 ng/ml (p=0.3239). Our retrospective study shows that transfusional Fe overload is not rare among adults with SCD and develops predominantly as a result of episodic blood transfusions. This underscores the importance of the development and dissemination of evidence based guidelines, especially for episodic transfusions in SCD. A careful study of the extent and degree of organ damage associated with transfusional Fe overload in SCD and why less than half (46.2%) of patients are exposed to chelation therapy needs to be done. These studies should include liver iron concentration (LIC), cardiac iron and liver histology, when indicated, in parallel with serum hepcidin levels. The fact that the reduction in serum ferritin levels with deferasirox did not reach statistical significance in this cohort can be explained by the relatively small number of patients as well as by the short period (6 months) of exposure to chelation therapy. Disclosures: No relevant conflicts of interest to declare.

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Malinowski, A. Kinga, Kevin H. M. Kuo, George A. Tomlinson, Richard Ward, and Nadine Shehata. "Prediction of Risk for Adverse Pregnancy Outcomes in Women with Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 1009. http://dx.doi.org/10.1182/blood-2019-130087.

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Introduction: Pregnancies in women with Sickle Cell Disease (SCD) are at risk of adverse maternal and fetal outcomes. There are no studies characterizing features predictive of pregnancy-related complications that would enable targeted interventions towards those at high-risk, whilst avoiding exposure of those at low risk to the potential intervention-associated complications. Objective: To explore risk factors associated with adverse pregnancy outcomes in women with SCD and to develop a prediction rule identifying women at different levels of risk for adverse pregnancy outcomes. Methods: Retrospective cohort study of pregnant women with SCD at a tertiary care center. Maternal composite outcome (MCO) includes any of the following: severe, complicated anemia, multi-organ failure, venous thromboembolism, vaso-occlusive episodes requiring admission, blood transfusion, maternal mortality, hypertensive disorder of pregnancy (HDP), cardiac, pulmonary, hepatobiliary, MSK/skin, splenic, neurologic, or renal complication. Fetal composite outcome (FCO) includes any of the following: perinatal mortality, preterm birth, or small for gestational age size. Both composite outcomes were defined a priori. SCD-associated MCO were defined based on a published classification of SCD manifestations. HDP were divided to include gestational hypertension or pre-eclampsia, as noted in the health record. For twin pregnancies, the FCO was considered present if either infant met criteria. Predictor variables included SCD-related and non-SCD related maternal factors, which have been shown in the literature and through clinical experience to potentially result in adverse pregnancy outcomes. For a variable to be interpreted as a potential cause of an adverse outcome, it must have been present before the outcome and must not have been part of the outcome definition. Regression models for MCO and FCO were constructed using generalized estimation equation (GEE) logistic regression with clustering by woman to account for non-independence of outcomes in women with several pregnancies during the study period. From a set of 21 potential predictors for MCO and 26 potential predictors for FCO, those with univariate p-values <0.2 in GEE were included in a multivariable GEE regression model. Using cross-validation, predictive performance of the fitted model was evaluated using the concordance statistic and accuracy of prediction using a calibration curve; for each of 10 90%:10% splits of the dataset, a model was fitted on the 90% and used to obtain predicted probabilities on the 10%. Results: Of 199 pregnancies in 131 women between 1990 and 2016, MCO and FCO occurred in 71% and 45% of pregnancies, respectively. Risk for MCO was predicted by low maternal BMI, low first-trimester hemoglobin, VOE in the year preceding pregnancy, high LDH in pregnancy, history of multiple transfusions, and history of cardiac complications (heart failure, cardiomyopathy, or cardiomegaly). While presence of MCO was not part of the model given the inability to include it in a prediction rule for primiparous women, its manifestation was a risk factor for recurrence in subsequent pregnancies. FCO risk was predicted by older maternal age, high LDH in pregnancy, and maternal composite outcome during pregnancy. The model was discriminative for (a) MCO with a concordance statistic of 0.84 (se=0.03) on the observed data, and a cross-validated value of 0.80 (se=0.03), and (b) FCO with a concordance statistic of 0.72 (se=0.04) on the observed data, and a cross-validated value of 0.69 (se=0.04). Except at the extremes, predicted risk agreed well with observed risk for both the MCO and the FCO (Figure 1). Predicted risk of the MCO, separated pregnancies into groups having as low as a 35% to as high as a 95% chance, while predicted risk of FCO separated pregnancies into groups as low as 10% to as high as 70% (Figure 1). Conclusions: Our study shows that readily available clinical and laboratory variables can predict the degree of risk for an adverse pregnancy outcome in women with SCD. In our models, SCD genotype itself does not predict adverse maternal or fetal outcome, while presence of MCO or FCO are important predictors alongside other prespecified variables. The prediction rules will enable identification of sub-groups of women at higher risk of adverse events, allowing for consideration of targeted interventions such as prophylactic transfusion. Disclosures Malinowski: Alexion: Consultancy, Honoraria. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Pfizer: Consultancy; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria.

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Peeke, Stephen Zachary, Qi Gao, Jaeun Choi, Khadijah Abdallah, Ashley Buscetta, Andrew Crouch, Shuo You, Vence L. Bonham, and Caterina P. Minniti. "Immunophenotypes and Clinical Outcomes in Adult Patients with Sickle Cell Disease: Lymphopenia Correlates with End Organ Damage." Blood 136, Supplement 1 (November 5, 2020): 12–13. http://dx.doi.org/10.1182/blood-2020-142634.

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Introduction: Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy in the United States. While the primary event is polymerization of HbS under deoxygenation in red cells, the contribution of white blood cells and inflammation to SCD pathology has been increasingly recognized. Prior investigations of lymphocytes in SCD revealed varied abnormalities some of which have been shown to be corrected by hydroxyruea (HU) though not uniformly (Nickel 2015, Allali 2019). Alterations in lymphocyte subsets have previously been correlated with survival in elderly populations (Ferguson 1995) and with non-AIDS related mortality in HIV (Helleberg 2014). The aim of this study was to analyze alterations of leukocyte populations in relation to different clinical outcomes in a large set of adult patients with sickle cell disease at steady state. Methods: Patients were consented and data was obtained as part of the INSIGHTS study (NCT02156102). Only patients with HBSS/Sβ0 from whom lymphocyte subset panels had been prospectively collected were included in this analysis. Panels consisted of total CD3+ T cells, CD4+/CD8- (CD4+) and CD8+/CD4- (CD8+) T cells, CD19+ B cells and CD16/56+ NK cells; absolute neutrophil count (ANC), white blood cell count (WBC), CD4/CD8 and ANC/ALC (absolute lymphocyte count) ratios were examined as well. Patients were classified as having cardiovascular events (CVE) if they reported prior stroke, pulmonary embolism, deep vein thrombosis, myocardial infarction, arrhythmia, cardiomyopathy, coronary artery bypass or stent. Ulcer status was defined as history of, or current active cutaneous lower extremity ulcer. Also analyzed were self-reported pulmonary hypertension (pHTN), diabetes mellitus (DM), and a combined End Organ Damage Score (EODS) consisting of one point for each of the following clinical outcomes: CVA, Any Ulcer, pHTN, CAD (MI/CABG/stent), cardiomyopathy, PE/DVT, DM. Multivariate analysis was performed controlling for age, gender and active HU use and Spearman correlation coefficients were calculated using SAS software. Results: 170 patients were included in this analysis, 54.7% female, mean age of 38.7 years, 95.3% HbSS, 64.1% on active HU treatment, and 15.9% chronically transfused. Mean leukocyte counts were within reference ranges except for CD19+ cells (666 c/uL) which were double the upper limit of normal (ULN 321 c/uL) consistent with prior reports. The 40% of patients with a CVE history showed an overall decrease in their lymphocyte populations (CD3+, CD4+, CD8+, CD19+) and WBC compared to those without (Table 1). Patients with a pHTN history (15.3%) had lower total CD3+, CD8+, CD19+, ANC's and WBC's. This resulted, somewhat surprisingly, in a significantly lower ANC/ALC ratio than in those patients without pHTN. No significant correlations with organ damage outcomes were noted for CD4/CD8 ratios or NK cells. Similar to the CVE findings, increased EODS was associated with significantly lower total T lymphocytes, CD4+, CD8+, and CD19+ cells while ANC/ALC ratio was significantly increased (Tables 2 & 3). DM is very rare overall in SCD and was in our adult population (2/170) as well (Morrison 1979). It is notable that these 2 patients had significantly lower overall T and B cells and elevated ANC/ALC ratios. Compared to patients without any history of cutaneous ulcer, those with active ulcers had significantly lower total T cells (CD3+) and CD8+ cells (Table 4) while higher total WBC was seen in patients with a history of but no active ulcer compared to those without an ulcer history. Discussion: Our analysis of a large cohort of adult SCD patients at steady state revealed significant alterations in leukocyte populations in relation to a variety of clinical events. The salient finding was that B and T cell lymphocyte populations were significantly decreased in relation to clinical outcomes such as CVE and pHTN. The potential impact of this finding is highlighted by the adverse survival outcomes associated with lymphopenia seen in studies of general adult populations and in those with other medical problems such as cancer (Zidar 2019, Ray-Coquard 2009). While the interpretation of this study is limited to correlations further follow-up and study of SCD immunophenotypes may reveal important prognostic information that could enhance future care strategies. Disclosures Minniti: Bluebird bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CLS Bering: Consultancy; Roche: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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Saraf, Pankhoori, Sari H. Jacoby, Shailja Shah, Habib Nazir, Martin Gimovsky, and Alice J. Cohen. "Adverse Pregnancy Outcomes In High Risk Sickle Cell Women." Blood 122, no. 21 (November 15, 2013): 2218. http://dx.doi.org/10.1182/blood.v122.21.2218.2218.

