Study Of Clinical Characteristics Of Sickle Cell Disease Patients Developing Cor-Pulmonale During Acute Hospitalization

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

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Cardiac Iron Overload in Sickle Cell Disease: When to Screen and How to Intervene

Blood ◽

10.1182/blood-2018-99-114123 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 528-528

Author(s):

Amy Y Tang ◽

Cassandra D Josephson ◽

Kristina Lai ◽

Peter A. Lane ◽

Ross M. Fasano

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Clinical Characteristics ◽

Iron Loading ◽

Cell Disease ◽

Transfusion Therapy ◽

Cardiac Iron ◽

Cardiac Iron Overload

Abstract Background Iron overload is a recognized consequence of chronic transfusion therapy in patients with sickle cell disease (SCD), but most of the focus to date has been on the effects of increased liver iron concentration (LIC) with increasing transfusion burden. Even though there is a robust body of literature concerning cardiac iron overload (CIO) in patients with thalassemia major, there remains a paucity of data in how to detect and treat CIO in patients with SCD, particularly in the pediatric and young adult population. While CIO is seen less commonly in sickle cell disease than in thalassemia, patients with SCD remain at risk, with recent studies demonstrating an incidence of 2-5% of CIO in chronically transfused patients with SCD. We performed a retrospective chart review of patients with cardiac MRIs (cMRIs) and LICs by Ferriscan performed at our institution to identify risk factors for CIO, as well as to characterize institutional practice for assessing cardiac iron in the absence of defined practice guidelines. Methods We reviewed clinical characteristics of all patients with SCD who had cMRIs performed at Children's Healthcare of Atlanta between June 2012 and December 2017. We then queried our institutional sickle cell database for patients who were at least 3 years old in 2010, genotype SS or S Beta zero thalassemia, were on chronic transfusions for at least 5 years by 2017, and had not undergone a cMRI. Patients who were status post bone marrow transplant were excluded. For comparison of age, average ferritin, and transfusion duration, significance among means between patients with and without CIO was calculated using a two-tailed unpaired t-test. For comparison of LIC, significance among medians was calculated using the Mann Whitney test. A p value of <0.05 was considered significant. Statistical analyses were performed using Prism 6 (GraphPad Software, Inc.). Results Of 36 evaluable patients who had undergone cMRI, there were 11 with CIO, as defined by a T2* < 20ms. Clinical characteristics are shown in Figure 1. Patients were 7-28 years of age, and had received chronic transfusion therapy for a range of 22 months to 228 months. Between patients who did and did not have CIO, there was no significant difference in average 1-year ferritin level (6786 vs 6373 ng/mL, p=0.79), transfusion duration (103 vs 123 months, p=0.41), or age (15 vs 18 years, p=0.12). There was a higher median LIC by Ferriscan of > 43 mg/g in those with CIO vs 34 mg/g in those without CIO, although this was not statistically significant (Figure 1). Interestingly, CIO was seen as young as 7 years of age and after as little as 22 months of chronic transfusions, and with concurrent LIC values as low as 8.1 mg/g. Of the 11 patients with CIO, 6 had follow-up cMRI data available, and all 6 had normalization of cardiac iron (T2* > 20ms) on subsequent MRIs (Figure 2 and Table 2). There was 1 patient who did not have full transfusion and chelation history available for analysis. Of the remaining 5, 5/5 had increased or more aggressive chelation added, including 2 who were started on high-dose IV Desferal every 2 weeks; 3/5 also had partial manual exchange (PME) added to their chronic transfusion regimens. There were 80 patients who were on chronic transfusions but did not have a cMRI performed; as a group, they had a median LIC of 17 mg/g (range: 1.7 - >43 mg/g), an average 1-year ferritin of 3641 ng/mL (range: 520 - 8478 ng/mL), and had been on chronic transfusions for a mean of 87 months at time of Ferriscan study (range: 14 - 192 months). Overall, these patients had a lower transfusion burden than those who received cMRIs, but there were several in this group who had significant iron overload, including 10 who had LIC values of > 43mg/g. Conclusion CIO in SCD may be a more salient issue, and occur earlier, than previously described. We did not find a strong relationship between CIO and ferritin levels or LIC by Ferriscan, but we did find that CIO was reversible with more aggressive chelation or the addition of PME. While guidelines for monitoring for CIO in SCD are largely extrapolated from thalassemia data, the rate and physiology of iron loading may be completely different. Due to a paucity of information in this area, more studies are needed to guide screening and to fully assess risk factors that may put certain individuals more at risk for cardiac iron loading. Disclosures No relevant conflicts of interest to declare.

