Cerebral Blood Flow and Oxygen Delivery In Response To Hyperoxia In Sickle Cell Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2210-2210
Author(s):  
Adam M Bush ◽  
Matthew Borzage ◽  
Thomas Coates ◽  
John C. Wood
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Oxygen Delivery ◽  
Sickle Cell Trait ◽  
Control Group ◽  
Population Difference ◽  
O2 Delivery ◽  
And Control

Abstract Neurovascular sequalae are a common occurrence in Sickle Cell Anemia (SCA), with 11% of patients suffering cerebral vascular accident (CVA), or overt stroke by their twentieth birthday and 40% of patients developing silent cerebral infarcts (SCI) by age 14. Elevated transcranial Doppler (TCD) velocity of the middle cerebral artery identifies patients at risk for stroke, and this risk can be reduced by chronic transfusion therapy. However, the specificity of TCD is low causing many patients to be transfused unnecessarily. To further refine cerebrovascular risk stratification, we are studying factors responsible for normal and pathophysiologic cerebral blood flow (CBF) in SCD patients. Cerebral blood flow is increased in SCA patients compared to controls, but is believed to be a compensatory mechanism for chronic anemia and systemic desaturation. In order to test this hypothesis, we studied whole CBF and oxygen delivery (DO2) at rest and in response to hyperoxia in subjects with SCA and sickle cell trait (SCT). All patients were recruited at Children's Hospital Los Angeles through an IRB approved protocol. Informed consent was obtained for all patients. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. EKG, peripheral arterial oxygen saturation (SaO2), and fractional inspired oxygen (fiO2) were measured continuously throughout the study. Imaging consisted of a survey, reference scan, angiography localization, and nine axial phase contrast (PC) images. PC slices were placed inferior to the Circle of Willis, perpendicular to the carotids and basilar arteries. Participants received room air and 100% O2 through a non rebreathing respiratory circuit at 10 L/m. Room air exposure 20 minutes with six PC images collected throughout. Oxygen was delivered for 5 minutes followed by three more PC images. Blood for hemoglobin (HGB) and hematocrit (HCT) were drawn prior to MRI testing. No adverse events were reported upon follow up. Nine patients with SCA (5 male, 22.5 ± 6.7 yo p<0.05) and 3 with sickle cell trait (2 male, 36.7 ± 8.7 yo p<0.05) were studied. Baseline HGB was 25% lower (9.7 ± 1.3 versus 12.9 ± 0.1) and baseline HCT was 41% lower (28.0 ± 3.6 versus 47.3 ± 0.14 SCT) in SCA patients (p<0.05). Baseline whole brain CBF was elevated in SCA (1398 ± 400 ml/min versus 700 ± 172 ml/min). After correcting for HGB and SaO2, DO2 remained higher in SCA (192 ± 75 ml/min versus 105 ± 1.4 ml/min, p<0.05). During hyperoxia, whole brain CBF decreased by 10-15%, but the change was proportional to increased oxygen carrying capacity such that there was no change in DO2 in either populations. The increase in CBF we observed in SCA patients has been described using other modalities. However, we are the first to demonstrate that the increased flow observed is almost double what can be explained by their anemia and arterial desaturation alone. There are several possibilities for this observation. 1) SCA patients could have increased cerebral metabolic rate. If so, their mixed cerebral venous saturation will be normal and the flow is appropriate; 2) SCA patients have a mismatch between cerebral perfusion and metabolic demand, whether much of the increased flow does not effectively unload oxygen. If so, cerebral venous saturation would be high. We are currently optimizing MRI and NIR's technologies to estimate cerebrovascular metabolic rate, mixed cerebral venous saturation, and local supply-demand balance. Figure 1 Baseline CBF and O2 delivery in SCA and control group. ** statically significant population difference Figure 1. Baseline CBF and O2 delivery in SCA and control group. ** statically significant population difference Figure 2 Responce to 100% oxygen exposure. *statistically significant change from baseline Figure 2. Responce to 100% oxygen exposure. *statistically significant change from baseline Disclosures: Coates: Novartis Inc.: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Wood:Shire: Consultancy, Research Funding; Apopharma: Honoraria, Patents & Royalties; Novartis: Honoraria.