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Abstract Background Life expectancy in patients with sickle cell disease (SCD) has increased with the institution of newborn screening, antibiotics and Hydroxyurea (HU). Prior studies have reported maternal mortality rate to be 2.2 times that of normal pregnancies. With improved high risk obstetrical services and hematological care, more women with SCD are choosing to carry a pregnancy (P). In order to see if outcomes have improved, we performed a review of women with SCD who had recent P at our hospital with a focus on maternal and fetal outcomes. Methods Patients (pts) were identified by a chart review of all women of childbearing age followed at both the Comprehensive Sickle Cell Center and the high risk obstetrics clinic. Data included: genotypes of SCD, fetal complications, P outcomes, transfusions (T), hospital admissions, previous HU use. Results 71 pregnancies were identified in 53 women from 2008 to 2013. Pregnancy outcomes See Table 1. Live births rates were equal in both GR I and GR II. The mean gestational age (weeks) in GR I was 35.13 and GR II 38.28 (p=0.0077) with more preterm births in GR I 16/36 (44%) compared to GR II 2/18 (11%). The most common mode of delivery was C-section in both GR I and II. Reasons for C- section were fetal distress 60% (20), repeat C-section 27% (9), other (5% or less) for breech, elective, preeclampsia, placenta previa. There were equal numbers of induced and spontaneous labor in each group. Complications in GR I 8/36 (22%) and GR II 2/18(11%) included PIH, Chorioamniotis, placenta previa, death (cardiac arrest). Fetal outcomes Low birth weight occurred in 20/33(61%) of GR I and 3/18(17%) of GR II (p= 0.0016) births. Other complications (41 % of births) including IUGR, meconium aspiration, oligohydramnios and Apgar scores <7 @ 1 min occurred equally in both GRs. Maternal outcomes: During P mean values for events in GR I and GR II respectively were: transfusions 5.56 units (U) and 1.22 U (p=0.0022), admission for vasoocclusive crisis (VOC) 3.33/pt and 1.44/pt (p=0.0173). Other complications were urinary tract infection (7), pneumonia (4), acute chest syndrome (4), cardiomyopathy (1), renal failure (1), hepatic crisis (2), DVT (1). Six patients were on HU pre- pregnancy (PP). In these patients 13 simple blood T were required PP and 56 during P (p=0.0297). VOC events increased from 13 PP to 35 during P (p=0.1011). 2 patient required exchange T during P. Conclusion Despite improved antenatal care for SCD women, P remains a high risk event for mother and fetus, with lower birth weights and more preterm deliveries in SS/SB 0 thal pts compared to SC/SB+ thal. Prior use of HU PP was not protective. New insights and studies are warranted to understand the pathophysiology of SCD causing adverse pregnancy outcomes and possible effects of HU withdrawal. Disclosures: No relevant conflicts of interest to declare.

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Qureshi, Naveen, Kishor Avasarala, Sylvia Titi Singer, Drucilla Foote, Ekua Hackney-Stephens, Robert Hagar та Elliott P. Vichinsky. "Utility of Holter Electrocardiogram Monitoring in Iron over Loaded β Thalassemia and Sickle Cell Disease." Blood 104, № 11 (16 листопада 2004): 3784. http://dx.doi.org/10.1182/blood.v104.11.3784.3784.

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Abstract BACKGROUND: Cardiac disease is a leading cause of morbidity and mortality of β thalassemia and sickle cell (SCD) patients. Arrhythmias often precede the development of cardiomyopathy and can result in sudden death. Since early intervention may improve outcome, routine screening of iron overloaded patients with 24 hour Holter electrocardiographic analysis is recommended, although its usefulness has not been studied. Infrequent and unpredictable electrocardiographic changes in these patients may limit its usefulness. The objective of this study is to determine the diagnostic yield of 24 hour holter EKG monitoring and its correlation with patient symptoms and disease status. METHODS: 44 iron overloaded hemoglobinopathy patients underwent a cardiac questionnaire, standard 24 hour Holter monitoring, echocardiogram, quantitative liver iron by SQUID (Superconducting Quantum Interfering Device). A chart review was completed initially and repeated on follow up visits. Holter monitoring outcomes were classified into 3 groups: clinically significant, clinically insignificant and normal. Echocardiograms were classified as normal, normal with pulmonary hypertension and abnormal. Thalassemia and SCD were analyzed separately. RESULTS: 27 transfusion dependent thalassemia patients at a mean age of 19 years (3–46), including 14 males and 13 females. Mean quantitative liver iron for the group was 15.0 mg/gm d/wt (3.3–46.4). 17 SCD patients had a mean age of 16.4 years, (11–33), including 9 males and 8 females. Mean quantitative liver iron for SCD was 13.5 mg/gm d/wt (3.3–46.4) and was similar to thalassemia. The questionnaire revealed cardiac symptoms, (palpitations, syncopy, etc.) were reported in 11/27 (40.7%) thalassemia patients, and in 1/17 (5.9%) sickle cell patient. In thalassemia, 4/27 (15%) of patients had clinically significant arrhythmias detected on holter (frequent PVCs, ventricular bigeminy, supraventricular tachycardia [SVT] and atrial flutter). Of the remaining, 37% of thalassemia patients had clinically insignificant holter findings and 48 % were normal. Age, sex, liver iron were similar in each holter subgroup. 30% of thalassemia patients had pulmonary hypertension (tricuspid regurgitant jet >2.5 ms) with normal echocardiogram. In addition, 50% of the clinically significant holter group demonstrated pulmonary hypertension. In SCD, there were no patients in the clinically significant holter group, 8/17 in the clinically insignificant group and 9 with normal findings. 29% (5/17) had pulmonary hypertension with normal echocardiograms. On follow up, 3 patients (2 thalassemia and 1 SCD) developed acute cardiac complications secondary to arrhythmias. The first patient experienced frequent PVCs during the screening and 1 month later developed acute palpitations and dizziness associated with atrial flutter. The second patient, following a clinically insignificant screening developed months later, supraventricular tachycardia and atrial flutter. There were no predictive risk factors in these 3 patients. CONCLUSION: 14% of transfusion dependent thalassemia and SCD patients developed an abnormal EKG on screening or follow up. 3 patients experienced serious complications. Echocardiogram, pulmonary hypertension and iron stores were not predictive. Early detection of cardiac arrhythmias is indicated; however, the standard holter EKG method is insensitive. The transelephonic event recorder may be evaluated in arrhythmia surveillance in thalassemia.

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van den Tweel, Xandra W., Johanna H. van der Lee, Harriët Heijboer, Marjolein Peters, and Karin Fijnvandraat. "Development and Validation of a Pediatric Severity Index for Sickle Cell Patients." Blood 110, no. 11 (November 16, 2007): 3391. http://dx.doi.org/10.1182/blood.v110.11.3391.3391.

