Neurodevelopment in Infants with Sickle Cell Anemia: Baseline Data from the Baby HUG Trial

Abstract Delays and deficits in neurodevelopment are known complications of sickle cell anemia (SCA) in young children1. Hydroxyurea is a chemotherapeutic agent that increases production of fetal hemoglobin, and has proven effective in reducing pain and other SCA-related complications in adults, adolescents, and school-age children. To determine whether treatment with hydroxyurea for 24 months would benefit infants with SCA, the NHLBI initiated a multi-center, randomized, double-blind, placebo-controlled clinical trial (NCT00006400) in 2003 (BABY HUG). After screening 233 infants for eligibility, 193 infants 9 to 17 months of age from 14 participating institutions were randomized. While the primary outcomes for BABY HUG are spleen and kidney function, neurodevelopment is an important safety assessment and a secondary outcome. Two hundred and seven (male=89, female = 117) infants were administered the Bayley Scales of Infant Development-2nd Edition (BSID-II) by qualified psychological examiners during the screening phase of the trial. The infants also completed a transcranial Doppler ultrasound (TCD) to determine flow velocity in seven ascending arteries of the brain. The analyses for this report focused on the relationships between neurodevelopmental function on the BSID-II, age at study entry and TCD flow velocities. Overall the mean neurodevelopmental function of the sample was in the average range (mean Motor Developmental Index= 96.8; mean Mental Developmental Index = 96.3). Age at study entry (continuous and categorical) was significantly correlated with the Mental Scale of the BSID-II (p=0.0042, p=0.0001, respectively). On average, a child’s Mental Developmental Index (MDI) decreased by 0.75 for every one month increase in age. Age (categorical) was also significantly associated with the Motor Scale of the BSID (p=0.0255). TCD velocity has been shown to be a sensitive indicator of existing and future risk for central nervous system (CNS) events in children with SCA. In children age 2–16 years, flow velocities over 200mm/ sec are associated with significant stroke risk; flow velocities between 170–200 mm/sec are associated with potential risk for neurodevelopmental deficits. Early associations between TCD and neurodevelopment could be considered important clinical indicators of risk for future CNS events. BSID Mental Scale scores were significantly associated with the maximum (of left or right) flow velocity in the M-1 artery (p=0.04) and the Behavior Rating Scale scores were significantly associated with the dICA velocity (p=0.008). In both of these cases, higher flow velocity was associated with poorer neurodevelopmental function. These results reflect the function of a large group of infants and toddlers with SCA prior to the initiation of any treatment targeting the CNS. Although the overall function of the group was in the average range, it is concerning to find strong relationships between increasing age at enrollment and decreasing MDI and between higher TCD flow velocity and decreased neurodevelopmental function in these very young children. The importance of early screening and perhaps sequential assessment of infants with both TCD and neurodevelopmental assessments is raised by these findings, as is the importance of continuing efforts to determine whether interventions, such as early HU therapy, might favorably impact the CNS complications of this disease that affect neurodevelopment.

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Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

Blood ◽

10.1182/blood.v128.22.1018.1018 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1018-1018 ◽

Cited By ~ 1

Author(s):

Banu Aygun ◽

Nicole Mortier ◽

Zora R. Rogers ◽

William Owen ◽

Beng Fuh ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Chelation Therapy ◽

Venous Access ◽

Study Entry ◽

Iron Loading ◽

Advisory Committees

Abstract Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely. Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes. Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment. Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3). A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA. An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin. Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. Disclosures Rogers: Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

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Efficacy of Hydroxyurea To Prevent Organ Damage in Young Children with Sickle Cell Anemia.

Blood ◽

10.1182/blood.v110.11.3386.3386 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3386-3386 ◽

Cited By ~ 3

Author(s):

Courtney D. Thornburg ◽

Natalia Dixon ◽

Shelly Burgett ◽

Nicole A. Mortier ◽

Sherri A. Zimmerman ◽

...

