scholarly journals Contribution of Vascular Cell Adhesion Molecule to Hemodynamics in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 958-958
Author(s):  
Noor Mary Abi Rached ◽  
David R. Archer ◽  
Jayre A Jones ◽  
Morgan Sterling ◽  
Hyacinth I Hyacinth
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Brain Tissue ◽  
Sickle Cell ◽  
Research Funding ◽  
Flow Reversal ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Cerebral Microvasculature ◽  
Flow Reversals

Abstract Vaso-occlusive events (VOEs) and pain crises are common clinical features of sickle cell disease (SCD) that result from sickle-shaped erythrocytes and leukocytes blocking blood flow, particularly in small vessels (Kato 2018). Activated endothelium also plays a role in the pathogenesis of VOEs in SCD. For example, VCAM-1 is expressed on blood vessels after activation by chemical and/or mechanical stimulation, which results in cytokine release. Studies have shown that patients with SCD have higher steady-state serum levels of soluble VCAM-1 compared to controls and that these levels are elevated during VOEs (White 2020). Furthermore, overexpression of these adhesion molecules on the endothelium results in prolonged adherence of white blood cells (WBCs), which has been shown to contribute to the development of VOEs and possibly cerebral vasculopathy. These findings raise the need to explore further the role of aberrant WBC- and/or RBC-endothelial interaction, mediated via VCAM-1, in the pathophysiology of cerebral microvascular hemodynamics and vasculopathy leading to cerebral microinfarcts in SCD. Therefore, we hypothesized that sickle cell mice will show greater cerebral cortical expression of VCAM-1 compared with age-matched controls and that this deposition will be associated with significant evidence of abnormal cerebral microvascular hemodynamic abnormalities. To examine the relationship between abnormalities in cerebral microvascular hemodynamics and VCAM-1 deposition in the cerebral microvasculature, we utilized a humanized sickle cell (with HbSS) and corresponding control (with HbAA). After cranial-window procedures, cortical capillaries, precapillary arterioles, and post-capillary venules were imaged using two-photon microscopy at two time points. In addition, this experiment included pre-and post-transfusion groups as we intend to study the impact of blood transfusion on hemodynamics. Using custom-written but well-validated MATLAB scripts, we analyzed line scans to identify the number and duration of rolling or adherent WBCs and RBCs, the RBC velocity in cerebral microvasculature, and the frequency and magnitude (mL/sec) of cerebral microvascular blood flow reversals. Rolling WBCs were defined as lasting two seconds or more, and adherent RBCs were defined as lasting 0.5 seconds or more. To quantify the expression of VCAM-1, we used immunohistochemistry to stain 50-micron sections of brain tissue for VCAM-1, Lectin to localize the vasculature, and Neun to localize neuronal nuclei. Images were analyzed using Phenochart and ImageJ software to examine the deposition of VCAM-1 throughout the brain tissue. As shown in Figure 1, at the first time point (baseline), we observed a significantly higher maximum RBC velocity (p<0.001) in the sickle cell mice compared to controls (figure 1a). We also found that there was significantly higher expression of VCAM-1 (p<0.001) (figure 1b) as well as significantly more leukocyte rolling (p<0.001) (figure 1c) in the sickle cell mice compared to controls. Additionally, we noted that the sickle cell mice have a significantly higher frequency of blood flow reversals (p<0.01) (figure 1d) as well as higher magnitude of microvascular blood flow reversals (p<0.001) (figure 1e) compared to controls. Interestingly, the sickle cell mice have a slightly lower average or mean capillary blood flow velocity compared to control (figure 1f), but this was not statistically significant (p=0.079). Since the mean capillary velocity is obtained as a smoothened difference between the forward flow and reversals, this decrease was surprising given the significant differences in frequency and magnitude of microvascular blood flow reversal in the sickle cell mice compared to controls (figs 1d and 1e). In conclusion, we see that the high velocity of blood flow might be a mechanical force, among other factors contributing to cerebral microvascular VCAM-1 expression in sickle cell mice. This might be responsible for the increased leukocyte-endothelial interactions and adhesion, ultimately leading to higher frequency and magnitude of cerebral microvascular blood flow reversal. Taken together, this may contribute to the observed slightly lower mean or effective microvascular forward blood flow. These pathophysiological changes might contribute to the reported higher rate of cerebral microinfarct and silent infarct in sickle cell disease. Figure 1 Figure 1. Disclosures Archer: Global Blood Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding. Hyacinth: Novartis: Consultancy; Acuta Capital: Consultancy.