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Abstract Background: The clinical picture in patients with sickle cell disease (SCD) is heterogeneous. In order to study determinants of a severe clinical course well designed etiological studies are needed, using a valid outcome measure for disease severity. At this moment there is no generally accepted instrument to measure severity in pediatric SCD patients. Objective: The aim of this study was to develop and validate a severity index (SI) for SCD in children. Methods: Item selection for the SI was based on an item pool (n=50) retrieved from a systematic review of all disease severity assessment instruments for SCD. Items from this pool were rejected in case they were not applicable to children, non-specific for SCD or confounded. To address differences in severity among the items we included a transparent weighting process in the summation of the score. Three different weighting systems to summarize the items of the SI were used. First, all items were summed with an equal weight of 1 (score A). Secondly, acute life-threatening events and neurological complications were assigned more weight, receiving a score of 10, with all other items receiving a score of 1 (score B). Finally, items were weighted according to the severity of the different complications and the frequency of occurrence, ranging from 5–50 points (score C). We tested the validity of the SI using data from 92 patients (mean age 9.7 years, range 2–18 years) with SCD who were regularly seen at the study center. We evaluated whether different scores were obtained for patient groups classified according to severity subjectively by two pediatric hematologists (expert classification) and objectively by an existing score. Furthermore, we tested whether the index could differentiate patients classified by genotype (HbSS/HbS-β0-thalassemia versus HbSC/HbS-β+-thalassemia) or the number of alpha-gene deletions. Finally, we evaluated whether the SI correlated with age. Results: The resulting SI consisted of the following 23 items: acute chest syndrome, aplastic crisis, avascular bone necrosis, cardiomyopathy, overt and silent cerebral infarction, cerebral vasculopathy, enuresis nocturna or renal concentration problems, failure to thrive, gall stones, hemolytic crisis, hepatic and splenic sequestration, leg ulcers, painful crisis, pneumococcal septicemia and/or meningitis, priapism, retinopathy and 5 laboratory values (Hb, HbF, bilirubin, leucocytes, reticulocytes). For all weightings there was a significant difference in the scores of patient groups classified as mild, moderate and severely subjectively by experts or by the existing score (p<0.001). The index clearly differentiated patients by genotype (p<0.001) or alpha-gene deletions (p<0.001). Unexpectedly, there was no correlation with age (Spearman’s ρ = 0.19). Score C, with the most extensive differentiation in weighting of the items, discriminated best. Conclusion: In conclusion, we developed and validated a SCD severity index by a transparent and rigorous process. Further validation is of this SI is needed in a larger prospective cohort study of patients diagnosed by neonatal screening. After further refinement and adaptation of this index, it may contribute in achieving consensus on outcome assessment in etiological research in pediatric patients. This is important to enhance the comparability of study results and enable statistical pooling in meta-analyses.

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Kuo, Kevin H. M., Eiran Warner, Mathew Sermer, and Richard Ward. "The Effect of Comprehensive Care on Maternal and Fetal Outcomes in Sickle Cell Disease Pregnancies." Blood 118, no. 21 (November 18, 2011): 4842. http://dx.doi.org/10.1182/blood.v118.21.4842.4842.

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Abstract Abstract 4842 Introduction: Patients with Sickle Cell Disease (SCD) have increased rates of maternal and fetal complications compared to the general population, including premature rupture of membranes, post-partum infection, low birth weight, small for gestational age (SGA), intrauterine growth retardation (IUGR) and preterm delivery. They also experience higher rates of antepartum complications: painful vasoocclusive crises (VOC), infections, PIH/preeclampsia, abruption, antepartum bleeding, cardiomyopathy, pulmonary hypertension, cerebral vein thrombosis, pneumonia, pyelonephritis, deep vein thrombosis (DVT), transfusion and systemic inflammatory response syndrome. Comprehensive care reduces morbidity and mortality in infancy and early childhood and is the cornerstone of care in SCD. However, the effect of comprehensive care on maternal and fetal outcome in patients with SCD has not been examined. We hypothesize that pre-conception comprehensive care improve maternal and fetal outcomes and reduced rates of antepartum complications in patients with SCD. Methods: We conducted a retrospective review of patients with SCD (SS, SC, S/beta-thalassemia) who delivered at the Mount Sinai Hospital (MSH), a high risk obstetrics care institution in Central Ontario, Canada, between 2000 and 2010 based on the Antenatal Database, Delivery Database, electronic and paper-based medical records. Patients were jointly managed by a maternal-fetal medicine (MFM) specialist and hematologist specialized in hemoglobinopathies. We analyzed the maternal and fetal characteristics and outcomes (age at delivery, genotype, gravida, gestational age, birth weight, number of Caesarian sections and vaginal deliveries), antepartum complications (pregnancy induced hypertension (including pre-eclampsia and eclampsia), gestational diabetes mellitus, preterm premature rupture of membranes, oligohydramnios, abruption/previa, venous thromboembolism, urinary tract infection), and SCD-specific complications (painful vaso-occlusive crises, acute chest syndrome, pneumonia, and transfusion) based on the presence or absence of comprehensive care prior to pregnancy by the Red Blood Cell Disorders (RBCD) Clinic at the University Health Network, a SCD comprehensive care centre from the same catchment area as MSH. t-test was used to compare means of two groups, Fisher's exact test and chi-squared tests were used to compare categorical frequency data, where appropriate. Alpha value of 0.05 was chosen as the level of significance. Results and Discussion: We identified 79 deliveries by 64 patients with SCD who received obstetric care at MSH. Mean gestational age at delivery was 37.69 weeks (95% CI 37.00 to 38.37 weeks) and 21 (27%) were preterm (< 37 weeks). Thirty-one deliveries (39%) were by Caesarian section and 48 were delivered vaginally. Seventeen (22%) were low birth weight (< 2500 g) and 11 (14%) were small for gestational age. Maternal and fetal outcomes and rates of antepartum complications were similar to the existing literature (Powars, 1986; Smith, 1996; Serjeant, 2004; Barfield, 2010). Twenty-eight deliveries by 22 of the 64 patients received comprehensive care at the RBCD clinic prior to their pregnancies for a mean duration of 5 years. There was no significant difference in maternal or fetal outcomes or antepartum complications. The results suggest that the role of comprehensive care prior to conception may not be as crucial in pregnancy outcomes of patients with SCD as previously thought. The lack of difference may also be due to the fact that the patients' care was closely monitored during the pregnancy by both specialists in hemoglobinopathies and high risk obstetrics. Limitations of the study include its single-centered and retrospective nature, exclusion of stillbirths and miscarriages, and small sample size. Also, patients who were enrolled in the comprehensive care program may carry more comorbidities and SCD-specific complications, compared to patients referred from the community, but this was not examined in the present study. Further prospective observational studies of SCD patients in the child-bearing age, with attention to the frequency and type of pre-pregnancy SCD-specific complications, as well as standardized application of comprehensive care, will be helpful in determining whether comprehensive care is useful in reducing antepartum complications in patients with SCD. Disclosures: Kuo: Novartis Canada: Research Funding.

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Niss, Omar, Michael D. Taylor, Robert Fleck, Tarek Alsaied, Jeffrey Towbin, Punam Malik, and Charles T. Quinn. "Diffuse Myocardial Fibrosis Is a Common Feature of Sickle Cell Anemia That Is Associated with Diastolic Dysfunction and Restrictive Cardiac Physiology." Blood 128, no. 22 (December 2, 2016): 8. http://dx.doi.org/10.1182/blood.v128.22.8.8.

