Effects of Chronic Transfusion Therapy on MRI and MRA in Children with Sickle Cell Anemia at Risk for Primary Stroke: Baseline Imaging from the Twitch Trial

Abstract Introduction : Stroke is a major cause of morbidity and mortality in children with sickle cell anemia (SCA), and current efforts seek to prevent primary stroke in this high-risk population through transcranial Doppler (TCD) screening programs and prophylactic blood transfusions for children with abnormally high intracranial TCD velocities. During the SWITCH trial (ClinicalTrials.gov NCT00122980), a novel MRA vasculopathy grading (VOG) scale was developed, which documented baseline bilateral vessel stenosis and parenchymal injury in children receiving transfusions for secondary stroke prophylaxis, and provided a severity scale suitable for future clinical trials. We now describe the baseline brain magnetic resonance imaging/angiography (MRI/MRA) results and vasculopathy grading scores in children with SCA on primary stroke prophylaxis, and report correlations with intracranial TCD velocities and duration of transfusion. Methods: TCD With Transfusions Changing to Hydroxyurea (TWiTCH) is a Phase three randomized, controlled, multicenter clinical trial (ClinicalTrials.gov NCT01425307), comparing transfusions versus hydroxyurea for children with abnormal TCD velocities. Children were eligible for TWiTCH enrollment if they currently receive monthly transfusions for primary stroke prophylaxis, and had no known history of stroke, transient ischemic attack, or severe vasculopathy. All TWiTCH participants underwent baseline MRI/MRA examinations with central review after study enrollment. Baseline TCD examinations were also centrally reviewed and Time-Averaged Mean Velocities (TAMV) were recorded for the distal internal carotid artery (dICA), internal carotid bifurcation (BIF), first segment middle cerebral artery (MCA) = M1, mid MCA (MCA), and posterior cerebral artery (PCA). MRA vasculopathy grades were recorded bilaterally and compared to the TCD velocities and duration of transfusion. Results: Of 159 enrolled subjects, 143 had complete baseline MRI/MRA data. The mean age at study enrollment was 9.8 years, with a 2:3 male:female ratio, and mean age at the original abnormal (Index) TCD exam was 5.4 years. A total of 62 children had parenchymal abnormalities identified on baseline brain MRI, including 2 with infarcts, 54 with leukoencephalopathy, 5 with encephalomalacia, and 20 with lacunae lesions (not mutually exclusive). A total of 124 children had baseline MRA vasculopathy scores ≤3, while 19 had grades 4-6 (severe vasculopathy) that required removal from the study. There were significant positive associations between the baseline hemisphere vasculopathy grades and the corresponding TAMV velocities in the Left dICA (p=0.02), Left BIF (p˂.0001), Left MCA (p=.0002), Right BIF (p=.0003) and Right MCA (p=.0002). Likewise, when TCD velocities were categorized as low (<70 cm/s), normal (70-169 cm/s) or conditional/abnormal (≥170 cm/s), there were positive associations between left-sided vasculopathy and the left BIF (p=.04) and MCA (p=.003), along with right-sided vasculopathy with the right dICA (p=.04). The mean duration of transfusion for subjects with baseline MRA vasculopathy scores ≤3 was 1557 days, while those with severe vasculopathy (grades 4-6) was 1985 days; p= 0.053. Conclusions: Since the TWiTCH study excluded the enrollment of children on chronic transfusion therapy for primary stroke prevention with a known history of stroke, TIA, or severe vasculopathy, the prevalence of baseline brain MRI and MRA abnormalities was relatively higher than expected and 19 participants failed screening due to unrecognized severe vessel stenosis. The recent published SWiTCH vasculopathy grading scale was validated in the TWiTCH population, with more severe stenosis found to be associated with higher ipsilateral TCD velocities. Exit brain MRI/MRA exams will be compared to entry studies, to provide longitudinal data including comparisons between the effects of continued transfusions and hydroxyurea. Disclosures No relevant conflicts of interest to declare.

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Transcranial Doppler in Sickle Cell Anemia Adult Patients: Brazilian Experience.

Blood ◽

10.1182/blood.v104.11.3736.3736 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3736-3736

Author(s):

Gisele S. Silva ◽

Maria S. Figueiredo ◽

Perla Vicari ◽

Airton R. Massaro ◽

Adauto Castelo Filho ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Stroke Risk ◽

Arterial Disease ◽

Neurological Complications ◽

Adult Patients ◽

History Of ◽

The Mean

Abstract Sickle cell anemia (SCA) may cause a variety of neurological complications, including stroke and headaches. Stroke occurs in up to 9% of children with SCA, and transcranial Doppler (TCD) studies have demonstrated that increased velocities are related to higher stroke risk. Throbbing headache occurs in SCA but its cause, frequency, and relationship to TCD velocities have received little attention. On the other hand, there are few TCD studies in adult patients. Our aims were: 1) to describe the main features of TCD in adult SCA patients, and 2) to investigate if there were correlation between TCD features and presence of headache. TCD was performed in 56 adult SCA patients (≥ 16 years old) and in 56 healthy individuals (HI), matched by age and race. There were 6 patients with a remote history of stroke but none were on chronic transfusion. The SCA group was submitted to a neurological evaluation and specifically asked about the occurrence of headache and its characteristics. The highest flow velocity (maxFV) recorded for each artery was considered the most representative. We analyzed the frequency of FV asymmetry (side-to-side difference > 20%) and focal FV changes. The mean maxFV was significantly higher in patients (117.7 ± 21.6 cm/s) than in HI (72.45 ± 11.48 cm/s) (p<0.005). Only one patient had maxFV higher than 170 cm/s. The frequencies of asymmetry and of focal FV changes were significantly higher in SCA. Forty-one patients (73.2%) reported having headaches. Twenty-eight patients (50%) had severe (= 5 for pain intensity at a 1–10 scale) and frequent headaches (at least once a month). This group of patients presented TCD velocities significantly higher than patients without or with milder headaches (p=0.035). In conclusion, TCD maxFV was significantly higher in adult patients with SCA than HI, however, only one patient was considered at risk of stroke according to TCD criteria described in children. FV asymmetry and focal FV changes may be markers for arterial disease in adult SCA patients, and need to be further confirmed by neuroimaging and clinical follow up studies. The patients with severe headaches presented TCD velocities significantly higher than patients without or with milder headaches, but this finding needs to be confirmed by more and larger studies.

