Abstract 109: Non-invasive Detection of Capillary Arteriovenous Shunting in Patients With Sickle Cell Anemia

Introduction: High blood velocity can cause rapid erythrocyte transit through capillaries, reducing efficiency of oxygen delivery to tissue (capillary arteriovenous shunting). Arterial spin labeling (ASL) is an MRI technique that utilizes magnetic labeling of arterial blood water for CBF quantitation. Labeled water that traverses capillaries without exchanging with tissue leads to hyperintense venous signal indicative of arteriovenous shunting. We hypothesized that venous hyperintensity is present in sickle cell anemia (SCA) adults, correlates with flow velocity, and corresponds with clinical impairment and oxygen extraction fraction (OEF). Methods: ASL for shunting determination, TRUST for OEF measurement, phase contrast angiography for velocity assessment, and FLAIR / MRA for infarct / vasculopathy evaluation were performed at 3T in adults with SCA (n=36) and age- and race-matched controls (n=11). Three reviewers assessed for hyperintensity in the superior sagittal sinus on ASL images (Fig) and assigned scores of 0 (none), 1 (mild, focal), 2 (significant, focal), or 3 (significant, diffuse). Shunting scores were compared with the presence of clinical impairment (prior infarcts, stenosis>50%, or severe disease requiring transfusions) and OEF. Results: Interobserver agreement was excellent (Fleiss’ κ=0.91). Consensus shunting score in SCA adults (1.2±1.1) was higher (p<0.01) than controls (0.1±0.3), Median age 27.6 y, 57% F. Elevated shunting scores were observed in SCA adults with (1.23±1.07) vs. without (1.07±1.16) clinical impairment. A trend (p=0.068) for elevated OEF was observed in those with shunting scores ≥2 (0.44±0.07) vs. those with shunting scores ≤1 (0.40±0.07). Cervical flow velocity was elevated in subjects with shunting scores ≥2 (30.2±4.8 cm/s) vs. ≤1 (25.3±4.8 cm/s). Conclusion: Venous hyperintensity in ASL images may indicate capillary arteriovenous shunting and may reflect higher clinical impairment and elevated OEF.

Download Full-text

Reduced oxygen extraction efficiency in sickle cell anemia patients with evidence of cerebral capillary shunting

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20913123 ◽

2020 ◽

pp. 0271678X2091312

Author(s):

Meher R Juttukonda ◽

Manus J Donahue ◽

Spencer L Waddle ◽

Larry T Davis ◽

Chelsea A Lee ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Quantitative Measure ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

Arterial Blood ◽

Endogenous Contrast ◽

Hyperintense Signal ◽

Cerebral Capillary ◽

Magnetic Resonance Imaging Mri

Arterial spin labeling (ASL) magnetic resonance imaging (MRI) utilizes arterial blood water as an endogenous contrast agent to provide a quantitative measure of cerebral blood flow (CBF). Recently, hyperintense signal within dural venous sinuses in ASL images of sickle cell anemia (SCA) patients has been shown to be consistent with elevated flow velocities and may indicate capillary shunting and reduced oxygen extraction. Here, we performed oxygen extraction fraction (OEF) and CBF measurements in adults (cumulative n = 114) with ( n = 69) and without ( n = 45) SCA to test the hypothesis that hyperintense venous ASL signal is associated with reduced OEF. Higher categorical scores of shunting on ASL MRI were associated with lower OEF in participants with silent cerebral infarcts or white matter hyperintensities ( p = 0.003), but not in those without lesions ( p = 0.551). These findings indicate that venous hyperintense signal in ASL images in SCA patients may represent a marker of capillary-level disturbances in oxygen exchange efficiency and small vessel pathology.

Download Full-text

Abstract TMP93: Elevated Oxygen Extraction Fraction Measured With Noninvasive MRI may be Discriminatory for Stroke Risk in Adults With Sickle Cell Anemia

Stroke ◽

10.1161/str.47.suppl_1.tmp93 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Lori C Jordan ◽

Melissa Gindville ◽

Allison Scott ◽

Megan K Strother ◽

Adetola Kassim ◽

...

Keyword(s):

Linear Regression ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Risk ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