Keyword(s):

Young Children ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Brain Mri ◽

Organ Damage ◽

Study Entry ◽

Acute Chest Syndrome ◽

Time Interval ◽

Splenic Sequestration ◽

Increased Risk

Abstract Hydroxyurea (HU) prevents many acute complications of sickle cell anemia (SCA) in adults and children, but its potential to delay or prevent chronic organ damage has not been defined. The objectives of this prospective IRB-approved study were to assess the safety and efficacy of HU in young children with SCA (age 18 mon–5 years) and to determine whether 2 years of therapy preserves renal function, reduces transcranial doppler ultrasound (TCD) values, and prevents development of brain ischemia as evidenced by magnetic resonance imaging/angiography (MRI/MRA). Fourteen children with SCA (11 male, 3 female; mean age 35±11 mon) enrolled and underwent evaluation including blood counts, %HbF measurement, determination of the glomerular filtration rate (GFR) by radionuclide DTPA clearance and Schwartz estimate, TCD mean cerebral artery (MCA) velocities, and brain MRI/MRA. HU was started at 20 mg/kg/day and escalated by 5mg/kg/day every 8 weeks to a maximum tolerated dose (MTD) or 30 mg/kg/day (mean dose 28±4 mg/kg). Children were evaluated initially every 4 weeks. All baseline tests were repeated at study exit (mean time 25±3 months). HU was tolerated well by all children. Hematological changes occurred as expected, with significant increases observed in hemoglobin concentration, MCV, and %HbF and significant decreases in reticulocytes, WBC, and neutrophils. The average GFR value did not rise as expected in this age range; the DTPA GFR decreased by 5.1 mL/min/1.73 m2 (p=0.26) with only 3 of 11 exit studies exceeding 150 mL/min/1.73 m2 and the Schwartz estimate increased by 16.5 mL/min/1.73 m2 (p=0.17). During HU therapy, the average TCD values significantly decreased with a mean decrease of 26±28 cm/sec in the right MCA (p<.01) and mean decrease of 27±33 in the left MCA (p<.05). At study entry, 3 children had conditional TCD velocities, but all were normal at study exit. One child had mild small vessel ischemic changes on MRI at study entry that were unchanged at study exit. Two children had mild MRA changes that were stable or improved at the end of the study. All children had normal or improved rates of growth and development during therapy. Two children required PRBC transfusion for acute events (acute chest syndrome and hypoplastic anemia during a viral illness). There was one episode of Moraxella catarrhalis bacteremia that was unrelated to myelosuppression and responded to antibiotic therapy. One child was removed from study at week 82 due to the development of thrombocytopenia and hypersplenism, another had acute splenic sequestration but continued HU without recurrence, and a third child with previous acute splenic sequestration did not have recurrence during the study. In conclusion, HU therapy appears to be well tolerated in young children with SCA. In addition to providing beneficial changes in hematological parameters, HU has salutary effects on both the kidney and brain. HU therapy was associated with a stable GFR value during a time interval when hyperfiltration develops, and led to significant decreases in TCD velocities. However, preservation of splenic tissue could lead to an increased risk of splenic complications. Follow-up studies are warranted to determine if long-term HU therapy can preserve or restore organ function in this patient population.

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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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Correlation Between Cerebral Blood Flow Velocities Measured By Magnetic Resonance and Transcranial Doppler Ultrasound in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v128.22.2496.2496 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2496-2496

Author(s):

Monica L. Hulbert ◽

Dustin K. Ragan ◽

Hongyu An ◽

Cihat Eldeniz ◽

Geetika Khanna ◽

...