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Clinical Complications in Adult Patients with Sickle Cell Anemia and β-Thalassemia-Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4767.4767 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4767-4767

Author(s):

Giovanna Graziadei ◽

Alessia Marcon ◽

Martina Soldarini ◽

Ilaria Gandolfi ◽

Luisa Ronzoni ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Acute Chest Syndrome ◽

P Value ◽

Cell Disease ◽

Transfusion Therapy ◽

Clinical Complications ◽

Significant Difference ◽

The Mean

Abstract Abstract 4767 Background. Sickle-Cell Disease (SCD) is one of the most common severe monogenic inherited disorders worldwide, due to hemoglobin S (HbS), with reduced affinity for the oxygen. HbS polymerization, leading to erythrocyte rigidity, vaso-occlusion and hemolytic anemia, is central in the pathophysiology and crucial for the clinical outcome. The term SCD refers to Sickle Cell Anemia (SCA) due to homozygosis for βS allele, HbS/β-thalassemia (T-SCD) due to compound of β-thal and βS allele, and HbSC disease, owing to the coinheritance of βS and βcalleles. SCD is a multiorgan disease characterized by recurrent acute events and progressive organ damage, worsening during the life. Aims. This is a retrospective monocentric study aimed to assess and compare the clinical complications among 59 adult SCD patients, followed at the Hereditary Anemia Centre of the Foundation IRCCS “Ca Granda” Ospedale Maggiore Policlinico, in Milan, Italy. Methods. Mutation analysis of the b globin gene was established by direct DNA sequencing on the ABI Prism 310 genetic analyzer. Clinical and hematological features were evaluated by routine tests and physical examination, with special attention to the erythropoiesis stress parameters as LDH values and extramedullary erythropoietic (EE) masses. Results. Fifty-nine adult SCD patients, 16 SCA and 43 T-SCD, were evaluated. In T-SCD patients detected b-mutations were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2%. The mean age of SCA patients was 36±9 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years, while the mean age at the presentation in our Centre was 32±8 years in SCA patients and 31±10 years in T-SCD ones. Five out of 16 (31.2%) SCA patients and 16/43 (37.2%) T-SCD patients were male. HbF mean levels were 6.9±5.1% and 10.1±7.2%, respectively in SCA and T-SCD group; surprisingly Hb mean levels were lower in SCA (9.3±1.3 g/dl) than in T-SCD (9.9±1.4 g/dl) patients. Comparing SCA and T-SCD, there was statistically significant difference in splenic features: splenectomy was performed in 2/16 (12.5%) SCA patients vs 21/43 (48.8%) T-SCD patients (p-value < 0.01). Splenomegaly was absent in SCA, while was detected in 11/22 (50%) T-SCD (p-value < 0.0001); all SCA patients had functional asplenia, not observed in T-SCD patients; splenic infarctions were absent in SCA patients and were detected in 7/22 (31.8%) T-SCD patients, of whom 5 had splenomegaly and 2 had normal spleen size (pvalue <0.001). On the other side, there was not statistically significant difference in the prevalence of stroke, acute chest syndrome (ACS), bone pain crisis, sepsis, leg ulcers and priapism. However, we observed some clinical differences, even if not statistically significant. Cholecistectomy was performed in 4/16 (25%) SCA patients vs 17/43 (39.5%) T-SCD patients, and gallstones were detected respectively in 5/12 (41.7%) and in 14/26 (53.8%) of SCA and T-SCD patients. Thrombotic events were absent in SCA patients, compared to 4/43 (9.3%) T-SCD patients. Furthermore, we detected EE in 3/16 (18.6%) SCA and in 3/43 (7%) T-SCD, all carrying b° thal mutations. We underlie that Hb levels and LDH values were higher in SCA than in T-SCD patients (823±295 vs 689±209 U/L). About the treatment, 14/16 (87.5%) SCA and 31/43 (72%) T-SCD underwent to top-up transfusion; 5/43 (11.6%) T-SCD were regularly transfused. Seven out of 16 (43.8%) SCA and 18/43 (41.8%) T-SCD patients were treated with Hydroxycarbamide (HU). Criteria for transfusion therapy were: painful crisis not responsive to HU, major clinical complications, such as stroke or ACS, extramedullary erythropoietic masses associated with high LDH levels and low Hb values. Conclusions. These data suggest that SCA and T-SCD patients have similar clinical course. Splenomegaly is present only in T-SCD patients, probably due to the increased amount of extravascular hemolysis. Surprisingly, SCA patients showed EE and lower Hb levels with higher LDH values compared to T-SCD ones. This could be related to the prevalence of intravascular hemolysis, that can lead to erythropoietic stress in SCA, even if tissues are better oxygenated in these patients because of biochemical characteristic of HbS in terms of decreased oxygen affinity. These observations could be important to evaluate transfusion and HU treatment. Disclosures: Cappellini: Novartis: Research Funding.