scholarly journals Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease

PLoS ONE ◽  
2019 ◽  
Vol 14 (7) ◽  
pp. e0218783 ◽  
Author(s):  
Jonathan R. Lindner ◽  
Todd Belcik ◽  
Michael Widlansky ◽  
Leanne M. Harmann ◽  
Matthew S. Karafin ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Microvascular Blood Flow ◽  
Contrast Enhanced Ultrasound ◽  
Cell Disease ◽  
Contrast Enhanced

scholarly journals Contrast-Enhanced Ultrasound Detects Differences in Microvascular Blood Flow in Adults with Sickle Cell Disease Administered Regadenoson

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2705-2705
Author(s):  
Jonathan R. Lindner ◽  
Michael Widlansky ◽  
Melinda D. Wu ◽  
Jillian Dargatz ◽  
Leanne M. Harmann ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Microvascular Blood Flow ◽  
Study Cohort ◽  
Cell Disease ◽  
Non Invasive ◽  
Contrast Enhanced

Abstract Background: Outcome measures for therapeutic studies in patients with sickle cell disease (SCD) are poor.Abnormal microvascular blood flow (MBF), the basis for tissue ischemia and injury associated with vaso-occlusion, would be an optimal outcome measure for SCD studies. Ideally, a modality to measure blood flow in SCD would non-invasively quantify microvascular tissue perfusion rather than assess conduit arterial flow through large vessels. Limitations of existing techniques to measure blood flow prevent their widespread use in clinical trials of patients with SCD. Contrast-enhanced ultrasound (CEU) is a non-invasive and portable technique that uses standard ultrasound equipment to measure microvascular perfusion and functional capillary patency. The primary objective of this study was to determine whether CEU is able to detect differences in the MBF of skeletal muscle: 1) before and after infusion with the adenosine A2A receptor (A2AR) agonist regadenoson, and 2) between steady state and vaso-occlusive crisis (VOC). Methods: CEU measurements were obtained in forearm skeletal muscle in adult HbSS patients. Two measures are used to calculate MBF: 1) velocity of RBCs through capillaries and 2) volume of blood perfused in an area of tissue. MBF is the product of RBC velocity and volume of blood. In one study cohort, MBF was measured in steady-state patients during a 24-hour infusion of regadenoson (1.44 µg/kg/hour). CEU perfusion imaging was obtained at baseline, 6 and 24 hours after initiation of regadenoson. In the second study cohort, CEU measurements were obtained within the same patient during a hospital admission for VOC and at steady state. MBF was expressed in terms of a ratio to baseline flow (pre-regadenoson) in cohort 1 and as a ratio of VOC to steady-state flow for cohort 2. Results: CEU measurements were obtained in13 patients administered regadenoson, and 7 patients at steady state and during VOC. Median age (range) of all patients studied was 24 years (20-45) and 55% were female. During regadenoson infusion, there was a median increase in skeletal muscle MBF of 29% at 6 hours (ratio 1.29, IQR 0.81) and 9% at 24 hours (ratio 1.09, IQR 1.40). Increase in MBF during regadenoson administration was largely due to higher RBC velocity (6 hours ratio: 1.24, IQR 0.88; 24 hours: ratio 1.12 IQR 0.85). There was a median decrease of 40% in skeletal muscle blood flow during VOC compared to steady state (ratio 0.60, IQR 0.27). Similarly, a decrease in RBC velocity accounted for most of the reduction in MBF in VOC compared to steady state (ratio 0.63, IQR 0.35). Conclusion: CEU measures of skeletal muscle MBF increased during a 24-hour infusion of regadenoson and decreased in VOC compared to steady state. Changes in RBC velocity, as opposed to the volume of blood perfused, accounted for most of the differences in MBF seen during regadenoson infusion and VOC. Alterations in rheology or vascular tone could explain these changes. These data provide additional evidence for the A2AR agonist regadenoson as a therapeutic modality for patients with SCD and suggest that CEU is a valid measure of blood flow in VOC. Taken together, the findings of this preliminary study demonstrate that CEU, a non-invasive, portable technique to measure MBF, could be used as an objective outcome measure for therapeutic studies in SCD. Disclosures Field: NKTT: Consultancy, Research Funding. Off Label Use: IND for regadenoson for treatment of VOC in sickle cell disease.