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Abstract Background: We have recently shown that the cardiomyopathy of sickle cell anemia (SCA) is characterized by restrictive physiology (diastolic dysfunction, left atrial [LA] enlargement and normal systolic function) superimposed on hyperdynamic features (left ventricular [LV] enlargement and eccentric hypertrophy) (JACC Cardiovasc Imaging 9:244-253;2016; PNAS 2016 in press). Similar to other restrictive cardiomyopathies, SCA-related cardiomyopathy may lead to mild, secondary pulmonary hypertension (PH) with elevated tricuspid regurgitant jet velocity (TRV), and can be complicated by arrhythmias and sudden death. Diastolic dysfunction is the principal pathology leading to restrictive physiology. Myocardial fibrosis is a common cause of non-SCA restrictive physiology, but the cause of the diastolic dysfunction that underlies SCA-related cardiomyopathy is undetermined. Focal fibrosis, as detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), is rare in SCA. However, diffuse myocardial fibrosis, which is not detected by LGE, has not been studied before in SCA. Therefore, we aimed to detect myocardial fibrosis in SCA using a novel CMR T1-mapping technique to quantify the myocardial extracellular volume (ECV) fraction, which correlates with histologic diffuse fibrosis. Methods: We conducted a prospective study of children and adults with SCA (NCT02410811) who underwent CMR, echocardiography, and laboratory testing (including N-terminal pro-brain type natriuretic peptide [NT-proBNP], a marker of ventricular stress). ECV was measured from pre- and post-gadolinium T1 maps using a modified Look-Locker inversion recovery (MOLLI) sequence. Chamber sizes and cardiac performance were evaluated using CMR, while TRV and diastolic parameters were measured by echocardiography. Results: Twenty-five patients with a median age of 19 years (range 6-61 years) were evaluated. ECV was increased in all SCA patients (mean 44 ± 8% vs. 25 ± 3% in normal subjects, P<0.001). One patient had focal fibrosis by LGE and one had systolic dysfunction. Among patients with normal systolic function, 17 patients (71%) had diastolic abnormalities and 7 (29%) had normal diastolic function. Seven out of 17 patients with diastolic abnormalities (29% of the total group) met the definition of diastolic dysfunction, and 10 had inconclusive classification. Patients with diastolic dysfunction had significantly higher ECV (49 ± 7% vs 37 ± 4%, P=0.01; Panel A), NT-proBNP (191 ± 261 vs. 33 ± 33 pg/mL, P=0.04; Panel B), and lower hemoglobin (8.4±0.3 vs.10.9±1.4 g/dL, P=0.004, Panel C) compared to patients with normal diastolic function. Systolic function was similar in both groups (LV ejection fraction 61 ± 4% vs. 62 ± 3.4%, P=0.86). In patients with higher ECV (³40%), LV diastolic abnormalities were more common (99% vs 33%, P=0.003) and LA volume index was significantly increased (57 ± 11 vs. 46 ± 12 mL/m2, P=0.04) compared to patients with ECV <40%. Increased ECV was associated with anemia (R=-0.46, P=0.03; Panel D) and elevated NT-proBNP (R=0.62, P=0.001; Panel E), but not with LV ejection fraction (P=0.66; Panel F), LV mass (P=0.92) or TRV (P=0.65). Conclusions: ECV is markedly elevated in SCA, indicating the presence of significant diffuse myocardial fibrosis in all patients studied. High ECV is associated with more severe anemia, diastolic dysfunction, and high NT-proBNP. Diffuse myocardial fibrosis is a novel process underlying diastolic dysfunction and SCA-related cardiomyopathy, the features of which may be mistaken for pulmonary arterial hypertension. Identifying and therapeutically targeting the root-cause of myocardial fibrosis, or interrupting the development of myocardial fibrosis, should be studied to mitigate cardiopulmonary disease and decrease early mortality in SCA. Figure. Figure. Disclosures Quinn: Silver Lake Research Corporation: Consultancy; Eli Lilly: Research Funding; Amgen: Research Funding.

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Blinder, Morey A., Francis Vekeman, Alex Trahey, Medha Sasane, Carole S. Paley, and Mei Sheng Duh. "Age-Related Iron Chelation Utilization and Healthcare Costs in Patients with Sickle Cell Disease (SCD)." Blood 118, no. 21 (November 18, 2011): 338. http://dx.doi.org/10.1182/blood.v118.21.338.338.

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Abstract Abstract 338 Background: For patients (pts) with SCD receiving regular blood transfusions (tf), iron chelation therapy (ICT) alleviates complications associated with iron overload. Pediatric pts tend to receive comprehensive care, including blood tf to avoid SCD-related complication and, as necessary, ICT. However, as pts transition to adult care, follow up is less constant and discrepancies are seen in care management. The aim of this study is to evaluate tf patterns, utilization of ICT among chronically transfused pts, and healthcare costs in pediatric and adult pts with a focus on the transitioning period from pediatric to adult care. Methods: State Medicaid data from the FL (1998–2009), NJ (1996–2009), MO (1997–2010), IA (1998–2010), and KS (2001–2009) were used for this study. Pts with ≥2 SCD diagnoses (ICD-9 282.6x) and ≥1 tf following the 2nd SCD diagnosis were included. Pts were followed for as long as they were enrolled in Medicaid. Pts were considered chronically transfused from the time of their 8th tf. Each tf event was defined as a unique day when ≥1 procedure code for packed RBCs, whole blood, or exchange tf was recorded. Quarterly rate of tf was calculated among all SCD pts and proportion of pts receiving ICT was calculated among pts who received ≥8 tf. Quarterly healthcare costs, stratified by outpatient (OP) and inpatient (IP) services and prescription drug (Rx) costs were calculated. Regression analyses were conducted to identify the main drivers of healthcare costs among pts with ≥8 tf. Covariates included, among others, transition age (<18 vs ≥18 yrs), SCD complications (pain, infection, stroke, cardiomyopathy, renal disease, and Moyamoya disease), current and previous tf, prescription of hydroxyurea, relevant comorbidities, and resources utilization. Results: 3,208 pts were included (FL: 1,550, NJ: 992, MO: 489, KS: 121, IA: 56) in the study. Each pt was observed for an average (SD) of 6.0 (3.1) yrs. 917 pts received ≥8 tf during their observation period. The proportion of pts with ≥8 tf increased from 4% at 2 yrs of age to approximately 24% at 16 yrs old (Fig 1). The proportion of pts with ≥8 tf remained relatively stable around 20% thereafter, in contrast with the overall rate of tf which decreased after age 16. The proportion of chelated pts increased from 4% at 2 yrs of age to a maximum of 50% at age 13 (Fig 1). The proportion of chelated pts then decreased steadily during the following 10 yrs to reach 10% at age 23 and oscillated around that level thereafter. Healthcare costs increased from ages 5 to 19 for all SCD pts ($3,907 to $10,317 per pt-quarter) and those with ≥8 tf ($4,500 to $15,078 per pt-quarter), and remained high through adulthood. Pts with ≥8 tf had greater healthcare costs than the overall SCD population at all ages. Despite the higher Rx costs, pts receiving ICT incurred statistically significantly lower IP costs than chronically transfused pts receiving no ICT, resulting in no statistically significant cost difference (unadjusted cost difference, Rx: $2,285, p<.001; OP: $851, p=.156; IP: -$2,584, p<.001; total: $552, p=.493 [Table 1]; adjusted cost difference, Rx: $2,746, p<.001; OP: -$813, p=.036; IP: -$936, p<.001; total: $61, p=.098). Regression analyses also revealed that SCD complications was the main driver of healthcare costs among pts with ≥8 tf (incremental cost increase: $3,955; p<.001). Conclusions: Pts transitioning to adult care received less tf and ICT when chronically transfused, and had higher healthcare costs than pediatric pts. While other age-related factors are likely to impact SCD treatment patterns and healthcare resource utilization, the marked decrease in tf and proportion of chelated pts and increase in healthcare costs during the transition from pediatric to adult care suggest that tf and ICT are markers for lower healthcare costs in SCD patients. Disclosures: Blinder: Novartis: Honoraria. Vekeman:Analysis Group: Analysis Group has received research grant from Novartis pharmeceuticals, Employment. Trahey:Analysis Group: Analysis group received research grant from Novartis Pharmaceuticals, Employment. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment. Duh:Analysis Group: Analysis group received research grant from Novartis Pharmaceuticals, Employment.

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Pepe, Alessia, Antonella Meloni, Elena Facchini, Antonella Quarta, Vincenzo Spadola, Angela Ermini, Aurelio Maggio, et al. "Normal CMR Bi-Atrial and Biventricular Reference Values in Sickle Cell Disease Patients without Heart Damage." Blood 138, Supplement 1 (November 5, 2021): 3087. http://dx.doi.org/10.1182/blood-2021-144594.