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Hydroxyurea Reduces Conversion From Conditional to Abnormal TCD Velocities In Children with Sickle Cell Anemia (SCA)

Blood ◽

10.1182/blood.v116.21.270.270 ◽

2010 ◽

Vol 116 (21) ◽

pp. 270-270 ◽

Cited By ~ 1

Author(s):

Jennifer Rothman ◽

Shelly Burgett ◽

Russell E. Ware ◽

Courtney Thornburg

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Normal Range ◽

Original Cohort ◽

Transfusion Therapy ◽

Hydroxyurea Treatment ◽

The Mean ◽

Flow Velocities

Abstract Abstract 270 The use of transcranial Doppler ultrasound (TCD), a non-invasive imaging technique, is now clearly established for detecting high risk of stroke in children with sickle cell anemia (SCA). Children with TCD flow velocities ≥200 cm/s have a 10% risk of primary stroke per year. For these children, chronic blood transfusions (CBT) are recommended and have been shown to reduce the risk of primary stroke by up to 90%. The incidence of stroke has decreased to 0.06–0.17 per 100 patient-years since the institution of TCD screening (Fullerton et al. Blood 2004; Enningul-Egham et al., J Pediatr 2010). Although patients with conditional TCDs (flow velocities 170–199 cm/s) have an estimated stroke risk of 2–5% annually, and their rate of conversion from conditional to abnormal is 23% over an 18 month period (Hankins JS et al., BJH 2008), there are no clinical guidelines for primary stroke prevention in this group. We previously conducted a prospective cohort study of hydroxyurea in 37 children with SCA and TCD velocities >140 cm/sec, and demonstrated that TCD velocities decreased significantly after starting hydroxyurea (Zimmerman et al., Blood 2007; NCT00402480). In order to determine if hydroxyurea provided sustained reductions in TCD velocities, we conducted a retrospective review of these 37 children in this original cohort who had elevated TCD velocities and long-term hydroxyurea treatment. The following data were abstracted from the medical record between April 2000 and September 2009: treatment with hydroxyurea and CBT; adherence with treatments; stroke and non-stroke neurological events; and TCD time-averaged mean velocities (TAMV) immediately prior to initiation of hydroxyurea and at the end of extended follow-up. The primary outcome was comparison of pre and post TCD TAMV using a paired t-test. The mean age of enrollment on the original study was 6.8 years (1.8-14.8) and the mean age at follow-up was 12.9 years (5.3-18.5). The mean follow-up was 5.8 years (0.8-8.5) with an overall follow up of 215.1 patient years. Twenty males and 17 females were enrolled. The mean hydroxyurea dose was 25.2 ± 5.6 mg/kg/day, with one patient discontinuing therapy after 15 months. At follow-up, the mean hemoglobin was 8.9 ± 1.2 g/dL and mean HbF was 16 ± 7.2%. Sustained decreases were observed in both the right MCA (164.8 ± 25.5 cm/s to 124.9 ± 35 cm/s, p<0.001) and left MCA (167.9 ± 25.2 cm/s to 126.9 ± 30 cm/s, p<0.001) for all 37 patients. For the 15 patients with conditional TCD velocities at enrollment, 13 had maximal TAMV that reverted to and were sustained in the normal range (185.8 ± 10.0 cm/s to 132.9 ± 14.5 cm/s, p<0.001). Two converted to abnormal TCD velocities at 1.6 years and 4.5 years for a conversion rate of 13%; one was non-adherent but the other was adherent with hemoglobin of 10.8 g/dL and HbF of 23.5%. These two patients were started on CBT and remain stroke free. There were no primary stroke events observed in the 15 subjects with conditional TCD velocities over a total of 78.1 patient years. Of the 5 patients who had abnormal TCD velocities on enrollment and whose parents refused CBT, 1 patient had a stroke after 0.8 years of hydroxyurea therapy. This was the only patient who continued to have abnormal TCD velocities at MTD, 7 months after starting hydroxyurea. The remaining 4 patients continued to have TCD velocities in the normal range off transfusion therapy over 26.3 patient years. Overall, these data illustrate that treatment with hydroxyurea at MTD in children with SCA and elevated TCD velocities resulted in significantly lower and sustained improvements in TCD velocities. Additionally, for children with conditional TCD velocities, hydroxyurea resulted in a lower than expected conversion to abnormal values, thereby sparing many children from CBT without any noted increase risk of stroke. Hydroxyurea did not, however, protect fully against stroke in one patient who had persistently abnormal TCD velocities and therefore CBT remains the standard of care in this population until larger randomized trials are conducted. Further studies are required to evaluate hydroxyurea for primary stroke prevention in children prior to conversion to abnormal TCD and in children who already have abnormal TCD. The currently funded TCD With Transfusions Changing to Hydroxyurea (TWiTCH) clinical trial, which is scheduled to begin enrollment in late 2010, will help answer this important clinical question. Disclosures: Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.

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Therapeutic Phlebotomy in Children with Sickle Cell Anemia, Stroke, and Iron Overload: The SWiTCH Experience

Blood ◽

10.1182/blood.v118.21.1044.1044 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1044-1044 ◽

Cited By ~ 1

Author(s):

Banu Aygun ◽

Nicole A Mortier ◽

Karen Kesler ◽

Willliam H Schultz ◽

Ofelia A. Alvarez ◽

...

Keyword(s):

Adverse Events ◽

Iron Overload ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Recurrent Stroke ◽