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Vaso-occlusion in Children With Sickle Cell Disease: Clinical Characteristics and Biologic Correlates

Yearbook of Pediatrics ◽

10.1016/s0084-3954(07)70057-x ◽

2006 ◽

Vol 2006 ◽

pp. 65-67

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Characteristics ◽

Cell Disease

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Prevalence of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: A Retrospective US Claims Database Analysis

Blood ◽

10.1182/blood-2020-140756 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Abiola Oladapo ◽

Elyse Swallow ◽

Allison Briggs ◽

Miriam L. Zichlin ◽

Bjorn L Mellgard

Keyword(s):

Health Care ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Characteristics ◽

Cell Disease ◽

Publicly Traded ◽

Database Analysis ◽

Claims Database ◽

Blood Disorder ◽

The Mean

Introduction: Sickle cell disease (SCD) is an inherited blood disorder affecting ~100,000 individuals in the US. SCD is considered a chronic, lifelong condition that requires comprehensive management. Vaso-occlusive crises (VOCs) are the most common complications of SCD, resulting in intense pain and potential irreversible organ damage. The objective of this study was to characterize the demographic and clinical characteristics of patients with SCD. Methods: A retrospective database analysis was conducted using data from the IBM MarketScan Commercial Claims and Medicare-Supplemental Claims database (July 1, 2013 to June 30, 2018). Patients were included if they met the following criteria: ≥2 diagnoses of SCD on different claims between July 1, 2013 and January 1, 2017, ≥6 years of age on January 1, 2017, and continuous enrollment throughout the 1-year study period (January 1, 2017 to December 31, 2017). Descriptive statistics were used to assess patient demographics (age and sex) and clinical characteristics (Charlson Comorbidity Index [CCI] and other selected comorbidities). In addition, the following outcomes were assessed: the proportion of patients who experienced ≥1 VOC, the frequency of VOCs by care setting, the duration of inpatient VOCs, the monthly VOC risk, and the time between subsequent VOCs. Results: A total of 8174 patients met the inclusion criteria. The mean (± standard deviation [SD]) age was 40.8 (±19.5) years and 63.5% of the patients were female. The mean (±SD) CCI was 0.6 (±1.3), with chronic pulmonary disease, diabetes, renal disease, cerebrovascular disease, and stroke identified as the most common comorbidities. Approximately 20% (n=1659) of patients experienced ≥1 VOC and the mean monthly VOC risk was 0.07 (±0.19). Among patients with ≥1 VOC, the mean (±SD) number of VOCs was 5.2 (±7.7) and the median (interquartile range) time from first to second VOC was 2.4 (0.5-8.2) months. Approximately 18% (n=1461) of patients experienced ≥1 VOC managed in an outpatient setting and 10% (n=844) of patients experienced ≥1 VOC managed in an inpatient setting. Approximately 8% (n=646) of patients experienced ≥1 inpatient and ≥1 outpatient VOC during the study period. Among patients with ≥1 outpatient VOC, the mean (±SD) number of outpatient VOCs was 4.6 (±6.9); among patients with ≥1 inpatient VOC, the mean (±SD) number of inpatient VOCs was 2.2 (±2.3) and the mean (±SD) inpatient VOC duration was 6.6 (±6.4) days. Conclusions: VOCs are common complications of SCD, affecting a subset of patients who often experience recurrent VOC episodes requiring professional health care. VOCs are associated with a significant disease burden on the patient and, potentially, the health care system. Disclosures Oladapo: Takeda:Current Employment, Current equity holder in publicly-traded company.Swallow:Analysis Group, Inc.:Current Employment.Briggs:Analysis Group, Inc.:Current Employment.Zichlin:BMS:Other: Employee of Analysis Group Inc., which received consulting fees.Mellgard:Baxalta US Inc., a Takeda company:Current Employment, Current equity holder in publicly-traded company.

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Pulmonary Hypertension in Children with Sickle Cell Disease: Clinical Characteristics and Co-Morbidities.