Keyword(s):

Blood Flow ◽

Magnetic Resonance ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Arterial Stenosis ◽

Acquisition Time ◽

Transfusion Therapy ◽

Blood Flow Velocities ◽

Flow Velocities

Abstract Background Transcranial Doppler (TCD) ultrasonography is the standard stroke screening test for children with sickle cell anemia (SCA). However, approximately 10% of children have inadequate ultrasonographic windows for a successful TCD study, and some clinical sites may lack the equipment or personnel to perform TCDs in children. Magnetic resonance imaging (MRI) techniques can also measure blood flow velocities and could substitute for TCD in these clinical scenarios. We tested the hypothesis that MRI-derived middle cerebral artery (MCA) blood flow velocities would correlate with TCD-derived MCA blood flow velocities in children with SCA. Methods Children age 6 years and up with SCA at their baseline state of health underwent TCD and MRI as part of a prospective clinical study. Imaging TCD of the bilateral MCAs to determine time-average mean of maximum blood flow velocities (TCD-CBFV) were performed using clinical ultrasound equipment. MRIs were performed at 3T without sedation. MRI cerebral time-averaged mean blood flow velocities (MR-CBFV) were measured in the MCAs using phase contrast sequences without cardiac cycle gating to shorten acquisition time and reduce ghosting artifacts. TCD- and MR-CBFV of each hemisphere were compared. Silent cerebral infarctions (SCIs) were categorized as present or absent in each hemisphere. Non-parametric tests were used with a level of significance of <0.05. Statistics were performed in SPSS version 21. Results Twenty hemispheres from 15 children had both TCD-CBFV and MR-CBFV measurements. Median age was 9 years (IQR 6.25-10). In these children, two hemispheres had unobtainable TCDs due to skull thickness, and eight hemispheres had MR-CBFV excluded due to patient motion or poor positioning. The median TCD-CBFV was 116 cm/sec (IQR 90.25-124) and none of the included hemispheres had arterial stenosis or TCD-CBFV in the conditional or abnormal range. Eight included hemispheres were from children receiving chronic blood transfusion therapy for primary or secondary stroke prevention. There was a linear relationship between TCD-CBFV and MR-CBFV (Spearman correlation, ρ=0.781, p<0.001, Figure) although MR-CBFV values were lower than TCD-CBFV values (median difference 32.6%, IQR 26.7-42.8). When evaluating only the children not receiving chronic transfusion therapy, MR-CBFV was significantly higher in 8 hemispheres without SCIs (median 80 cm/sec, IQR 77.8-87.8) than in 4 hemispheres with SCIs (median 60 cm/sec, IQR 44.6-72.3, p=0.004). In a multivariate model adjusting for age, MR-CBFV continued to be associated with presence of SCIs (p=0.036). There was no significant difference in TCD-CBFV when analyzed by SCI status (p=0.2), consistent with published studies of TCD-CBFV and SCIs. Conclusions In this small cohort of children with SCA, MR-CBFV correlated significantly with TCD-CBFV, but MR-CBFV values were approximately 30% lower than TCD-CBFV. This may be due to the method of acquiring MR-CBFV via non-gated methodology, which is known to produce lower blood flow velocity estimates. Further work is needed to determine a threshold for high-risk MR-CBFV values before this modality could be used as a substitute for TCD screening. Lower MR-CBFV was associated with SCIs, suggesting a potential role for MR-CBFV in predicting SCI risk. The relationship between MR-CBFV and SCIs should be explored further. Disclosures Hulbert: Pfizer, Inc.: Other: spouse employment. Fields:NeuroPhage Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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In Vitro Red Blood Cell Segregation in Sickle Cell Anemia

Frontiers in Physics ◽

10.3389/fphy.2021.737739 ◽

2021 ◽

Vol 9 ◽

Author(s):

Viviana Clavería ◽

Philippe Connes ◽

Luca Lanotte ◽

Céline Renoux ◽

Philippe Joly ◽

...