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Abstract Background. Cardiac function indices in patients with hemoglobinopathies are different from those in healthy population, mainly due to chronic anemia. Normal reference values specific for SCD patients are not available by CMR. Aim. We aimed to define the normal cut-off value in SCD patients for bi-atrial and biventricular cardiac magnetic resonance (CMR) parameters. Methods. We considered forty-eight adult SCD patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2*≥20 ms, consecutively enrolled in the MIOT network (Myocardial iron overload in thalassemia). SCD patients were compared with ninety-six healthy controls and 96 thalassemia major (TM) patients without cardiac damage, both matched for age and gender. Nine pediatric SCD patients were also analysed in comparison with 9 TM patients and 9 healthy subjects matched for age and gender. Cine images were acquired to quantify biventricular function parameters: LV and RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized for body surface area (EDVI, ESVI, SVI), as well as biventricular mass and atrial areas. Myocardial iron overload was assessed by segmental T2* technique. Late gadolinium enhancement (LGE) images were acquired for evaluation of macroscopic myocardial fibrosis. Results. In all three groups males showed higher biventricular volumes and mass indexes than females. SCD male patients had significantly higher LVEDVI (p<0.0001), LVESVI (p=0.010), LVSVI (p=0.003), cardiac index (p=0.002), LV and RV mass index (p=0.008 and p=0.001, respectively) and left and right atrial areas (p<0.001 and p=0.011) than healthy subjects. No significant differences were found in RVEDVI, EVESVI and biventricular EF. Compared to healthy volunteers, females with SCD showed a larger LVEDVI (p=0.020), LVSVI (p=0.039), RV mass index (p=0.002) and left atrial area (p=0.008). SCD and TM patients showed comparable values of bi-atrial and biventricular volumes and function. When compared to TM, SCD patients showed a larger LV (p<0.001) and RV mass index (p=0.001) in male group and a larger RV mass index (p=0.001) in female group. Table 1 shows the cut-offs for bi-atrial and biventricular MR parameters for adult SCD patients by gender. No significant differences in MR parameters were found among the pediatric groups. Conclusions. Normal reference ranges of bi-atrial and biventricular MR parameters for adult males and females SCD patients were established. The use of these reference values will prevent possible misdiagnosis of cardiomyopathy in patients with SCD. Figure 1 Figure 1. Disclosures Pepe: Chiesi Farmaceutici S.p.A: Other: no profit support; Bayer S.p.A.: Other: no profit support. Quarta: Sanofi - Genzyme: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Blue Bird Bio: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Celgene: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Takeda: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; speaker at conferences; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at conferences. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Adamkiewicz, Tom, Adel Driss, Hyacinth I. Hyacinth, Jacqueline Hibbert, and Jonathan K. Stiles. "Determinants Of Mortality and Survival In Children With Sickle Cell Disease (SCD) In Sub Saharan Africa." Blood 122, no. 21 (November 15, 2013): 4676. http://dx.doi.org/10.1182/blood.v122.21.4676.4676.

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In Africa, the natural history of SCD is often assumed to be same to the African Diaspora in the US, Jamaica, Europe or Latin America. Yet the environment can be different, including different pathogen exposure, such as malaria. To help better understand this, over 2000 references were identified using the names of all current or past names of African continent countries and the truncated word sickl$, followed by secondary nested and cross reference searches. Six cases series describing causes of death were identified, representing 182 children (Ndugwa, 1973, Athale, 1994, Koko, 1998, Diagne, 2000, Rahimy, 2003, Van-Dunem, 2007). Gender was reported in 172, 73 were female (42%). Age was reported in 118, 52 were < 5 years (44%). Four studies described some impediment to care or arrival for care in extremis in1/4 to over ½ of patients that died. In Uganda, 9/12 (75%) patient died at home. In Gabon 6/23 (26%) patients died within 4 hours of reaching the hospital and 11/23 (48%) within 24 hours. In Benin 2/10 (20%) died of splenic sequestration diagnosed at home; 38/64 (53%) of patients in Mozambique that died, lived outside of the capital. Causes of death were identified in 146 individuals. These included: fever/sepsis: n=59 (40%), including meningitis: n=15 (10%) and pyelonephritis: n=2 (1%); acute anemia: n=43 (29%), including spleen sequestration: n=28 (19%) and aplastic anemia: n=8 (5%); pain: n=22 (15%); acute chest syndrome/pneumonia: n=18 (12%); CNS: n=8 (5%), including stroke: n=4 (3%), seizure/ coma: n=5 (3%); liver disease: n=5 (3%) including hepatitis: n=3 (2%); Other: n=19 (13%) including wasting/ malnutrition: n=7 (5%), heart failure/cardiomyopathy: n=4 (3%), diarrhea and vomiting: n=3 (2%), transfusion reaction: n=2 (1%). Infectious pathogens were identified in 26, including malaria: n=10 (38%), S. pneumoniae: n=3 (12%), Salmonella: n=2 (8%), H. influenza, Klebsiella and Citrobacter: n=1 (4%) each; viral agents were reported in n=8 (31%) including HBV: n=5 (19%), HIV: n=3 (12%). Reported general population hemoglobinopathy surveys after birth revealed the following Relative Risk (RR) of observing individuals with hemoglobin SS compared to Hardy Weinberg expected frequencies (some age cohorts overlap; Tanzania '56, Benin '09, Burkina Faso '70, Central African Republic'75, Gabon'65/'80, Gambia'56, Ghana '56/‘57/'00/'10, Kenya '04/'10, Malawi '72/'00/'04, Mozambique '86, Nigeria '56/'70/'79/'81/'84/'05, Senegal '69, Sierra Leone '56). Age 0-1 years, total n=2112 observed n=22 (1.0%), expected n=16.5 (0.8%), RR=1.3 (95% CI=0.7,2.5), p=0.441. Age 0-6 years, total n=4078; observed n=39 (1.0%); expected n=40.6 (1.0%); RR=1.0 (95% CI=0.6,1.5), p=0.925. Age 5-19 years, total n=1880; observed n= 5 (0.3%); expected n= 24.8 (1.3%); RR=0.2 (95% CI=0.1,0.5); p<0.001. Adults, total n=12814; observed n= 20 (0.2%); expected n= 118.9 (0.9%); RR=0.2 (95% CI=0.1,0.3), p<0.001. Pregnant, total n=5815; observed n= 19 (0.3%); expected n= 78.5 (1.3%), RR=0.2 (95% CI=0.1,0.4), p<0.001. Cohorts of children with SCD are indicated in the table. In summary, access to care, as well as acute anemias are a frequent cause of mortality. Along with viral pathogens and transfusion related deaths this indicates the importance of a safe blood supply. By adulthood, the observed frequency of individuals with SCD is only 1/5 of expected. However, reported clinic cohorts suggest similar if not better survival than in the general population, possibly due to lost to follow up, but also malaria/bacterial infection prevention and nutritional support. Careful prospective studies are needed.TableCohorts of children in Africa with Sickle Cell AnemiaCountryAge median years, (range)Death/TotalnFollow up yearsPatient-yearsDeaths/100 patient-yearsU5M/100 child-yrs♦Uganda, 735 -9, (0-20)12/6282--2.7Senegal, ‘008 (0-22)11/323710331.12.2Senegal, 03330/55612--2.2Benin,032.910/2361.5-6.59831.02.4Kenya,096 (0-13)2/1241.21181.72.7♦: Under five year old mortality 2009 (source: Unicef), divided by 5Prophylactic interventions: Uganda: chloroquine; Senegal: chloroquine (wet season), nets, penicillin prophylaxis <5 yrs, folic acid, parasite treatment & iron supplement as needed; Benin: chloroquine, nets, penicillin prophylaxis, antibiotics for fever, folic acid, nutritional support; Kenya; Proguanil, folic acid, nutritional support, parasite treatment & iron supplement as needed. Disclosures: No relevant conflicts of interest to declare.

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Biernacki, Melinda A., Maureen Okam, Shalini Shenoy, Lakshmanan Krishnamurti, Mitchell E. Horwitz, Donna Neuberg, Joseph H. Antin, and Catherine J. Wu. "Long-Term Follow-up of Adults with Severe Sickle Cell Disease After Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning." Blood 116, no. 21 (November 19, 2010): 261. http://dx.doi.org/10.1182/blood.v116.21.261.261.