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602 ◽  
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

scholarly journals Up-Regulation of Mir-21 and Mir-130a and Serum Leptin Levels on Leg Ulcers Development in Sickle Cell Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 975-975
Author(s):  
Thais Helena Chaves Batista ◽  
Rodrigo Marcionilo Santana ◽  
Marcondes José de Vasconcelos Costa Sobreira ◽  
Gabriela da Silva Arcanjo ◽  
Diego Arruda Falcao ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Leg Ulcer ◽  
Acute Chest Syndrome ◽  
Control Group ◽  
Blood Collection ◽  
Leg Ulcers ◽  
Serum Leptin ◽  
Ulcer Group ◽  
And Control

Introduction: Leg ulcers (LUs) are a cutaneous complication of sickle cell anemia (SCA), whose etiology is considered multifactorial. In the search for new candidates for modulators of SCA clinical events, recent evidence suggests the significant role of mechanisms related to post-transcriptional regulation, especially microRNAs (miRNAs). Thus, the analysis of miRNAs miR-21 and miR-130a differential expression in patients with SCA becomes an interesting approach, since both act in the regulation of several biological mechanisms related to the pathophysiology of LU, especially the tissue repair process. In addition, these miRNAs have already been related to the regulation of serum leptin levels, a strong angiogenic pleiotropic hormone that acts in the healing process of skin lesions. Therefore, the aim of the study was to investigate the influence of miR-21 and miR-130a and serum leptin levels on the development of LUs in SCA patients. Methods: After analyzing medical records, 60 SCA patients were selected. Patients who presented some of the main clinical manifestations that may have etiology due to the underlying disease (for example: osteonecrosis, stroke, priapism and acute chest syndrome) were not included. Patients with a history of LU were considered cases, and those who did not develop this complication (n=20), were considered control (median age: 26 years, range: 19-61, 50% males). The control group was called "HbSS-Control" and the case group was divided into two subgroups: Active leg ulcer group, composed of 19 patients with active LU at the time of blood collection (median age: 35 years, range: 24-56, 68% males), and healed leg ulcer group, composed of 21 patients with healed LU at the time of blood collection (median age: 34 years, range: 22-52, 43% males). In addition, it was analyzed a group of 10 donors with normal hemoglobin profile (median age: 25 years, range: 20-30, 50% males), identified as "HbAA-Control". Expression levels of miRNAs extracted from peripheral blood, using mirVanaTM PARIS Kit (Invitrogen™) were evaluated by RT-qPCR technique utilizing TaqMan® probes. Serum leptin levels of the patients were evaluated employing the ELISA method (Human Leptin ELISA Kit, Millipore®). Mann-Whitney and Kruskal-Wallis tests were applied to compare continuous variables. Results: Up-regulation of both miRNAs was observed in the active leg ulcer group in contrast to the healed leg ulcer (miR-21: P&lt;0.0001, Figure 1A, Fold change [FC]=14,2; miR-130a: P=0.0004, FC=18,8, Figure 1B) and Control-HbSS groups (miR-21: P&lt;0.0001, FC=34,4, Figure 1A; miR-130a: P=0.0006, FC=15,3, Figure 1B) and the HbAA-Control group (miR-21: P&lt;0.0001, FC=5,8, Figure 1C; miR-130a: P=0.0009, FC=10,9, Figure 1D). However, there was no significant difference between the healed leg ulcer, HbSS-Control and HbAA-Control groups (miR-21: P=0.1829, Figure 1E; miR-130a: P=0.3537; Figure 1F). Furthermore, the active leg ulcer group had lower serum leptin levels when compared to the healed leg ulcer and Control-HbSS groups (P=0.0058; Figure 2A). The levels of leptin in the healed leg ulcer group did not differ from the Control-HbSS group (P=0.5929; Figure 2B). Conclusion: Our results demonstrated an inverse relation between the miRNAs miR-21 and miR-130a expression with serum leptin levels, suggesting that the up-regulation of these miRNAS may be related to the chronicity and healing of LUs in individuals with SCA through decreased of serum leptin levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Inverse correlation between cerebral blood flow measured by continuous arterial spin-labeling (CASL) MRI and neurocognitive function in children with sickle cell anemia (SCA)