Extraction Fraction ◽

Clinical Impairment ◽

Mean Differences ◽

Oxygen Carrying Capacity

Introduction: No screening procedures exist for evaluating stroke risk in adults with sickle cell anemia (SCA). Reduced oxygen carrying capacity is present in SCA, which may initially be compensated for by an increase in cerebral blood flow (CBF) and then by increased oxygen extraction fraction (OEF). Hypothesis: OEF and CBF can be measured noninvasively and reproducibly with MRI using clinically-available equipment in adults with SCA; elevated OEF provides added discriminatory capacity for clinical impairment relative to vasculopathy extent and CBF alone. Methods: Structural, CBF-weighted, and MRA imaging, together with a noninvasive OEF-weighted T 2 -relaxation-under-spin-tagging (TRUST)-MRI method was applied in SCA adults (n=26) and race and age-matched controls (n=11). A Kruskal-Wallis test was applied to evaluate mean differences between SCA and control parameters. Linear regression assessed how elevated OEF correlated with increasing clinical impairment defined by presence of infarct, vasculopathy, or use of regular blood transfusions for SCA. Results: OEF had high reproducibility within the same scan session, n=37 (ICC = 0.989). Whole-brain OEF and CBF were increased in SCA adults (OEF=0.46±0.08; CBF=52.4±8.3 ml/100g/min) versus controls (OEF=0.35±0.06; CBF=43.6±5.1 ml/100g/min). Hematocrit and OEF were inversely correlated (R 2 =0.72; p<0.01). Linear regression revealed a stronger relationship of OEF than CBF with clinical impairment. In SCA adults without impairment (n=12) CBF and OEF have an inverse relationship (R 2 =0.41; p=0.01, Fig. 1A) but with clinical impairment (infarct, vasculopathy or severe pain requiring regular transfusions, n=14) CBF and OEF become uncoupled (R 2 =0.08; p=0.16; Fig. 1B) as CBF may not be able to increase further and may plateau or decline. Conclusion: TRUST-MRI OEF is a rapid, reproducible measure. OEF shows promise as screening tool for hemodynamic impairment and stroke risk in adults with SCA.

Download Full-text

Arterial blood pressure in adult Nigerians with sickle cell anemia

Journal of Cardiology ◽

10.1016/j.jjcc.2010.07.001 ◽

2010 ◽

Vol 56 (3) ◽

pp. 326-331 ◽

Cited By ~ 11

Author(s):

N.I. Oguanobi ◽

B.J.C. Onwubere ◽

O.G. Ibegbulam ◽

S.O. Ike ◽

B.C. Anisiuba ◽

...

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Arterial Blood

Download Full-text

Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia

Blood ◽

10.1182/blood-2018-09-876318 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2436-2444 ◽

Cited By ~ 16

Author(s):

Melanie E. Fields ◽

Kristin P. Guilliams ◽

Dustin Ragan ◽

Michael M. Binkley ◽

Amy Mirro ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Metabolic Stress ◽

Brain Magnetic Resonance Imaging ◽

Border Zone ◽

Oxygen Extraction Fraction ◽

Transfusion Therapy ◽

Whole Brain ◽

Disease Modifying Therapy ◽

Disease Modifying

Abstract Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

Download Full-text

Hemoglobinuria Is a Risk Factor For Kidney Disease Progression In Sickle Cell Anemia

Blood ◽

10.1182/blood.v122.21.996.996 ◽

2013 ◽

Vol 122 (21) ◽

pp. 996-996

Author(s):

Santosh L. Saraf ◽

Xu Zhang ◽

Tamir Kanias ◽

James P. Lash ◽

Robert E. Molokie ◽

...

Keyword(s):

Steady State ◽

Kidney Disease ◽

Kidney Function ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Red Blood Cell Transfusion ◽

Free Hemoglobin ◽

Arterial Blood

Abstract Chronic kidney disease (CKD) is a frequent complication of sickle cell anemia (SCA) and is a predictor of early mortality. To determine the predictors of deteriorating kidney function in SCA, we followed 164 patients treated at the University of Illinois at Chicago for a median of 32 months (range 3-88 months). Steady-state estimated glomerular filtration (eGFR), albuminuria, and hemoglobinuria assessments were obtained at baseline and during the follow-up period. Steady-state was defined as greater than four weeks from a vaso-occlusive pain episode or a red blood cell transfusion. Hemoglobinuria was defined as positive for blood on dipstick and < 2 red blood cells on microscopy. Fifty-six (34%) of the patients had hemoglobinuria at baseline. We confirmed in a subset of 43 patients that dipstick positive hemoglobinuria (n=17) was associated with higher urine cell-free hemoglobin concentrations determined by ELISA than dipstick negative urine (n=26) (23.1 vs. 11.5 ng/mL, p<0.0001) (Figure 1). Age and mean arterial blood pressures were similar in patients with hemoglobinuria at baseline compared to those without but markers of hemolysis were higher (LDH, indirect bilirubin, AST, and reticulocyte percentage; p<0.0001). Sixty-one percent (95%CI: 48-73%) of patients with hemoglobinuria at baseline had hemoglobinuria at most recent follow up compared to 9% (95%CI: 5-18%) of patients without hemoglobinuria at baseline (p<0.0001). The proportion of patients with CKD progression defined by a 50% reduction in eGFR calculated by the CKD-EPI formula or requirement for hemodialysis or kidney transplant was higher in patients with baseline hemoglobinuria (13%, 7/56) versus without hemoglobinuria (1%, 1/108) (HR 14, 95%CI: 2-113; logrank p=0.001) (Figure 2). Progression of albuminuria category from normoalbuminuria (albuminuria < 30mg/g creatinine) to either microalbuminuria (albuminuria = 30-300 mg/g creatinine) or macroalbuminuria (albuminuria > 300mg/g creatinine) or microalbuminuria to macroalbuminuria was also higher in patients with baseline hemoglobinuria (42%, 11/26) versus without hemoglobinuria (13%, 9/67) (HR 3.1, 95%CI: 1.3-7.7; logrank p=0.004) (Figure 3). In conclusion, hemoglobinuria determined by urinalysis at steady-state is a valid assessment of increased urine cell-free hemoglobin concentration and is fairly consistent on repeat testing at steady-state visits. The presence of hemoglobinuria is significantly associated with a greater risk for progression of CKD and albuminuria. Our findings are consistent with the possibility that cell-free hemoglobin contributes to the progression of kidney disease in SCA. Further research including measures to decrease cell-free hemoglobin exposure to preserve kidney function are warranted.Figure 1Figure 1. Figure 2Figure 2. Figure 3Figure 3. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The HBG2 rs7482144 (C > T) Polymorphism is Linked to HbF Levels but not to the Severity of Sickle Cell Anemia