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Abstract Abstract 261 Despite advances in care, sickle cell disease (SCD) continues to be associated with considerable morbidity and premature mortality, particularly in adulthood. Myeloablative hematopoietic stem cell transplantation (HSCT) in children 16 years or younger with matched sibling donors is effective, well-tolerated, and controls SCD-mediated damage. In adults, HSCT after myeloablative conditioning carries unacceptable transplant-related mortality. Several recent studies suggest the feasibility of using reduced intensity conditioning regimens (RIC) in adults. However, these reports were generated with few patients, using different regimens, and with short follow-up periods. To determine the common features of these regimens, and to assess the long-term outcomes of RIC-HSCT in adults (16 years or older), we reviewed all reports published on the subject as manuscripts or abstracts from 2002 to 2010. Six distinct RIC-HSCT regimens were used (see table). All included fludarabine and/or alemtuzumab. Twenty previously reported adult patients (age 16–45, median 21 years) and 4 new adult patients were identified. Nine of the 24 patients received bone marrow stem cells, while the rest received peripheral blood stem cells. All had HLA-matched donors. From reported outcomes, RIC-HSCT was well-tolerated with minimal transplant-related toxicity. At a median of 2.5 years, overall survival was 95% and disease-free survival was 85%. Two patients developed acute graft-versus-host disease (GvHD), and 2 developed limited chronic GvHD. To determine long-term outcomes of RIC-HSCT in adults, we obtained follow-up information on 12 of the 24 adult patients from 3 of the 6 centers. At follow-up of up to 6 years, 11 of 12 patients were alive with stable donor chimerism (median 100%, range 0–100%) and no new SCD symptoms. Two developed acute GvHD progressing to chronic extensive GvHD. One had limited chronic GvHD but expired from an embolic event 9 months after HSCT. A fourth developed limited chronic GvHD that resolved off steroids. Six patients were able to discontinue all immunosuppressive medications. In summary, our review of published data and report of subsequent follow-up demonstrate that adult patients with SCD tolerate a variety of RIC. Conditioning regimens combining immunosuppressive agents with moderate ablation appear sufficient to generate sustained donor engraftment and disease control. Though GvHD was common, a majority of patients (6 of 11) eventually discontinued immune suppression. These data together provide compelling rationale for formal clinical trials of RIC-HSCT in adults with severe SCD. Center (Reference) Preparative regimen GvHD prophylaxis Total # subjects in published report Age (years) of adult subjects Published outcomes Latest follow up Follow up (yrs) Death (months) Complications Most recent follow up (yrs) On IS GvHD % donor chimerism University of Pittsburgh (Krishnamurti, 2008) BU 8 mg/kg, Flu 135 kg/kg, ATG 120 mg/kg, TLI 500 cGy CsA, MMF 7 16, 16, 18, (18) 2, 1.5, 3.5 None Pancreatitis (n=1) Graft loss from IS nonadherence (n=1) 5, 5, 6, (1) 1 of 4 1 of 4 (limited cGvHD) 100, 90, 0, (70) Washington University (Shenoy-multicenter, 2008) Mel 140 mg/kg, Alem 48 mg, Flu 150 mg/kgTLI 200 cGy CsA, methylpred, MTX 5 18, 17, (17), 17, (18), (22) 0.6, 0.75, 0.9 One patient, embolus (9) TAM, pancreatitis, hemolytic anemia, pulmonary process (n=1) 3, 1.5, (0.75), -, (0.6), (0.9) 4 of 5 3 of 6 (1 limited cGvHD, 2 aGvHD/extensive cGvHD) 100, 100, (100), -, (56), (96) Duke University (Horwitz, 2007) Cy 2000/m2, Alem 100 mg, Flu 120 mg/kg CsA, MMF 2 21, 27 1.3, 2.0 None Dilated cardiomyopathy (n=1) 4.3, 5.0 0 of 2 0 of 2 91, 60 Munich (Schleuning, 2008) Cy 120/kg, Flu 120 mg/kg CsA, MMF 1 22 1 None None U/A U/A U/A U/A NHLBI (Hsieh, 2009) Alem 1mg/kg,TBI 300 cGy Sirolimus 10 16, 21, 21, 24, 26, 26, 26, 27, 40, 45 1.3-4.5 None Graft loss (n=1), 2nd HSCT successful U/A U/A U/A U/A Columbia University (Bhatia, 2008) BU 16 mg/kg, Alem 62 mg/m2, Flu 180 mg/kg +/- rATG CsA, MMF 7 16 1 None None U/A U/A U/A U/A Alem, alemtuzumab; ATG, antithymocyte globulin; Bu, busulfan; Cy, cyclophosphamide; Flu, fludarabine; Mel, melphalan; TBI, total body irradiation; TLI, total lymphoid irradiation; TAM, transplant-associated angiopathy; HTN, hypertension; IS, immunosuppressive medications; U/A, unavailable. Parentheses indicate previously unreported patient. Disclosures: No relevant conflicts of interest to declare.

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Sultana, Riffat, Dayaram Makwana, Fazal Ur Rehman, Iram Jehan Balouch, Waqar Azim, and Imran Ellahi Soomro. "Prediction of Patient Death due to Sudden Cardiac Arrest with Left Ventricular Dysfunction by Analyzing the Value of BNP: a Prospective Longitudinal Study." Pakistan Journal of Medical and Health Sciences 15, no. 12 (December 30, 2021): 3868–70. http://dx.doi.org/10.53350/pjmhs2115123868.

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Aim: The purpose of this study was to predict the patient’s death due to sudden cardiac arrest with left ventricular dysfunction by analyzing the value of BNP Study design: Prospective longitudinal study Place and duration: This study was conducted at Karachi institute of heart diseases Karachi, Pakistan from Feb 2020 to Feb 2021 Methodology: This cross sectional study was conducted from Feb 2020 to Feb 2021 on 70 patients who were pin pointed with acute STEMI complicated by left ventricular systolic failure and hospitalized in our hospital. A total of 70 patients who were recognized with STEMI, 48 of whom got primary PCI, and 17 of whom received thrombolytic treatment. Results: The average age of the patients was 57.6 years and the range being from 35 to 80 years. Male patients constituted 73.3 percent of the study. It was discovered a mean of NYHA of 2.5, an average Killip classification of 2.8 and an average TIMI score of 8.1. A 90-day follow-up showed that 48 patients survived out of which 7 were reported to have a life-threatening arrhythmia and 12 had sickle cell disease. When ROC curve was shown, Pro-BNP indicated Sc.D. and unanticipated cardiac death was forecasted which also stipulated an AUC of 0.76, while the AUC was 69.6 percent of the ROC curve of the same neuropeptide in evaluating accuracy in prediction of VT, by. A Kaplan-Meier analysis reveals that an increase in pro-BNP over 3.2ng/ml has a significant predictive influence on SCD [OR 0.748 (CI 95 percent: 0.07-0.932), p-value .039] Conclusion: BNP levels in individuals with ischemic cardiomyopathy after an acute MI are a significant, independent predictor of sudden death. Keywords: BNP levels, ischemic cardiomyopathy, sudden death, myocardial infarction

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Vijenthira, Shangari, Jenny Nguyen, Donald R. Branch, Gwen Clarke, Richard Ward, Samia Saeed, and Christine Cserti-Gazdewich. "The Monocyte Monolayer Assay to Build a Personalized Pipeline of Transfusion Support in Highly Sensitized Sickle Cell Disease." Blood 138, Supplement 1 (November 5, 2021): 3247. http://dx.doi.org/10.1182/blood-2021-152762.