Blood ◽

10.1182/blood.v106.11.3791.3791 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3791-3791

Author(s):

Steven J. Ambrusko ◽

Sriya Gunawardena ◽

Allison Sakara ◽

Beth Windsor ◽

Lizabeth Lanford ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Clinical Characteristics ◽

Total Bilirubin ◽

Asthma Therapy ◽

Cell Disease ◽

Transfusion Therapy ◽

Jet Velocity ◽

Post Therapy

Abstract BACKGROUND: Pulmonary hypertension is a potentially life threatening complication described in adults with sickle cell disease and other hemolytic disorders. There has been little to no information on the occurrence of this condition in pediatric patients. METHODS: Retrospective case review of sickle cell patients at Children’s Hospital of Pittsburgh to determine the clinical characteristics and co-morbidities of patients previously diagnosed with pulmonary hypertension, as detected by tricuspid regurgitant (TR) jet velocity of ≥ 2.5 m/sec on Doppler echocardiography. RESULTS: Nine patients with sickle cell disease (all HbSS) were diagnosed with pulmonary hypertension, with an initial mean TR jet velocity of 2.98±0.19 m/sec. All had some history of respiratory disease, 4 had a cerebrovascular disease, and 4 were previously on a chronic transfusion program. Laboratory results reveal low hemoglobin, reticulocytosis, and elevated total bilirubin and lactate dehydrogenase in a majority of patients, suggesting clinically significant chronic hemolysis. Therapy initiated for these patients included increasing transfusion therapy, oxygen supplementation, hydroxyurea, and tonsillectomy when indicated. These interventions resulted in a reduction in mean post-therapy TR Jet to 2.61±0.21 m/sec (p=0.0015) in 8 of 9 patients. CONCLUSIONS: Pulmonary hypertension occurs in children with sickle cell disease and is associated with manifestations of increased hemolysis and co-morbid respiratory or cerebrovascular diseases. Aggressive sickle cell-directed therapy and management of co-morbidities reduces the degree of pulmonary hypertension. Table I Pt #/Age/Sex Complications/Co-morbidities Hemoglobin % Reticulocytes Ferritin Total Bilirubin LDH Therapies/Intervention Abbreviations: LDH, lactate dehydrogenase; MCA, middle cerebral artery; OSA, obstructive sleep apnea; TRX, transfusion therapy; O2, oxygen; ACS, acute chest syndrome; VOC, vasoocclusive crisis 1: 13/F Asthma, OSA, MCA stenosis, pneumonia/ACS, iron overload 8.7 14.4 2010 8.1 n/a Chronic TRX, asthma therapy, Tonsillectomy 2: 18/M ACS (multiple), hyperhemolysis, allosensitization, aplastic crises, central hypopnea, cor pulmonale 5.8 34 774 6.4 527 Chronic TRX, O2 at night, initiation of hydroxyurea 3: 14/M Asthma, nocturnal enuresis, constipation, OSA, ACS, recurrent VOC 8.8 11.1 4330 2 657 Periodic TRX, O2 at night, hydroxyurea, asthma therapy 4: 18/M Asthma, Hepatitis C, silent stroke, Moya-Moya syndrome, priaprism, sepsis (multiple), aplastic crises, iron overload 9.1 7.3 4385 2.6 n/a Chronic TRX, O2 at night, asthma therapy 5: 17/F Hepatitis C, asthma, restrictive lung disease, chronic dyspnea, blain gliosis, silent stroke, ACS, cardiomegaly, allosensitization 7.1 19.7 n/a 5.7 n/a Infrequent TRX (due to allosensitization), O2, asthma therapy 6: 12/M Asthma, nocturnal enuresis, sepsis 7.9 17 310 5.1 485 Increased frequency TRX, asthma therapy 7: 16/M ACS, stroke, intracranial hemorrhage 8.2 9.5 2012 3.5 440 Chronic TRX, O2 at night 8: 14/F ACS, cardiomegaly 8.8 14 n/a 3.9 n/a Initiaion of TRX, O2 at night 9: 9/M Tonsillar hypertrophy, possible OSA, cardiomegaly 6.1 20.7 n/a 4.1 667 Increased frequency TRX Table II Patient # Maximum TR Jet TR Jet Post-Therapy TR Jet: tricuspid regurgitant jet velocity (m/sec) 1 2.6 2.4 2 3 2.7 3 3 2 4 2.8 2.6 5 3.3 2.8 6 3.5 3 7 3 2.7 8 3 2.7 9 2.65 n/a yet

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Economic Burden of End Organ Damage Among Patients with Sickle Cell Disease in the US

Blood ◽

10.1182/blood-2019-127173 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3388-3388

Author(s):

Xue Song ◽

Andrew D. Campbell ◽

Ze Cong ◽

Irene Agodoa ◽

Diane Martinez ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Economic Burden ◽