Keyword(s):

Red Blood Cells ◽

Flow Velocity ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Blood Cells ◽

Vascular Wall ◽

Mean Flow ◽

The Mean ◽

The Impact ◽

Mean Flow Velocity

Red blood cells in sickle cell anemia (sRBC) are more heterogeneous in their physical properties than healthy red blood cells, spanning adhesiveness, rigidity, density, size, and shape. sRBC with increased adhesiveness to the vascular wall would trigger vaso-occlusive like complications, a hallmark of sickle cell anemia. We investigated whether segregation occurs among sRBC flowing in micron-sized channels and tested the impact of aggregation on segregation. Two populations of sRBC of different densities were separated, labeled, and mixed again. The mixed suspension was flowed within glass capillary tubes at different pressure-drops, hematocrit, and suspending media that promoted or not cell aggregation. Observations were made at a fixed channel position. The mean flow velocity was obtained by using the cells as tracking particles, and the cell depleted layer (CDL) by measuring the distance from the cell core border to the channel wall. The labeled sRBC were identified by stopping the flow and scanning the cells within the channel section. The tube hematocrit was estimated from the number of fluorescence cells identified in the field of view. In non-aggregating media, our results showed a heterogeneous distribution of sRBC according to their density: low-density sRBC population remained closer to the center of the channel, while the densest cells segregated towards the walls. There was no impact of the mean flow velocity and little impact of hematocrit. This segregation heterogeneity could influence the ability of sRBC to adhere to the vascular wall and slow down blood flow. However, promoting aggregation inhibited segregation while CDL thickness was enhanced by aggregation, highlighting a potential protective role against vaso-occlusion in patients with sickle cell anemia.

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Doppler velocimetry of the orbital arteries in patients with sickle cell anemia: relationship with biomarkers of hemolysis

Radiologia Brasileira ◽

10.1590/0100-3984.2015.0180 ◽

2017 ◽

Vol 50 (2) ◽

pp. 103-108 ◽

Cited By ~ 2

Author(s):

Thiago de Oliveira Ferrão ◽

Paulo Ricardo Martins-Filho ◽

Cleverton Aragão ◽

Marlyson Santana ◽

Allan Nascimento ◽

...

Keyword(s):

Steady State ◽

Vascular Resistance ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Ophthalmic Artery ◽

Central Retinal Artery ◽

Control Group ◽

Doppler Velocimetry ◽

Retinal Artery ◽

Flow Velocities

Abstract Objective: To investigate orbital vascular resistance by Doppler velocimetry in patients with steady-state sickle cell anemia, as well as to characterize its relationship with biomarkers of hemolysis. Materials and Methods: This was a cross-sectional study of two groups: 71 outpatients with sickle cell anemia; and 32 age- and gender- matched, healthy subjects (control group). All participants underwent Doppler velocimetry of the orbital arteries and laboratory tests. Results: All biochemical laboratory markers were abnormal in the sickle cell anemia patients (p < 0.0001 vs. controls). In the patient group, Doppler velocimetry revealed increased flow velocities in the ophthalmic artery and reduced flow velocities in the central retinal artery, as well as high values for the resistance index (RI) and pulsatility index (PI) in both arteries (p < 0.0001 vs. controls). Biomarkers of hemolysis were found to correlate significantly with the RI and PI indices. In the ophthalmic artery, the reticulocyte count showed a moderate direct correlation with RI and with PI. In the central retinal artery, hemoglobin showed a strong inverse correlation with RI and with PI. Conclusion: Orbital vascular resistance, as evaluated by Doppler velocimetry, is elevated in patients with steady-state sickle cell anemia and shows a significant correlation with biomarkers of hemolysis.

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Effects of Ascorbic Acid Intake on the Intima-Media Thickness and Blood Flow Velocities of the Carotid Artery in Patients With Sickle Cell Anemia

Journal of Diagnostic Medical Sonography ◽

10.1177/8756479311416505 ◽

2011 ◽

Vol 27 (5) ◽

pp. 214-219

Author(s):

Omodele A. Olowoyeye ◽

Smith I. Jaja ◽

Michael O. Kehinde ◽

Gbolahan O. Awosanya ◽

Nicholas K. Irurhe ◽

...