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Abstract BACKGROUND: RBC transfusions play a role in organ- and life-preservation for patients with sickle cell disease (SCD). These in turn are subject to higher-fidelity matches to offset the particularly high condition-specific odds of seroconversion events. Adverse outcomes may be as severe as hyperhemolysis, and/or undertransfusion from the scarcity of suitable antigen profiles. In a woman with HbSS SCD and multiple alloantibodies (-K, -E, Jkb-, -Fya, -S), correspondingly antigen-negative units had nevertheless become invariably crossmatch-incompatible (iXM) owing to the development of an antibody to -Kna, a high-prevalence (but clinically insignificant) target antigen on CR1/CD35. Genotyping ruled out the absence of other rare antigen-negative states at risk of high-frequency antibodies (hrB, hrS, Joa, U). Due to uncertainties on the in-vivo effects of iXM RBC in this patient, the infeasibility of sourcing of complete antigen matches, and challenges ruling out other emerging (and potentially more harmful) antibodies, a prolonged period of transfusion-avoidance ensued. This deferral correlated with progression of SCD-associated dilated non-ischemic cardiomyopathy and restrictive interstitial pulmonary fibrosis. In order to qualify Kna-unselected iXM that were otherwise target-negative for her clinically significant antibodies, a monocyte monolayer assay (MMA) approach was taken to identify, transfuse, and maintain a personalized roster of RBCs for monthly top-up transfusions. METHODS: Selected donors (group O, ±D, ±C, E- K- Jkb- Fya-) were assessed at least once in the MMA by a 4:1 (patient serum) to (candidate unit RBC) ratio, incubated at 37°C for 1 hour. The total number of RBCs phagocytosed in 100 patient monocytes was reported as a phagocytic index (PI), with a significance cut-off of 5 (or lower, if rosettes were noted, and/or a noticeably more incompatible [≥3+] crossmatch was observed compared with other prepared units). Antibody screens (automated solid phase) and manual serologic crossmatches (by both conventional tube- and gel microtube- technique) were performed at each RBC sitting. Interval/pre-RBC tests incorporated hemolytic markers and hemoglobin electrophoresis (HbS%). RESULTS: Of 26 donors examined in 8 MMA arrays over 3 years, 10 were excluded due to high PI (median 6 [range 3.3-54]) and/or differential iXM. Of the remaining 16 (PI 0.9 [0.2-4.5]), RBCs have been transfused from 13, with 56 units [u] (51 fresh/5 frozen-deglycerolized) given in 27 sittings over 113 weeks. Most have donated >1u (7/13 with ≥1u transfused to this recipient, median 4u [range 1-8]). The HbS% fell from 91% to 45% [39-48] (median [IQR], pre-3rd-to-27th sitting) with improved hemolytic markers and freedom from overt incompatibility reactions. A minor allergic reaction on the 1 st sitting (with 2u from the same donor) led to a default mitigation strategy of supernatant reduction and antihistamine-premedication thereafter. All sittings (including 5u from the index donor) were reaction-free until a 2 nd minor allergic reaction 2 years later (associated with 2 other donors). Improvements occurred in cardiac function, performance status, pain, and quality of life over the 1 st 20 months of transfusions, though an acute pulmonary embolism and progressive iron overload have reversed the initial gains. Of 11 donors re-examined in 3 repeat MMA (29-112 weeks later), 10 were re-qualified; the 1 st donor was excluded due to an unexplained PI surge (2.5 to 5.6). Host tolerance otherwise increased to most re-qualified donors in a PI downtrend over time (in 8/10, median 1 st PI 2.1, vs median 2 nd PI 1.0, P=0.006 [paired, 2-sided t-test]). A new sensitization (anti-Cob) was noted before the 14 th sitting, with donor genotypes imputing and disqualifying donor 9. CONCLUSIONS: An MMA-vetted pipeline of RBCs in a once-prohibitively alloimmunized patient with SCD has re-enabled transfusion care by the coordinated efforts of the national blood collector with its donors, its MMA laboratory, and the supervising hospital transfusion service. An unexpected finding in repeated exposures to a limited number of donors was increased tolerance. When the viability of transfusions is restored in SCD, so too are opportunities in disease control and in transfusion-requiring curative treatment options. The number of similarly constrained patients, and the scalability of this innovation, remain to be determined. Disclosures No relevant conflicts of interest to declare.

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Detterich, Jon, Leila Noetzli, Susan Carson, Paul Harmatz, Thomas D. Coates, and John C. Wood. "Pulmonary Hypertension Is Uncommon In Well-Transfused Thalassemia Major Patients." Blood 116, no. 21 (November 19, 2010): 4273. http://dx.doi.org/10.1182/blood.v116.21.4273.4273.

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Abstract Abstract 4273 Introduction: Pulmonary hypertension is a common and serious cardiovascular complication in patients with thalassemia intermedia and sickle cell disease. Circulating platelet and erythrocyte fragments, as well as cell-free hemoglobin from intravascular hemolysis, may contribute to nitric oxide depletion, intimal proliferation, and pulmonary vascular remodeling. Splenectomy has been also been associated with pulmonary hypertension in some studies. Ineffective erythropoiesis, via release of PLGF and elevation of other proinflammitory cytokines, has also been associated with pulmonary hypertension. However, the risk for pulmonary hypertension in thalassemia major patients remains controversial, with prevalence estimates ranging from 10%-60%. We report echocardiography results from 80 thalassemia major patients enrolled in the Early Detection of Iron Cardiomyopathy Trial (EDICT) at Children's Hospital Los Angeles. Methods: Patients were enrolled from August 2004 until May 2009 in a combined cross-sectional and observational trial probing for early predictors of cardiac dysfunction. Patient visits were scheduled within one week of transfusion. All patients underwent echocardiography and cardiac MRI analysis within 4 months of each other; most were performed during the same clinical visit (median time between scans one day). Comprehensive assessments of pulmonary artery pressure (tricuspid and pulmonary regurgitation velocities), systolic function, and diastolic function were performed using two dimensional imaging, M-mode, and routine and tissue Doppler. All images were collected by experienced echocardiography technicians and analyzed by the principal investigator. Three to five beat averages were used to improve measurement stability. Tricuspid regurgitation (TR) jet was only reported if a full envelope was recognized; at our institution, the upper limit of normal for TR jet is 2.7 m/s. Results: Patient demographics are summarized in Table 1. Patients were gender-balanced and well distributed between 11 and 47 years of age. Patients who had been splenectomized (N=34) tended to be older. Iron overload was severe, with a mean liver iron concentration of 12.4 ± 14.2 mg/g dry weight. Roughly half of the patients had detectable cardiac iron and 9% had overt left ventricular dysfunction (LVEF < 56%). TR jet was detectable in 62/80 patients. Only one patient exhibited pulmonary artery hypertension (TR jet 2.9 m/s), however this patient also had severe cardiac iron overload and overt left ventricular systolic and diastolic dysfunction (LVEF 42.7%, E/E' 10). Two patients had TR jets of 2.6 ms and three had TR jets of 2.5 m/s. Pulmonary insufficiency jets were normal in all patients. TR velocity did not correlate with age, cardiac index, cardiac iron or liver iron, but demonstrated a weak (r=0.29, p=0.02) association with left ventricular diastolic dysfunction (E/E′). Discussion: The EDICT patient cohort suggests a low risk for pulmonary hypertension in well-transfused thalassemia major patients. The single elevated TR jet was explained by iron cardiomyopathy and normalized (2.2 m/s) after two years of aggressive chelation therapy. TR velocities at the upper limits of normal (2.5-2.7 m/s) were observed in five patients; these have been associated with poor outcomes in some sickle cell disease cohorts, but not in thalassemia major. Long-term surveillance remains critical as pulmonary hypertension risk may increase with age. Disclosures: Harmatz: Novartis: Research Funding. Coates:Novartis: Research Funding, Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

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Wood, John C., Maya Otto-Duessel, Michelle Aguilar, Hanspeter Nick, Marvin D. Nelson, Thomas D. Coates, and Rex Moats. "Cardiac MRI (T2,T2*) Predicts Cardiac Iron in the Gerbil Model of Iron Cardiomyopathy." Blood 104, no. 11 (November 16, 2004): 376. http://dx.doi.org/10.1182/blood.v104.11.376.376.

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Abstract Introduction: Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, creating a potential mechanism for iron quantitation. Validation of liver MRI has been achieved by studying patients undergoing clinically indicated liver biopsy. However, because of the danger and variability of cardiac biopsy, cardiac MRI studies have relied upon “clinical” validation, i.e., the association between low cardiac T2* and cardiac function. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver, using a gerbil iron overload model. Methods: Twelve gerbils underwent iron dextran loading (200 mg/kg/week) from 2–14 weeks; 5 age-matched controls were studied as well. Animals had in-vivo assessment of cardiac T2* as well as hepatic T2 and T2* using a General Electric 1.5 T CVi system with custom isofluorane anesthesia delivery system, imaging enclosure, coil and pulse sequences. Liver and heart were harvested following imaging, weighed, and portions collected for histology and quantitative iron (Mayo Metals Laboratory, Rochester, MN). Ex-vivo cardiac and liver T1 and T2 measurements were performed on fresh specimens (< 30 minutes post-sacrifice) using a Bruker minispectrometer. Results: Control animals had minimal detectable iron at baseline and did not accumulate iron in the liver or the heart over the 14-week study interval. Chemically-assayed heart iron concentration increased 0.078 mg/g(wet wt)/wk (r2=0.98) and iron content 0.022 mg/wk (r2=0.92) by linear regression analysis. Similarly, assayed liver iron concentration increased 1.15 mg/g(wet wt)/week (r2=0.93) over a 10 week interval and liver iron content increased 3.82 mg/wk (r2=0.96). Liver iron deposition was prominent in both sinusoidal cells and hepatocytes. Interstitial fibrosis was mild and there was no necrosis. Cardiac iron deposition was predominantly endomysial, generally sparing the myocytes themselves. Interstitial fibrosis was prominent, originating from areas of high iron concentration. No myocyte necrosis was observed, however myocyte hypertrophy was evident at high iron concentrations. Cardiac and liver R2* (1/T2*), R2 (1/T2), and R1 (1/T1) rose linearly with tissue iron concentration (r2 averaged 0.94 [0.74 to 0.98]. The slope of these parameter with respect to iron was15–29% steeper in heart than in liver, although these differences reached statistical significance only for R2. Systematic differences in wet-to-dry weight ratio between heart and liver (5.07 vs 3.82) antagonized this effect, however, such that calibrations were similar on a dry-weight basis. Conclusion: Cardiac iron is the primary determinant of cardiac MRI relaxivity. Calibration curves were similar between heart and liver on a dry weight basis. Extrapolation of liver calibration curves to heart may be a rationale approximation in humans where direct tissue validation is difficult and dangerous. Regardless of systematic differences in absolute calibration, these data support prior claims that cardiac R2 and R2* measurements reflect cardiac iron concentration