Research Funding ◽

Clinical Characteristics ◽

Index Date ◽

Organ Damage ◽

Cell Disease ◽

End Organ Damage ◽

Ibm Watson

Introduction Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin polymerization and red blood cell sickling, leading to chronic anemia, hemolysis, and episodic vaso-occlusion. Anemia affects the brain, kidneys and cardiovascular system, and is associated with neurocognitive dysfunction, silent cerebral infarction, stroke, renal dysfunction, pulmonary hypertension, and mortality. Limited research has been conducted to quantify the economic burden of end organ damage among patients with sickle cell disease in the US. Methods Patients with ≥3 nondiagnostic SCD ICD-9/ICD-10 codes within 5 years (Jan 1, 2013-Dec 31, 2017) were identified in the MarketScan® Medicaid claims databases. The first date of SCD diagnosis was the index date. At least three months of continuous enrollment with medical and pharmacy benefits prior to the index date, and at least 1 month of continuous enrollment following the index date were required to be included. Each patient's post-index period was divided into a series of 3-month intervals. For each 3-month interval, patients' entire available claims history (as early as 1/1/2008) was checked to identify four types of end organ damage experienced by SCD patients including stroke (within 1st year and >1 year after an acute stroke event), chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). Total healthcare costs (plan paid and patient out-of-pocket payment) and healthcare resource utilization (HRU) information were determined for each 3-month interval. Patient characteristics, HRU, and costs were summarized descriptively by type of end organ damage. Three multivariate generalized linear models with loglink function and gamma error distribution (assuming the cost follows an exponential relationship to the weighted average of covariates) were employed to estimate the relative cost ratios of patients with vs. without end organ damage, controlling for patients' demographic and clinical characteristics. Annualized costs for adult patients with each type of end organ damage were estimated based on the regression results. Results A total of 10,784 patients with SCD on Medicaid were identified. Patients were followed for 3.35 years on average, contributing 152,455 intervals (age ≥18: 42.7%; female: 54.6%; urban: 84.4%). Approximately 20% of the intervals had end organ damage. Patients with end organ damage had more days in hospital, ER visits, outpatient visits, lab tests, and outpatient pharmacy claims per month than patients without organ damage (Figure). The mean (SD) cost per hospitalization for acute stroke was $55,314 ($76, 847). In multivariate regression model 1 (accounting for end organ damage only), patients with any end organ damage had significantly higher costs than those without these conditions. After controlling for patient demographic characteristics (model 2) and additional clinical characteristics (model 3), the results were similar. The costs of SCD patients in the first year after stroke are 4.68 times as high as the costs of patients without any organ damage (2.08 times if >1 yr after stroke; 2.32 times for PH; 2.19 times for CKD; and 3.40 times for ESRD) (Table). The transitional age group (18-30 years) had significantly higher costs than other age groups. Having other SCD complications such as avascular necrosis, gallstones, cholelithiasis, cholecystitis, leg ulcers, osteomyelitis, or priapism also significantly increased the total costs. Based on model 3, after controlling for patient demographics and clinical characteristics, the predicted mean annual costs for adult patients with SCD in the first year after a stroke is $285,816; $127,393 if more than one year after a stroke; $148,174, $135,492, or $209,172 if the patient had PH, CKD or ESRD, respectively. Patients with multiple SCD complications had even higher costs. For example, the predicted mean annual cost for adult patients with CKD and avascular necrosis is $270,513. Conclusions Sickle cell disease is associated with substantial economic burden. When patients experience end organ damage such as stroke, renal dysfunction, or cardiopulmonary conditions, this economic burden is significantly elevated. SCD management strategies that can potentially reduce the risks of end organ damage offer both clinical and economic values to patients and society. Disclosures Song: Global Blood Therapeutics: Other: Xue Song is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Campbell:Cyclerion: Consultancy, Research Funding; Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Martinez:Global Blood Therapeutics: Other: Diane Martinez is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lew:Global Blood Therapeutics: Other: Carolyn Lew is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Black:Global Blood Therapeutics: Other: Danae Black is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Varker:Global Blood Therapeutics: Other: Helen Varker is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Chan:Global Blood Therapeutics: Other: Chris Chan is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lanzkron:Pfizer: Research Funding; Ironwood: Research Funding; Global Blood Therapeutics: Research Funding; HRSA: Research Funding; NIH: Research Funding; PCORI: Research Funding.

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