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 379-381 ◽  
Author(s):  
John J. Strouse ◽  
Christiane S. Cox ◽  
Elias R. Melhem ◽  
Hanzhang Lu ◽  
Michael A. Kraut ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Arterial Spin Labeling ◽  
Complete Blood Count ◽  
Spin Labeling ◽  
Neurocognitive Impairment ◽  
Continuous Arterial Spin Labeling ◽  
L 14

Overt stroke, clinically “silent” cerebral infarct, and neurocognitive impairment are frequent complications of sickle cell anemia (SCA). Current imaging techniques have limited sensitivity and specificity to identify children at risk for neurocognitive impairment. We prospectively evaluated 24 children with SCA with a neurologic exam, complete blood count, transcranial Doppler ultrasound (TCD), measurement of intelligence quotient (IQ), and magnetic resonance imaging (MRI) with measurement of cerebral blood flow (CBF) using continuous arterial spin-labeling (CASL) MRI. Average CBF to gray matter was 112 ± 36 mL/100 g/min. We identified a strong inverse relationship between performance IQ and CBF (-1.5 points per 10 mL/100 g/min increase in CBF, P = .013). Elevated steady-state white blood cell count (≥ 14 × 109/L [14 000/μL]) was associated with lower full scale IQ (86 ± 9 vs 99 ± 10, P = .005). CASL MRI may identify children with neurocognitive impairment, before damage is evident by structural MRI or TCD. (Blood. 2006;108:379-381)

scholarly journals Predictors of cerebral blood flow in patients with and without anemia

2016 ◽  
Vol 120 (8) ◽  
pp. 976-981 ◽  
Author(s):  
Matthew T. Borzage ◽  
Adam M. Bush ◽  
Soyoung Choi ◽  
Aart J. Nederveen ◽  
Lena Václavů ◽  
...  
Keyword(s):  
Blood Flow ◽  
African American ◽  
Cerebral Blood Flow ◽  
Oxygen Content ◽  
Sickle Cell ◽  
Oxygen Supply ◽  
Complete Blood Count ◽  
Sickle Cell Trait ◽  
Supply And Demand ◽  
Cerebrovascular Reserve

Sickle cell disease (SCD) is the most common cause of stroke in childhood and results primarily from a mismatch of cerebral oxygen supply and demand rather than arterial obstruction. However, resting cerebral blood flow (CBF) has not been examined in the general African American population, in whom obesity, hypertension, cerebrovascular disease, and diminished cerebrovascular reserve capacity are common. To better understand the underlying physiological substrate upon which SCD is superimposed, we measured CBF in 32 young (age 28 ± 10 yr), asymptomatic African American subjects with and without sickle cell trait ( n = 14). To characterize the effects of chronic anemia, in isolation of sickle hemoglobin we also studied a cohort of 13 subjects with thalassemia major ( n = 10), dyserythropoetic anemia ( n = 1), or spherocytosis ( n = 2). Blood was analyzed for complete blood count, hemoglobin electrophoresis, cell free hemoglobin, and lactate dehydrogenase. Multivariate regression analysis showed that oxygen content was the strongest predictor of CBF ( r2 = 0.33, P < 0.001). CBF declined rapidly in the second and third decades of life, but this drop was explained by reductions in cerebral gray matter. However, age effects persisted after correction for brain composition, possibly representing microvascular impairment. CBF was independent of viscosity, hemoglobin S%, and body mass index. Hyperoxia resulted in reduced CBF by 12.6% ( P = 0.0002), and CBF changes were proportional to baseline oxygen content ( r2 = 0.16, P = 0.02). These data suggest that these hemoglobin subtypes do not alter the normal CBF regulation of the balance of oxygen supply and demand.

scholarly journals Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

2016 ◽  
Vol 37 (3) ◽  
pp. 994-1005 ◽  
Author(s):  
Lindsay S Cahill ◽  
Lisa M Gazdzinski ◽  
Albert KY Tsui ◽  
Yu-Qing Zhou ◽  
Sharon Portnoy ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Brain Tissue ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Cell Model ◽  
Ex Vivo ◽  
Tissue Hypoxia ◽  
Brain Physiology ◽  
The Brain

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

scholarly journals PF740 CEREBRAL BLOOD FLOW IN ADOLESCENTS WITH SICKLE CELL ANEMIA RECEIVING VOXELOTOR

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 324 ◽  
Author(s):  
J.H. Estepp ◽  
W. Wang ◽  
S. Hwang ◽  
C. Hillenbrand ◽  
R. Ogg
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell ◽  
Sickle Cell Anemia