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Delea, Thomas E., May Hagiwara, and Pradyumna D. Phatak. "Retrospective, Nested, Case-Control Study of the Association between Transfusion Frequency and Potential Complications of Iron Overload in Patients with Myelodysplastic Syndrome and Other Acquired Hematopoietic Disorders." Blood 108, no. 11 (November 16, 2006): 968. http://dx.doi.org/10.1182/blood.v108.11.968.968.

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Abstract Background Patients with myelodysplastic syndrome (MDS) and other acquired hematopoietic disorders frequently require chronic transfusion therapy. Although red cell transfusions are known to cause iron overload, data on the risk of iron-related complications in these patients are limited. Methods We conducted a retrospective, case-control study of the association between complications of iron overload and exposure to transfusions among patients in a large US health-insurance claims database with a diagnosis of MDS and other hematopoietic disorders (ICD-9-CM 238.7: neoplasm of uncertain behavior of other lymphatic and hematopoietic tissues) between 1997 and 2004. Patients with <1 year of claims data prior to this diagnosis (“diagnosis date”), <40 years of age as of diagnosis date, with potential complications of iron overload prior to the diagnosis date, or with diagnoses of thalassemia (ICD-9-CM 282.4) or sickle cell disease (ICD-9-CM 282.6), or were excluded. Complications included: cardiomyopathy/heart failure (ICD-9-CM 425, 428), conduction/rhythm disorders (ICD-9-CM 426, 427), diabetes (ICD-9-CM 250 or antidiabetes medication), and liver disease (ICD-9-CM 571, 572.2, 572.3, 572.8 573.0, 573.8, 573.9, 789.1, 789.5, v427). Cases were defined as subjects with complications of iron overload after the diagnosis date and were compared with a corresponding number of controls (patients without complications) with respect to receipt of transfusions, controlling for other demographic and clinical characteristics (e.g., age, sex, region, plan type, comorbidities, medical care utilization and expenditures), using multivariate conditional logistic regression. Results A total of 7113 patients met inclusion criteria. From these, we identified 511 patients with one or more complications after the diagnosis date and a corresponding number of controls. Patients with complications were older (mean age 60 vs 56 years, p<.0001) and had more comorbidities (mean Charlson index 2.8 vs 1.4, p<.0001) than those without complications. Mean (max) follow-up was 6.8 (46.0) months. Among those with complications, 22% received one or more transfusion post-diagnosis, compared with 5% of those without complications. Few patients in either group (<1%) received deferoxamine. After controlling for demographic and clinical characteristics using multivariate conditional logistic regression, risk of potential complications of iron overload was significantly associated with receipt of transfusions (Odds ratio [OR]=2.909, p=.0008). Results for specific potential complications were as follows: cardiomyopathy or heart failure (OR 1.616, p=.2955), conduction/rhythm disorders (OR=4.135, p<.0005), diabetes (OR=5.063, p=.0025), and liver disease (OR=3.325, p=.0008). Risk of complications also was associated with the number of transfusion episodes (unique days on which transfusions were received) (OR=1.096, p=.0483). Conclusions In patients with MDS and other acquired hematopoietic disorders, patients receiving transfusions are at increased risks of potential complications of iron overload. Iron chelation therapy may be appropriate especially for those with a relatively favorable prognosis.

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Pecker, Lydia H., and Sophie Lanzkron. "Sickle Cell Disease." Annals of Internal Medicine 174, no. 1 (January 2021): ITC1—ITC16. http://dx.doi.org/10.7326/aitc202101190.

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Driscoll, M. C. "Sickle Cell Disease." Pediatrics in Review 28, no. 7 (July 1, 2007): 259–68. http://dx.doi.org/10.1542/pir.28-7-259.

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McCavit, T. L. "Sickle Cell Disease." Pediatrics in Review 33, no. 5 (May 1, 2012): 195–206. http://dx.doi.org/10.1542/pir.33-5-195.

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Whelan, Jacqueline. "Sickle cell disease." Paediatric Nursing 3, no. 4 (May 1991): 24–27. http://dx.doi.org/10.7748/paed.3.4.24.s15.

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Yardumian, Anne, and Charles Crawley. "Sickle cell disease." Clinical Medicine 1, no. 6 (November 1, 2001): 441–46. http://dx.doi.org/10.7861/clinmedicine.1-6-441.

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Steinberg, Martin H. "Sickle Cell Disease." Annals of Internal Medicine 155, no. 5 (September 6, 2011): ITC3. http://dx.doi.org/10.7326/0003-4819-155-5-201109060-01003.

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Naoum, Paulo Cesar. "Sickle cell disease." Revista Brasileira de Hematologia e Hemoterapia 33, no. 1 (2011): 7–9. http://dx.doi.org/10.5581/v33n1a6.

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Kavanagh, Patricia L., Titilope A. Fasipe, and Ted Wun. "Sickle Cell Disease." JAMA 328, no. 1 (July 5, 2022): 57. http://dx.doi.org/10.1001/jama.2022.10233.

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Duffin, Christian. "Sickle cell disease." Emergency Nurse 16, no. 4 (July 23, 2008): 10–13. http://dx.doi.org/10.7748/en.16.4.10.s16.

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Driscoll, M. Catherine. "Sickle Cell Disease." Pediatrics In Review 28, no. 7 (July 1, 2007): 259–68. http://dx.doi.org/10.1542/pir.28.7.259.

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McCavit, Timothy L. "Sickle Cell Disease." Pediatrics In Review 33, no. 5 (May 1, 2012): 195–206. http://dx.doi.org/10.1542/pir.33.5.195.

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Brody, Herb. "Sickle-cell disease." Nature 596, no. 7873 (August 25, 2021): S1. http://dx.doi.org/10.1038/d41586-021-02137-x.

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Altstatt, Leslie B. "Sickle Cell Disease." American Journal of Tropical Medicine and Hygiene 36, no. 1 (January 1, 1987): 202. http://dx.doi.org/10.4269/ajtmh.1987.36.1.tm0360010202a.

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Thomas, Veronica Nicky, and Neill Westerdale. "Sickle cell disease." Nursing Standard 11, no. 25 (March 12, 1997): 40–47. http://dx.doi.org/10.7748/ns.11.25.40.s55.

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Ekong, Anietie. "Sickle cell disease." InnovAiT: Education and inspiration for general practice 10, no. 2 (September 27, 2016): 73–81. http://dx.doi.org/10.1177/1755738015626186.

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Анотація:

The haemoglobinopathies are the most common monogenetic diseases in the world. They include the thalassaemias and sickle cell syndromes. The sickle cell syndromes encompass several abnormal haemoglobin variants, of which homozygosity for the sickle cell gene – that is, sickle cell anaemia is the most common and most severe. Originally characteristic of the tropics and subtropics, recent mobility and migratory trends have meant that the prevalence of sickle cell disease (SCD) has significantly increased in the UK. It is important that GPs have an understanding of this disease, in order to help their patients deal with complications of every-day life. This article will address three main aspects of SCD: diagnosis, health maintenance, and some acute and chronic complications of SCD.

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