Keyword(s):

Blood Flow ◽

Ascorbic Acid ◽

Carotid Artery ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Intima Media Thickness ◽

Acid Intake ◽

Media Thickness ◽

Blood Flow Velocities ◽

Flow Velocities

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Preliminary evidence for cerebral capillary shunting in adults with sickle cell anemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17746808 ◽

2017 ◽

Vol 39 (6) ◽

pp. 1099-1110 ◽

Cited By ~ 3

Author(s):

Meher R Juttukonda ◽

Manus J Donahue ◽

Larry T Davis ◽

Melissa C Gindville ◽

Chelsea A Lee ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Preliminary Evidence ◽

Oxygen Extraction Fraction ◽

3.0 T ◽

Cerebral Capillary ◽

Prospective Trials ◽

Dural Venous Sinus ◽

Venous Signal ◽

Flow Velocities

Elevated flow velocities in adults with sickle cell anemia (SCA) may cause rapid erythrocyte transit through capillaries. This phenomenon could present as dural venous sinus hyperintensity on arterial spin labeling (ASL)-MRI and could be indicative of capillary shunting. Here, the prevalence of ASL venous hyperintensities and association with relevant physiology in adults with SCA was investigated. SCA ( n = 46) and age-matched control ( n = 16) volunteers were recruited for 3.0 T MRI. Pseudo-continuous ASL-MRI was acquired for cerebral blood flow (CBF) calculation and venous hyperintensity determination; venous signal intensity and a categorical venous score (three raters; 0 = no hyperintensity, 1 = focal hyperintensity, and 2 = diffuse hyperintensity) were recorded. Flow velocity in cervical internal carotid artery segments was determined from phase contrast data (venc = 40 cm/s) and whole-brain oxygen extraction fraction (OEF) was determined from T2-relaxation-under-spin-tagging MRI. Cerebral metabolic rate of oxygen was calculated as the product of OEF, CBF, and blood oxygen content. ASL venous hyperintensities were significantly ( p < 0.001) more prevalent in SCA (65%) relative to control (6%) participants and were associated with elevated flow velocities ( p = 0.03). CBF ( p < 0.001), but not OEF, increased with increasing hyperintensity score. Prospective trials that evaluate this construct as a possible marker of impaired oxygen delivery and stroke risk may be warranted.

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Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia

Blood ◽

10.1182/blood-2006-11-057893 ◽

2007 ◽

Vol 110 (3) ◽

pp. 1043-1047 ◽

Cited By ~ 133

Author(s):

Sherri A. Zimmerman ◽

William H. Schultz ◽

Shelly Burgett ◽

Nicole A. Mortier ◽

Russell E. Ware

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Maximum Tolerated Dose ◽

Multicenter Trial ◽

Clinical Severity ◽

Phase 2 Trial ◽

The Right ◽

Hydroxyurea Therapy ◽

Flow Velocities

Abstract Hydroxyurea has hematologic and clinical efficacy in sickle cell anemia (SCA), but its effects on transcranial Doppler (TCD) flow velocities remain undefined. Fifty-nine children initiating hydroxyurea therapy for clinical severity had pretreatment baseline TCD measurements; 37 with increased flow velocities (≥ 140 cm/s) were then enrolled in an institutional review board (IRB)–approved prospective phase 2 trial with TCD velocities measured at maximum tolerated dose (MTD) and one year later. At hydroxyurea MTD (mean ± 1 SD = 27.9 ± 2.7 mg/kg per day), significant decreases were observed in the right middle cerebral artery (MCA) (166 ± 27 cm/s to 135 ± 27 cm/s, P < .001) and left (MCA) (168 ± 26 cm/s to 142 ± 27 cm/s, P < .001) velocities. The magnitude of TCD velocity decline was significantly correlated with the maximal baseline TCD value. At hydroxyurea MTD, 14 of 15 children with conditional baseline TCD values improved, while 5 of 6 with abnormal TCD velocities whose families refused transfusions became less than 200 cm/s. TCD changes were sustained at follow-up. These prospective data indicate that hydroxyurea can significantly decrease elevated TCD flow velocities, often into the normal range. A multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values, and ultimately for primary stroke prevention in children with SCA.

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