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

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

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.

scholarly journals The Association of White Matter Hyperintensity Volume and Sickle Cell Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1321-1321
Author(s):  
Nicholas Farris ◽  
Henny H Billett ◽  
Craig A Branch ◽  
Caterina Minniti ◽  
Kelsey Branch ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
White Matter ◽  
Oxygen Saturation ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Laboratory Evaluation ◽  
Exclusion Criterion ◽  
Neurocognitive Performance ◽  
3T Mri

Abstract Background:While overt cerebrovascular accidents (CVAs) are well recognized in patients with Sickle Cell Anemia (SCA), more subtle cerebrovascular diseases, including neurocognitive performance deficits and silent cerebral infarcts (SCIs), are present but less well understood, particularly in adults. SCI manifests as asymptomatic white matter hyperintensities (WMH) found on T2-weighted, diffusion-weighted or Fluid Attenuated Inversion Recovery (FLAIR) magnetic resonance images. WMH volume has been found to be negatively associated with IQ in SCA. We sought to clarify the role of WMH load by MRI using region of interest volume calculations in patients particularly at risk, adult patients with SCA. Methods: SCA (HbSS/HbSβ0) and AA subjects, ages 18-55 years old, with no evidence of TIA/Stroke, prothrombotic history, clotting or bleeding disorder, and not on anticoagulation were recruited. Hydroxyurea use was noted but was neither an inclusion nor exclusion criterion. Evaluation included a routine questionnaire for basic social, educational and health information. Steady state laboratory evaluation was obtained within one week of imaging. Neurocognitive performance was evaluated by the Cogstate battery at the time of the MRI. Cogstate analysis included tests of executive function (the Groton Maze Learning Test or GMLT), recall, social and emotional cognition and learning. 3T MRI included 3D-T1w , T2, FLAIR, pseudo-continuous arterial spin labeling and diffusion tensor imaging (DTI). Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from DTI data and calculated for gray matter (GM) and white matter (WM). Cerebral blood flow (CBF) was also calculated for GM and WM separately. FLAIR images were reviewed (reviewer was blind for group) for WMHs using the NIH image analysis package MIPAV (http://mipav.cit.nih.gov/). WMH signal regions (ROI) were identified and selected/masked using the 'levelSet' ROI function on a slice-by-slice basis. ROIs were grouped, and average WMH volume (using slice thickness) calculated for each subject using the MIPAV Statistics Generator. Results:15 SCA and 11 AA subjects were recruited for the tailored questionnaire, 3T MRI, routine laboratory testing and neurocognitive testing. Both number and volume of ROI were increased in SCA patients (p=0.018 and p=0.052 respectively). GM and WM CBF were markedly increased in SCA patients (p=0.005 for both). GM-MD was increased in SCA patients (p=0.046) while increases in WM-FA and MD were of borderline significance (p=0.055 and p=0.564) respectively. These data are shown in the Table below. Although SCA patients fared significantly worse on the GMLT, p=0.020, there was no association of the GMLT with ROI volume (p=0.96). ROI volume was positively associated with MCHC (p=0.035), a dense cell biomarker, but we could not find an association with Hb, indirect bilirubin or reticulocyte count. MDWM FA and GM-MD also correlated significantly with MCHC but the major associations of DTI measurements, like those of both grey matter (GM) and white matter (WM) cerebral blood flow, were correlated with Hb levels (both GM and WM MD, p=0.004). There was no association of oxygen saturation or change in oxygen saturation with ROI number of volume. Conclusions: The etiology of the documented cognitive difference between SCA and HbA is unclear. Although there is some suggestion that WMH correlates with SCA outcome and may explain this discrepancy, the association is weak. We could not find as association of ROI number or ROI volume with cognitive outcome, nor could we find an association of ROI volume with any pertinent laboratory parameters except MCHC. Unlike CBF, WMH volume load, as represented by ROI volume, does not appear to correlate with the degree of anemia or with clinical disease. Whether cognitive impairment requires a "second hit" or whether it is multifactorial in nature, stemming from chronic oxidative stress, intermittent hypoxia or other factors, remains to be determined. Table Table. Disclosures No relevant conflicts of interest to declare.

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