Venous Access ◽

Study Entry ◽

Liver Iron ◽

History Of ◽

The Mean

Abstract Abstract 1044 Background: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH Clinical Trials.gov NCT00122980), an NHLBI-sponsored Phase III multicenter trial, compared chronic blood transfusions/chelation to hydroxyurea/phlebotomy for the reduction of recurrent stroke and improvement in iron overload management in children with sickle cell anemia (SCA) and history of overt stroke. To date, however, phlebotomy to manage iron overload has not been commonly performed in children, especially those with SCA. Objective: To describe the experience with SWiTCH phlebotomy procedures, including success rate, associated adverse events, and effect on liver iron stores. Methods: Quantitative liver iron concentration (LIC) was measured by liver biopsy at study entry. Only subjects with LIC > 5 mg Fe/gram dry weight liver (DWL) were eligible for randomization. Those randomized to hydroxyurea/phlebotomy received decreasing volumes of monthly transfusion during hydroxyurea dose escalation, which lasted 4–9 months. Phlebotomy was performed every 4±1 weeks after discontinuation of transfusions. The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) for Hb ≥ 8.0 gm/dL, and 5 mL/kg for Hb 7.0–7.9 gm/dL. Phlebotomy was held if Hb was <7.0 gm/dL. Phlebotomy was performed over 30 minutes with immediate normal saline replacement, typically using peripheral venous access. Exit LIC by liver biopsy was obtained in those completing 30 months of therapy. Ferritin was monitored monthly in all subjects using a centralized laboratory. Results: Sixty-seven children (mean age 13.0 ± 4.0 years; range 5.2–19.0 years) with history of previous stroke and transfusion therapy for an average of 7.4 ± 3.8 years (range 1.5–15.5 years) were randomized to the hydroxyurea/phlebotomy arm. Most of them had also received chelation therapy: 47 (71%) with deferoxamine for an average of 4.8 ± 3.2 years, and 57 (86%) with deferasirox for 1.5 ± 0.8 years prior to study entry. Their average entry LIC was 16.5 ± 9.4 mg/gram DWL. Sixty of 67 children (90%) successfully transitioned to hydroxyurea after 7.2 ± 2.4 months of transfusion overlap; one subject had a stroke during overlap and six failed to demonstrate adequate response/compliance to hydroxyurea to safely discontinue transfusions. These 60 subjects received an average of 8 ± 3 transfusions providing 63 ± 44 mL/kg PRBCs before completing transition and commencing phlebotomy, and 3 ± 3 transfusions providing 19 ± 20 mL/kg PRBCs after starting phlebotomy, for various clinical indications. During the course of the study, a total of 935 phlebotomies were performed (mean 16 per subject) removing an average total volume of 127 ± 74 mL/kg per subject. The mean pre-phlebotomy Hb level on hydroxyurea (9.1 gm/dL) was not significantly different than the mean pre-transfusion Hb during the transfusion overlap period (9.0 gm/dL). Mean ferritin for these 60 subjects on the hydroxyurea/phlebotomy arm decreased from 3523 ± 2150 ng/mL at study entry to 2227 ± 1646 ng/mL (p<0.0001) at exit; and decreased in 50 of 60 subjects. For the 23 patients on the hydroxyurea/phlebotomy arm who completed 30 months of study treatment, the average LIC was unchanged (18.5 mg Fe/gram DWL at entry compared to 18.1 mg Fe/gram at exit, p=0.817). However, average ferritin level for these subjects was significantly lower at exit (4216 ± 2799 ng/mL vs 2356 ± 2032 ng/mL, respectively, p=0.0003). Of 968 protocol-directed phlebotomy procedures, 935 (97%) were performed; 94% of which were at full prescribed volume. Of the 33 phlebotomy procedures that were not performed, 11 were held due to Hb < 7.0 gm/dL and 9 due to poor venous access. There were only 33 grade 2 adverse events (3.5% prevalence) reported in 12 subjects and no serious adverse events. The most common complication was hypotension (9 events; 5 subjects) followed by dizziness, syncope, headache and weakness. Six subjects had a recurrent stroke but there was no temporal relationship to the phlebotomy procedures. Conclusions: Therapeutic phlebotomies were well-tolerated and did not result in worsening anemia or stroke recurrence in this cohort of children with SCA and previous stroke switched to hydroxyurea. Although ferritin levels decreased significantly, we did not demonstrate an overall decrease in LIC in this heavily iron overloaded cohort, most likely due to continued iron loading with transfusions in the overlap period and subsequent short duration of phlebotomy. Disclosures: Off Label Use: Use of hydroxyurea in children with sickle cell anemia.

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Characteristics of Children with Abnormal TCD in the Modern Era: Results from the Displace Consortium

Blood ◽

10.1182/blood-2019-129951 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2270-2270

Author(s):

Julie Kanter ◽

Mary Dooley ◽

Logan P Sirline ◽

Martina Mueller ◽

Shannon Phillips ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

High Risk Group ◽

Phase Iii ◽

Dissemination And Implementation ◽

Advisory Committees ◽

Transfusion Therapy ◽

The Mean

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP), demonstrated that a high-risk group of children with SCA could be identified using Transcranial Doppler ultrasound(TCD) and that chronic red cell transfusion therapy (CRCT) could reduce the risk of first ischemic stroke in this group by over 90% (Adams, et al NEJM 1998).At STOP studyenrollment, 9.7% of children with SCA were identified as having an abnormal TCD. Baby HUG, (NCT00006400), an NHLBI supported phase III trial showed that severe anemia in SCA was associated with elevated white blood cell (WBC) and higher TCD velocities (Lebensburger, et al Blood 2010 ). It is unclear if lower hemoglobin (Hb) and/or higher WBC are causative of elevated TCD velocities or correlative biomarkers. As new disease therapies become available, it is important to know the current rate of abnormal TCD and characteristics of those patients. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary purpose is to identify barriers to implementation of stroke screening in SCA and test novel methods for improving outcomes. DISPLACE is a 3-part study: retrospective assessment of current practice, qualitative review of barriers and facilitators to screening and a cluster-randomized intervention implementation project to improve stroke screening. Part 1 of the study showedthat TCD screening rates varied widely among institutions ranging from 30-75.2% (mean 48.4%, median 47%). We are now reporting on the rate of abnormal TCD and the characteristics and outcomes of patients with abnormal TCD. Methods: DISPLACE is a consortium of 28 US centers. Each site performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016. To be eligible for inclusion, children must have been seen at their institution at least 2x during the study period and have confirmation of SCA. A custom electronic data capture (EDC) system facilitated entry of de-identified data including demographics, TCD and MRI results, medications, transfusions, and laboratory values. For children with SCA who had TCD or central nervous system imaging prior to 2012, these results were also entered into the EDC. TCD results were recorded in the EDC as normal, conditional or abnormal based on their institutional interpretation. Labs and vitals were entered for each patient in closest proximity to each TCD. Confirmation and adjudication of each abnormal TCD and associated outcomes were performed. Stroke status was also recorded as well as presence or absence of CRCT. Results: In total, 5247 children with SCA are included in the database of whom 5225 should have received a TCD. Of this cohort, 4210 children (80.6%) had at least one TCD recorded in the database. Within this group, 207 (4.9%) of children had an abnormal TCD and 816 (19.4%) had a conditional TCD. For those children who underwent TCD during the study (2012-2016) period, there were 105 (2.9%) abnormal TCD and 501 (13.6%) conditional TCD (Table 1). The mean age of children at the time of abnormal TCD was 6.6 years (range 2-16 yr). The majority of children were <10 yr at first abnormal TCD. Over 30% of patients with an abnormal TCD were identified as receiving hydroxyurea.The mean Hb associated with an abnormal TCD was 7.8 +/- 1.1g/dl (range 5.7-10.6) and the mean WBC was 13 x109/L+/- 3.6 (range 3.9-23.4) (Table 2). Of the 105 patients with abn TCD during the study period, 18% had a stroke. Of the total 5247 patients in the database, 3093 (59%) had been prescribed hydroxyurea (HU) and 999 (19%) were prescribed CRCT. CRCT was prescribed most often for abnormal TCD (37%) or secondary stroke prevention (31%). Discussion: DISPLACE is the largest contemporary cohort of children with SCA. The incidence of abnormal TCD in the DISPLACE cohort is significantly lower than at randomization in the STOP study. The number of children receiving CRCT is higher than expected which may partly account for the decrease in frequency of abnormal TCD. Many patients with abnormal TCD were receiving HU when their TCD was abnormal and were started on CRCT. Additionally, while the outcomes of children with conditional TCD are still being evaluated, many of those children reverted to normal TCD without intervention. These data may also help us redefine the use and interventions needed for abnormal TCD. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Consultancy; GLG: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria. Adams:GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