Skin Blood Flow Measured By LSCI Demonstrates Treatment Effect of Chronic Transfusion Protocol in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4871-4871
Author(s):  
Nicolas V Currier ◽  
Gersham Dent ◽  
Paul S. Swerdlow ◽  
Willem Birkhoff ◽  
Jacobus Burggraaf ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Healthy Volunteers ◽  
Sickle Cell ◽  
Skin Blood Flow ◽  
Vascular Complications ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Blood Flow Patterns ◽  
Transfusion Protocol

Abstract Background: Vascular complications such as stroke and pulmonary hypertension are central features of sickle cell disease (SCD) pathophysiology and are associated with early mortality among patients with SCD. Better understanding of the abnormal blood flow patterns in sickle cell disease is critical to assessing the therapeutic benefit of emerging therapies. Previous studies have shown abnormal blood flow patterns in sickle cell patients using laser speckle contrast imaging (LSCI) (Ikeda et al. poster 1080 ASH annual meeting, December 8, 2012), however, no test re-test variability or changes in response to therapeutic intervention were assessed. As part of a larger study using multiple imaging technologies to concurrently evaluate blood flow and oxygenation in several organs of healthy subjects and subjects with SCD, the present study has analyzed skin blood flow by LSCI in these patients longitudinally using a multiple visit protocol. Furthermore, we analyzed the effect of Chronic Transfusion Protocol, the most effective intervention against vascular complications on skin blood flow. Methods: We enrolled 9 SCD patients (age 30.2 ± 8.6 years 5 men / 4 women) and 4 age and ethnically matched healthy controls (age 24.5 ± 4.5 years, 2 men / 2 women). 5 of the 9 SCD patients were on Chronic Transfusion Protocol. Following a screening visit where patients consented for the study, had basic labs, 12-lead EKG and physical exam, cutaneous blood flow was directly measured using LCSI at baseline, during and after a standard brachial artery occlusion-reperfusion maneuver (inflation of an occlusive pneumatic cuff for 3-5 min depending on patient tolerance). For assessment of test, re-test reliability this visit protocol was repeated within 1-10 days for patients not on transfusion protocols and healthy volunteers. Three visits occurred for transfusion patients, the first 2-4 days prior to transfusion, the second 1-2 days post transfusion and the third 6-14 days after the first post-transfusion imaging visit. Results: Baseline microvascular blood flow measured by LSCI was greater in patients with sickle cell disease compared to healthy controls (47 + 11 vs. 27 + 3 arbitrary units (AU); p=0.002) with sickle cell patients on chronic transfusion protocols exhibiting an intermediate blood flow phenotype (32 + 7 AU p= 0.001 vs. non-transfused patients and p= 0.039 vs. HV). Surprisingly, transfusion had no impact on baseline blood flow both 1-2 days and 6-14 days following transfusions (34 + 9 AU pre-transfusion, 32 + 7 AU first post-transfusion, 33 + 6 AU second post-transfusion). Maximal microvascular blood flow was similar across all groups (86 + 14 AU sickle cell patients vs. 82 + 12 AU healthy volunteers vs. 75 + 15 AU sickle cell patients on chronic transfusion). All measured values exhibited significant longitudinal stability across visits with r2= 0.865 for baseline blood flow measurements for non-transfusion sickle cell patients and healthy volunteers between visit 1 and 2. For transfusion patients r2= 0.927 and r2= 0.866 between visits 1 and 2 and 1 and 3 respectively. No statistically significant differences were observed in our analysis of the time from half-maximum to maximum blood flow or time from maximum to half-maximum blood flow during the recovery period after occlusion across all subjects. Conclusion: Compared to healthy individuals, patients with SCD have greater baseline microvascular blood flow in skin and these numbers are stable over a multi-visit protocol. Furthermore, patients on chronic transfusion protocols exhibit lower, but not normal skin blood flow parameters. Surprisingly, these values are not impacted acutely by transfusion. These results not only further validate that LSCI could function as a non-invasive disease biomarker for vascular dysfunction in sickle cell disease but that it is sensitive enough to detect vascular changes that occur in response to effective therapy. Finally, these results suggest that the therapeutic changes in vascular function provided by Chronic Transfusion Protocols occur over the long term versus acutely. Disclosures Currier: Biogen: Employment, Other: shareholder. Dent:Biogen: Employment, Other: shareholder. Birkhoff:CHDR: Employment. Burggraaf:CHDR: Employment. de Vries:CHDR: Employment. Hobbs:Biogen: Employment, Equity Ownership, Other: shareholder. Verma:Biogen: Employment, Other: shareholder.

Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice

2004 ◽  
Vol 287 (1) ◽  
pp. H293-H301 ◽  
Author(s):  
Dhananjay K. Kaul ◽  
Xiao-du Liu ◽  
Stephana Choong ◽  
John D. Belcher ◽  
Gregory M. Vercellotti ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Leukocyte Adhesion ◽  
Endothelial Activation ◽  
Leukocyte Recruitment ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Anti Inflammatory ◽  
Hypoxia Reoxygenation

In sickle cell disease, inflammatory activation of vascular endothelium and increased leukocyte-endothelium interaction may play an important role in the occurrence of vasoocclusion. In sickle mouse models, inflammatory stimuli (e.g., hypoxia-reoxygenation and cytokines) result in increased leukocyte recruitment and can initiate vasoocclusion, suggesting that anti-inflammatory therapy could be beneficial in management of this disease. We have tested the hypothesis that inhibition of endothelial activation in a transgenic mouse model by anti-inflammatory agents would lead to reduced leukocyte recruitment and improved microvascular blood flow in vivo. In transgenic sickle mice, hypoxia-reoxygenation resulted in greater endothelial oxidant production than in control mice. This exaggerated inflammatory response in transgenic mice, characterized by increased leukocyte recruitment and microvascular flow abnormalities, was significantly attenuated by antioxidants (allopurinol, SOD, and catalase). In contrast, control mice exhibited a muted response to antioxidant treatment. In addition, hypoxia-reoxygenation induced activation of NF-κB in transgenic sickle mice but not in control mice. In transgenic sickle mice, sulfasalazine, an inhibitor of NF-κB activation and endothelial activation, attenuated endothelial oxidant generation, as well as NF-κB activation, accompanied by a marked decrease in leukocyte adhesion and improved microvascular blood flow. Thus targeting oxidant generation and/or NF-κB activation may constitute promising therapeutic approaches in sickle cell disease.

scholarly journals Skeletal and myocardial microvascular blood flow in hydroxycarbamide-treated patients with sickle cell disease

2017 ◽  
Vol 179 (4) ◽  
pp. 648-656 ◽  
Author(s):  
Vandana Sachdev ◽  
Stanislav Sidenko ◽  
Melinda D. Wu ◽  
Caterina P. Minniti ◽  
Hwaida Hannoush ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Microvascular Blood Flow ◽  
Cell Disease

scholarly journals Blood rheology biomarkers in sickle cell disease

2020 ◽  
Vol 245 (2) ◽  
pp. 155-165
Author(s):  
Madeleine Lu ◽  
Minke AE Rab ◽  
Sergey S Shevkoplyas ◽  
Vivien A Sheehan
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Rheology ◽  
Early Mortality ◽  
Microvascular Blood Flow ◽  
Novel Therapies ◽  
Cell Disease ◽  
Clinical Complications ◽  
Blood Disorder

Sickle cell disease (SCD) is the most common inherited blood disorder, affecting approximately 100,000 patients in the U.S. and millions more worldwide. Patients with SCD experience a wide range of clinical complications, including frequent pain crises, stroke, and early mortality, all originating from a single-point mutation in the β-globin subunit. The RBC changes resulting from the sickle mutation lead to a host of rheological abnormalities that diminish microvascular blood flow, and produce severe anemia due to RBC hemolysis, and ischemia from vaso-occlusion initiated by sticky, rigid sickle RBCs. While the pathophysiology and mechanisms of SCD have been investigated for many years, therapies to treat the disease are limited. In addition to RBC transfusion, there are only two US Food and Drug Administration (FDA)-approved drugs to ameliorate SCD complications: hydroxyurea (HU) and L-glutamine (Endari™). The only curative therapy currently available is allogeneic hematopoietic stem cell transplantation (HSCT), which is generally reserved for individuals with a matched related donor, comprising only 10–15% of the total SCD population. Potentially curative advanced gene therapy approaches for SCD are under investigation in ongoing clinical trials. The ultimate goal of any curative treatment should be to repair the hemorheological abnormalities caused by SCD, and thus normalize blood flow and prevent clinical complications. Our mini-review highlights a set of key hemorheological biomarkers (and the current and emerging technologies used to measure them) that may be used to guide the development of novel curative and palliative therapies for SCD, and functionally assess outcomes. Impact statement Severe impairment of blood rheology is the hallmark of SCD pathophysiology, and one of the key factors predisposing SCD patients to pain crises, organ damage, and early mortality. As novel therapies emerge to treat or cure SCD, it is crucial that these treatments are functionally evaluated for their effect on blood rheology. This review describes a comprehensive panel of rheological biomarkers, their clinical uses, and the technologies used to obtain them. The described technologies can produce highly sensitive measurements of the ability of current treatments to improve blood rheology of SCD patients. The goal of curative therapies should be to achieve blood rheology biomarkers measurements in the range of sickle cell trait individuals (HbAS). The use of the panel of rheological biomarkers proposed in this review could significantly accelerate the development, optimization, and clinical translation of novel therapies for SCD.