Journal of Pediatric Genetics ◽

10.1055/s-0041-1733950 ◽

2021 ◽

Author(s):

Bhaskar V. K. S. Lakkakula ◽

Smaranika Pattnaik

Keyword(s):

Disease Severity ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

High Performance ◽

Complete Blood Count ◽

Small Sample Size ◽

Severe Disease ◽

Small Sample ◽

Total Leucocyte Count ◽

Severity Scores

AbstractSickle cell anemia (SCA) is a severe disease characterized by anemia, acute clinical complications, and a relatively short life span. In this disease, abnormal hemoglobin makes the red blood cells deformed, rigid, and sticky. Fetal hemoglobin (HbF) is one of the key modulators of SCA morbidity and mortality. Interindividual HbF variation is a heritable trait that is controlled by polymorphism in genes linked and unlinked to the hemoglobin β gene (HBB). The genetic polymorphisms that determine HbF levels are known to ameliorate acute clinical events. About 190 well-characterized homozygous SCA patients were included in this study. Complete blood count (CBC), high-performance liquid chromatography (HPLC), and clinical investigations were obtained from patient's records. Severity scores were determined by using the combination of anemia, complications, total leucocyte count, and transfusion scores. HBG2 rs7482144 polymorphism was genotyped by using the polymerase chain reaction and restriction fragment length polymorphism. The association between HBG2 rs7482144 polymorphism and HbF levels as well as the disease severity of SCA were assessed. SCA patients carrying TT genotype were found to have higher HbF levels. In addition, SCA patients with increased severity showed significantly lower levels of hemoglobin, HbF, and hematocrit values. However, the genotypes of HBG2 rs7482144 polymorphism were not found to be associated with the risk of disease severity. In summary, this study demonstrated that HBG2 rs7482144 polymorphism is linked with HbF levels, but it does not affect disease severity. The sample sizes used and the pattern of association deduced from our small sample size prevents us from extrapolating our findings further.

Download Full-text

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

Blood ◽

10.1182/blood.v112.11.713.713 ◽

2008 ◽

Vol 112 (11) ◽

pp. 713-713 ◽

Cited By ~ 2

Author(s):

F. Daniel Armstrong ◽

T. David Elkin ◽

R. Clark Brown ◽

Penny Glass ◽

Renee C. Rees ◽

...

Keyword(s):

Flow Velocity ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Study Entry ◽

Secondary Outcome ◽

Scale Scores ◽

Developmental Index ◽

Mental Developmental Index ◽

The Average Range ◽

Flow Velocities

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.

Download Full-text

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.

Download Full-text

Venous cerebral blood flow quantification and cognition in patients with sickle cell anemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211072391 ◽

2022 ◽

pp. 0271678X2110723

Author(s):

Hanne Stotesbury ◽

Patrick W Hales ◽

Melanie Koelbel ◽

Anna M Hood ◽

Jamie M Kawadler ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Cognitive Performance ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Flow Quantification ◽

Arterial Oxygen ◽

High Signal ◽

Sagittal Sinus

Prior studies have described high venous signal qualitatively using arterial spin labelling (ASL) in patients with sickle cell anemia (SCA), consistent with arteriovenous shunting. We aimed to quantify the effect and explored cross-sectional associations with arterial oxygen content (CaO2), disease-modifying treatments, silent cerebral infarction (SCI), and cognitive performance. 94 patients with SCA and 42 controls underwent cognitive assessment and MRI with single- and multi- inflow time (TI) ASL sequences. Cerebral blood flow (CBF) and bolus arrival time (BAT) were examined across gray and white matter and high-signal regions of the sagittal sinus. Across gray and white matter, increases in CBF and reductions in BAT were observed in association with reduced CaO2 in patients, irrespective of sequence. Across high-signal sagittal sinus regions, CBF was also increased in association with reduced CaO2 using both sequences. However, BAT was increased rather than reduced in patients across these regions, with no association with CaO2. Using the multiTI sequence in patients, increases in CBF across white matter and high-signal sagittal sinus regions were associated with poorer cognitive performance. These novel findings highlight the utility of multiTI ASL in illuminating, and identifying objectively quantifiable and functionally significant markers of, regional hemodynamic stress in patients with SCA.

Download Full-text

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.

Download Full-text