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Impact of Hyperfiltration during Early Childhood on the Natural History of Albuminuria in Pediatric Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-115063 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 8-8

Author(s):

Jeffrey Lebensburger ◽

Lee Hilliard ◽

Thomas H. Howard ◽

Inmaculada Aban ◽

Daniel Feig

Keyword(s):

Early Childhood ◽

Natural History ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

First Episode ◽

Event Analysis ◽

Time To Event ◽

History Of ◽

The Mean

Abstract Introduction: Pediatric patients with Sickle Cell Anemia (SCA) are at risk for developing albuminuria. Hyperfiltration precedes the development of albuminuria in patients with diabetes but the natural history of hyperfiltration on the progression to albuminuria has not been studied in children with SCA. Methods: We have enrolled 185 participants with HbSS or SB0 thalassemia in a prospective pediatric cohort study evaluating progression to chronic kidney disease; the mean current age of participants in this cohort is 14 years. We have abstracted 817 urine microalbumin creatinine measurements and 891 estimations of GFR (eGFR) by Cystatin C. Abnormal urine albumin/creatinine is defined as >30mg/g. We defined persistent albuminuria as two abnormal spot urine microalbumin/creatinine measurements over three consecutive measurements and intermittent albuminuria as one abnormal urine measurement with two consecutive repeat measurement as normal. We performed descriptive and univariate statistics to characterize the natural history of the development of albuminuria. Next, as standard of care definitions of hyperfiltration (>140 ml/min/1.87) are not appropriate in SCA during early childhood (4-10 years of age), we a priori defined hyperfiltration as an eGFR ≥180 ml/min/1.87. We categorized patients with hyperfiltration during early childhood if the mean eGFR was >180 ml/min/1.87. We abstracted the mean white blood cell count (WBC), hemoglobin (Hb), and SCA therapy during early childhood and performed estimates of the odds ratio and used chi-squared test to compare the proportion of those who progressed to persistent albuminuria. Finally, we performed time to event analysis to obtain the estimated Kaplan-Meier curves for participants with and without hyperfiltration and used logrank test to compare their survival distributions. Results: Among the 185 participants, 55 participants (30%) were identified with at least one episode of albuminuria and 130 patients (70%) have not yet developed an episode of albuminuria. Among the 55 participants identified with an albuminuria event, 36 participants (66%) are categorized as having persistent albuminuria while 19 patients (34%) demonstrated intermittent or only one episode of albuminuria. The mean age at the identification of a first albuminuria event was 11.0 years (range 2-18 years). Comparing patients that progressed to persistent vs intermittent albuminuria, we identified no significant differences for age at first episode of albuminuria (13.2 vs 11.9 years, p=0.3) or type of SCA modifying therapy at first episode of albuminuria (p=0.4). We identified 90 participants with eGFR obtained between 4-10 years; 39 (43%) participants were categorized with hyperfiltration and 51 participants had a mean eGFR < 180 ml/min/1.87. Nine of the 39 (23%) participants categorized with hyperfiltration have progressed to develop persistent albuminuria as compared to 3 (6%) of the 51 without hyperfiltration progressed to persistent albuminuria; hyperfiltration was associated with a 4.8 higher odds of developing persistent proteinuria. (p=0.02). The mean eGFR during early childhood was also significantly higher among participants that progressed to albuminuria (186 vs 169 ml/min/1.87, p=0.04). We identified no significant impact of mean WBC (p=0.13), mean hemoglobin (p=0.07), or SCA therapy (p=0.22) in this subset of patients on progression to persistent albuminuria. As the current age of participants impacts identifying albuminuria outcomes, we performed a time to event analysis; participants identified with hyperfiltration during early childhood develop persistent albuminuria at an earlier age than participants without persistent albuminuria (logrank p=0.004). Finally, while persistent albuminuria was significantly associated with hyperfiltration during early childhood, we did not identify a difference in eGFR between patients with and without albuminuria during adolescence (Figure 1). Conclusion: Although 30% of patients with SCA will develop an episode of albuminuria during childhood, only 19% of cohort participants developed persistent albuminuria. Early hyperfiltration is predictive for developing albuminuria and therapies should target reducing hyperfiltration in the first decade of life. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Effects of Chronic Transfusion Therapy on transcranial Doppler Ultrasonography Velocities in Children with Sickle Cell Anemia at Risk for Primary Stroke: Baseline Findings from the Twitch Trial

Blood ◽

10.1182/blood.v124.21.87.87 ◽

2014 ◽

Vol 124 (21) ◽

pp. 87-87 ◽

Cited By ~ 6

Author(s):

Hamayun Imran ◽

Banu Aygun ◽

Barry R. Davis ◽

Sara L. Pressel ◽

William Herbert Schultz ◽

...

Keyword(s):

High Risk ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Doppler Ultrasonography ◽

Study Entry ◽

Red Cell ◽

Transfusion Therapy ◽

The Mean ◽

Red Cell Transfusion

Abstract Introduction: Transcranial Doppler ultrasonography (TCD) is an established screening modality used to predict stroke in children with sickle cell anemia (SCA). Children with abnormal TCD velocities are at high risk for primary stroke. Based on STOP and STOP 2 data, indefinite chronic red cell transfusion therapy is recommended for children with SCA and abnormal TCD velocity, defined as a maximum time-averaged mean velocity (TAMV) ≥200 cm/sec. The aim of the current analysis was to evaluate the long term effects of transfusion therapy on TCD velocities, in a large cohort of children with SCA who received chronic red cell transfusion therapy for primary stroke prophylaxis. Methods: The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase III, randomized, controlled, multicenter non-inferiority trial comparing hydroxyurea to transfusions for primary stroke prevention in children with SCA and abnormal TCD velocities (ClinicalTrials.gov NCT01425307). Children with SCA and a history of abnormal TCD who received at least 12 months of transfusion therapy were eligible to participate. All subjects’ index TCD velocities (the TCD examination that prompted the start of chronic transfusion therapy) were reviewed centrally to confirm study eligibility. At enrollment, study TCD velocities were obtained using the SONARA/tek TCD Module by trained examiners and reviewed centrally. In addition, all children were evaluated with brain magnetic resonance angiography (MRA) scans, which were also reviewed centrally. Associations between demographic, clinical, radiological, and laboratory findings and index/enrollment TCD velocities were examined. Results: One hundred and thirty eight children with complete data were included in this analysis. Mean age for the entire cohort at enrollment was 9.8±2.8 years; 40% were male and 98.8% had HbSS. Mean age at the diagnosis of index TCD was 5.5±2 years. The mean duration of transfusion therapy was 4.3±2.4 years with 63% receiving simple transfusions, 30% receiving partial exchange transfusions, and 7% undergoing erythrocytapheresis. The mean pre-transfusion hemoglobin at study entry was 9.1±0.8 gm/dL and the mean pre-transfusion %HbS for the last 6 months prior to study entry was 29.5±8.3%. The average index TCD TAMV was 217±22 cm/sec (range 147-325). At study entry, the average TAMV was lower at 150±27cm/sec overall (142±27 cm/sec on the left and 140±29 cm/sec on the right). In 77% of the subjects, the TCD velocities had decreased to normal levels (<170 cm/sec), while they remained conditional in 21% and abnormal in 3%. The average decline from index to study entry TCD was 67±31 cm/sec. Nineteen subjects (13.7%) had severe vasculopathy on brain MRA. Higher recent pre-transfusion %HbS (p=.04), fewer years of transfusion therapy (p<.001), and the presence of severe vasculopathy (p<.001) were associated with higher TCD velocities at study entry and with larger declines in velocity from index to study entry. Higher index TCD values were also associated with larger declines in velocity from index to study entry (p<.001). Age and transfusion type did not have an effect on TCD values. Conclusions: Most of the children with SCA at high risk for primary stroke enrolled in the TWiTCH study have normal TCD velocities at study entry, although 21% have conditional and 3% still have abnormal velocities. Longer duration of transfusion therapy was associated with lower TCD velocities, while the presence of severe vasculopathy on brain MRA and recent higher pre-transfusion %HbS values were associated with higher TCD velocities. The TWiTCH trial will serially perform TCD examinations to compare the effects of hydroxyurea versus transfusions. Disclosures Off Label Use: Use of hydroxyurea in children with sickle cell disease.

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Cognitive Dysfunction Occurs In Children with Sickle Cell Anemia without Cerebral Ischemic Insult or Vasculopathy

Blood ◽

10.1182/blood.v118.21.1076.1076 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1076-1076

Author(s):

Clarisse Lobo ◽

Patricia Moura ◽

Patricia Rio ◽

Heber Maia ◽

Juliana Fernandes ◽

...

Keyword(s):

Academic Achievement ◽

Cognitive Function ◽

Cognitive Dysfunction ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Brain Mri ◽

Neurocognitive Deficits ◽

Ischemic Insult ◽

Transfusion Therapy ◽

Significant Difference

Abstract Abstract 1076 Background: Sickle cell anemia (SCA) has been associated with impairments in general cognitive functioning as measured by IQ scores and other neurocognitive measures. Children with SCA and overt stroke are the most affected, but those with silent infarcts (SI) on brain magnetic resonance imaging (MRI) also have cognitive impairment. Transcranial doppler ultrasonography (TCD) screening has allowed identification of individuals at high risk for stroke, in whom institution of prophylactic transfusion therapy produces a dramatic reduction in the incidence of primary stroke. Elevated TCD velocities have been reported to predict neurocognitive impairment in patients with SCA. We hypothesize that children with SCA with normal TCD velocities and no overt stroke or SI on brain MRI will have normal cognitive performance when compared with normal-matched controls. We investigated the academic achievement and cognitive function among children with SCA with normal brain MRI and normal TCD velocities, and compared their results with normal age and race matched controls. Methods: School age children with SCA who had normal MRI and TCD exams were evaluated. Controls (classmates and siblings) were matched for race, age, and social-economic status. SCA patients receiving chronic transfusion therapy or with a history of prior overt stroke were not eligible. All participants were followed at Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO). All patients and controls underwent MRI examination (to document the absence of stroke and SI) and cognitive testing. In addition, SCA subjects underwent TCD testing and had hematologic laboratory testing. SCA subjects were not experiencing pain or any other complication during study evaluations. The WISC-III was obtained as a measure of intellectual function, and achievement scores in reading, writing, and arithmetic were used to evaluate school performance. Comparisons among patients and controls were made using the Mann-Whitney test. This study was approved by the HEMORIO Ethics committee and all participants signed informed consent. Results: SCA patients had significantly lower total IQ and academic achievement than healthy controls (Table). Discussion: This is the first report showing cognitive dysfunction in children with SCA with both normal MRI and TCD examination. Early neurocognitive deficits are known to occur in children with SCA. In general, a patient with SCA in Brazil has a low socioeconomic status, low educational level, and poor access to health services, placing these children at higher risk of neurocognitive complications from the disease. Our study shows that children with SCA perform worse on measures of key cognitive function when compared with healthy matched controls, even without evidence of elevated velocities in the main cerebral arterial vessels or radiological insult to the brain. There was a significant difference in total IQ and school achievement among SCA patients and controls; however this was not true for verbal or executive IQ, suggesting that the cognitive compromise in this population is global. Cognitive dysfunction may occur long before lesions are observed on the MRI (ischemic insult) or on the TCD (vasculopathy), underscoring the need for preemptive screening and treatment of cognitive dysfunction in children with SCA. Disclosures: Off Label Use: Hydroxyurea for prevention of neuropsychological changes in SCD.

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Increased Pre-Transfusion Reticulocytosis Among Chronically Transfused Sickle Cell Disease Patients Is Associated With More Severe Cerebral Vasculopathy

Blood ◽

10.1182/blood.v122.21.1163.1163 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1163-1163

Author(s):

Megha Kaushal ◽

Ross M. Fasano ◽

Colleen Byrnes ◽

Naomi L.C. Luban ◽

Emily Riehm Meier ◽

...

Keyword(s):

Magnetic Resonance ◽

Sickle Cell Disease ◽

Magnetic Resonance Angiography ◽

Sickle Cell ◽

Control Group ◽

Cell Disease ◽

Transfusion Therapy ◽

Blood Samples ◽

History Of ◽

The Mean

Abstract Chronic red blood cell transfusion therapy is indicated for primary and secondary stroke prevention in children with sickle cell disease (SCD). The main transfusion goal is achievement of pre-transfusion sickle hemoglobin (HbS) levels of 30%. Unfortunately, there continues to be a population of patients with a history of stroke who have progressive vasculopathy and/or secondary stroke, despite chronic transfusion therapy. Predictive markers for vasculopathy and cerebral events are needed to identify patients at risk for disease progression. Increased reticulocytosis was previously associated with other sickle cell disease complications, and adherent reticulocytes may contribute to the vascular pathology. The objective of this study was to explore the hypothesis that pre-transfusion reticulocytosis may serve as a disease severity marker for cerebral vasculopathy among chronically transfused children with sickle cell disease. After obtaining consent and assent, reticulocytosis was studied in a cohort of pediatric sickle cell patients treated with chronic transfusions (n=33, ages 2-17 years). The group was stratified into three groups: group 1 with an abnormal transcranial doppler (TCD) study in the absence of magnetic resonance angiography (MRA) detected vasculopathy [TCD(+), MRA(-), n=14], group 2 with a history of a stroke in the absence of MRA-detected vasculopathy [Stroke(+), MRA(-), n=5], and group 3 with a history of abnormal TCD or stroke and more severe vasculopathy detected by magnetic resonance angiography [MRA(+), n=14]. Pre-transfusion blood samples were analyzed within 72 hours of collection. Steady-state blood samples were also examined from a control group of pediatric SCD patients (>6 years of age) with normal TCD studies who were receiving supportive care in the absence of chronic transfusions or hydroxyurea (n=7). Hematologic data, including automated complete blood counts, absolute reticulocyte counts (ARC) with reticulocyte maturity were obtained. In addition, a flow cytometric approach was developed to further examine and quantitate reticulocyte subsets based upon staining with thiazole orange combined with CD36, CD45, CD49d, CD71, and CD235. The pre-transfusion HbS levels were not statistically different among the three transfused groups ([TCD(+), MRA(-)]: 30.2 ± 11.8%; [Stroke(+), MRA(-)]: 28.4 ± 3.3%; [MRA(+)]: 33.3 ± 9%, p>0.3). The high levels of reticulocytosis in the pre-transfusion samples were similar to those measured in the control group (ARC: 451 ± 126 K/uL in the chronically transfused cohort; ARC: 369 ± 94 K/uL in the control group, p=0.11). Pre-transfusion reticulocytosis was detected in every chronically transfused subject (ARC range 151-701 K/ul). The mean ARC in the [TCD(+), MRA(-)] group was not significantly different from the [Stroke(+), MRA(-)] group (411 ± 135 K/uL and 396 ± 97 K/uL respectively, p=0.82). However, the mean ARC in the [MRA(+)] group (512 ± 107 K/uL) was significantly higher than the control group, the [TCD(+), MRA(-)] group and the [Stroke(+), MRA(-)] group (p<0.05). The increased ARC in the MRA(+) group included higher absolute numbers of circulating reticulocytes at all stages of maturation including the immature reticulocyte subset [CD36(+), CD71(+)] that was detected in every sample. These data suggest that reticulocytosis with the release of immature CD36(+), CD71(+) cells into the peripheral blood remains as a characteristic feature of pediatric SCD even among chronically transfused patients. More severe vasculopathy, detected by MRA, was associated with significantly higher levels of pre-transfusion reticulocytosis. As such, reticulocytosis should be explored further as a marker or a potential contributor to more severe vasculopathy among chronically transfused children with SCD. Disclosures: No relevant conflicts of interest to declare.

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Hemoglobin Α Clearance Is Associated with RBC Antibodies in Chronically Transfused Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v128.22.3839.3839 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3839-3839

Author(s):

Marianne Elaine McPherson Yee ◽

Cassandra Josephson ◽

Anne M. Winkler ◽

Paula L. Jessup ◽

Sean R. Stowell ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Advisory Committees ◽

Total Blood ◽

Transfusion Therapy ◽

The Mean ◽

Clinically Significant ◽

Erythrocyte Antigen

Abstract Chronic transfusion therapy (CTT) for sickle cell anemia (SCA) reduces the risk of sickle complications by diluting hemoglobin S (HbS)-containing red blood cells (RBCs) with HbA RBCs and suppressing sickle erythropoiesis. HbS level is influenced by both endogenous hemolysis and clearance of transfused RBC. Minor RBC antigen (Ag) mismatches may result in alloimmunization and hemolytic reactions, but it is unknown if Ag mismatches independently influence HbA clearance. This study sought to: (1) determine the frequency of RBC minor Ag mismatches that occur in chronically transfused SCA patients receiving phenotype-matched transfusions; (2) determine the rate of clearance of transfused HbA following each transfusion; (3) explore associations of HbA clearance with RBC minor Ag mismatches. Children with SCA ages 3-20 years on CTT by either simple transfusions or partial manual exchange (PME) were enrolled in a prospective observational study. All RBC units were serologically matched for C/c, E/e, K (category 1); additional matching for Fya, Jkb, and Ag-negative for putative antibodies (category 2) was provided to patients with ≥1 clinically significant alloantibody or (in some cases) warm autoantibodies. RBC genotyping of SCA patients was performed using PreciseType™ Human Erythrocyte Antigen (HEA), RHCE, and RHD BeadChip assays (Immucor, Norcross, GA). Genomic DNA was extracted from unit segments of all RBC transfused over 12 months and tested using the prototype HEA Leukoreduced (HEA-LR) BeadChip assay to detect the same profile of RBC Ag. RH variant testing of units was not performed. Pre-transfusion HbA was recorded for all episodes, where HbA (g/dL) = Hb (g/dL) x HbA%. Hb electrophoresis was drawn 15-30 minutes post-transfusion in a subset of episodes. For other episodes, post-transfusion HbA was estimated based on the volume of transfusion (VolT), estimated unit hematocrit (Hct), phlebotomy volume (VolPh, if applicable) and total blood volume (TBV), using the following equation: Post HbA (g/dL) = Pre HbA (g/dL) + [(unit Hct) x VolT / 3 x Wt] - (Pre HbA%/100) x [(Pre Hb (g/dL) x VolPh / 3 x TBV]. HbA loss/day was calculated from the Post HbA to the next pre-transfusion HbA. There were 82 patients (54 category 1, 28 category 2) who received 2123 units in 1014 transfusion episodes; HEA-LR genotypes were obtained on 1827 units and 828 complete transfusion episodes. Altered RHC/c or e genotypes were present in 29 (36%), and partial D+ genotypes in 4 (5%). There were 46 historical alloantibodies, the majority against Rh (C, E, hrB, Goa, f, V, VS) and Kell (K, Kpa, Jsa). During the study, 5 patients developed 6 new alloantibodies: 3 Jsa, 1 Goa, 1 Wra, 1 AUS (category 2 transfusions alloantibody incidence 0.64/100 units; category 1 transfusions 0.074/100 units). The mean genotype-predicted Ag mismatches per transfusion was 3.52 for category 1 and 2.78 for category 2 (despite category 2 being matched for ≥2 Ags beyond category 1 matching). Ag mismatch frequency was different in category 1 vs. 2 transfusions for: C (3.8% vs. 0%, p=0.0009), e (24.5% vs. 36.8%, p=0.0002), and VS (21.2% vs. 13.6%, p=0.008). Overall concordance between HEA-LR and available serologic testing was 98%. Of the 169 transfusion episodes with post-transfusion HbA measurements (103 category 1, 66 category 2), the mean HbA loss was 2.38 g/dL/28 days for category 1 vs. 2.73 g/dL/28 days for category 2 (p=0.0047). Comparison of category 1 vs. 2 transfusions (see table) shows shorter transfusion interval and higher frequency of PME in category 2 transfusions. Estimated post HbA had a bias of -0.31 g/dL (95% C.I.-0.18, -0.46) and precision of 0.85 g/dL (95% C.I. 0.61, 1.18). Comparison of estimated HbA loss to Ag mismatches was limited to 533 transfusion episodes in which unit Hct could be estimated within <10% range. Estimated HbA loss had a small negative correlation with Ag mismatches for category 1 (r= -0.123, p=0.027) but not for category 2 transfusions. In linear regression, the only Ag associated with increased HbA loss was N which was limited to category 1 transfusions (p=0.027). HbA loss did not correlate with age of units. This is the first report to characterize RBC minor Ag mismatches in SCA patients on CTT receiving limited vs. extended phenotypically matched RBCs. These findings suggest that clearance of transfused RBCs may be influenced by the patient's history of immunologic response to RBC Ag rather than total or specific Ag mismatches. Table Table. Disclosures Josephson: Octapharma: Consultancy; Immucor: Consultancy; Biomet Zimmer: Consultancy. Winkler:Cerus Corporation: Honoraria; Siemens Healthcare Diagnostics, Inc.: Honoraria; Instrumentation Laboratory: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; HemoCue America: Membership on an entity's Board of Directors or advisory committees. Fasano:Terumo BCT: Other: educational speaking (non-branded) on Iron overload in SCD; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: educational speaking (non-branded) on Iron overload in SCD; Apopharma: Membership on an entity's Board of Directors or advisory committees; Immucor: Membership on an entity's Board of Directors or advisory committees.

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