scholarly journals Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease

Blood ◽  
2020 ◽  
Vol 136 (10) ◽  
pp. 1191-1200 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Maha Khaleel ◽  
Wanwara Thuptimdang ◽  
Patjanaporn Chalacheva ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Thermal Exposure ◽  
Thermal Stimulation ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Threshold Temperatures ◽  
Contralateral Hand ◽  
The Right

Abstract Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Laser Speckle Contrast Imaging Characterizes Delayed Reperfusion After Transient Brachial Artery Occlusion in Patients with Sickle Cell Diseas

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1080-1080
Author(s):  
Allison K. Ikeda ◽  
Tiffany C. Anaebere ◽  
Nitin Malik ◽  
Matthew D. Antalek ◽  
Miles L. Seidel ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Brachial Artery ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Microvascular Blood Flow ◽  
Healthy Controls ◽  
Cell Disease ◽  
Contrast Imaging

Abstract Abstract 1080 Background: The pathophysiology of sickle cell disease (SCD) involves vascular complications such as stroke and pulmonary hypertension. Elevated pulmonary artery pressure estimated by cardiac ultrasound or measured by invasive right heart catheterization is associated with early mortality among patients with SCD. Peripheral vascular dysfunction has also been observed in SCD and may be easier to assess than pulmonary vascular resistance and therefore more suitable for epidemiologic or interventional studies of SCD. Three previous studies found no difference in the maximal blood flow (or percentage increase) stimulated by occlusion and reperfusion of the brachial artery, a conduit vessel, when measured by Doppler ultrasound at periodic intervals. However, a study using continuous laser Doppler measurements of cutaneous microvascular blood flow found that patients with SCD had prolonged time to maximal blood flow and prolonged time to return to baseline compared to healthy controls. In our study, we used two-dimensional laser speckle contrast imaging (LSCI) to assess the cutaneous microvascular blood flow response in adults with SCD after five minutes of brachial artery occlusion. Methods: Nine subjects with sickle cell disease were enrolled and compared against nine healthy African-American control subjects matched for age, sex, ethnicity, and body mass index. Cutaneous blood flow was directly measured using LCSI at baseline, during and after a standard brachial artery occlusion-reperfusion maneuver (inflation of an occlusive pneumatic cuff for five minutes). This stimulates a transient increase in blood flow to levels above baseline during the reperfusion phase. Blood flow data were averaged over a defined region of interest on the medial aspect of the forearm. Microvascular blood flow responsiveness was calculated as the time to maximum (time elapsed from 50% of maximum to maximum blood flow) and the time to return to baseline (time elapsed from maximum to 50% of maximum blood flow). We performed measurements on each individual on two separate days, and compared the microvascular blood flow responses between the groups using two-way ANOVA with repeated measures. Results: We enrolled nine patients with sickle cell disease (age 35 ± 8.8, BMI 23 ± 3.9, 3 men/6 women) and nine healthy controls (age 35 ± 10.7 years, BMI 25 ± 3.2, 3 men/6 women). Baseline microvascular blood flow measured in arbitrary units (AU) was greater in patients with sickle cell disease compared to healthy controls (53.1 ± 9.2 AU vs 37.2 ± 4.4 AU, p < 0.0001) but maximal microvascular blood flow was similar (121.3 ± 29.3 AU vs 124.7 ± 26.6 AU, p = 0.58). Analysis of the time from half-maximum to maximum blood flow revealed that patients with sickle cell disease take longer to reach maximum blood flow (19.1 ± 11.6 s vs 11.8 ± 1.0 s, p = 0.03) and longer to decrease from maximum to half-maximum blood flow during the recovery period (43.5 ± 13.0 s vs 28.6 ± 10.4 s, p = 0.002). Conclusion: Compared to healthy individuals, patients with SCD have greater baseline microvascular blood flow but similar maximal blood flow during reperfusion. However, patients with SCD differ significantly from healthy control subjects in the time required to reach maximal blood flow and the time required to return to baseline, both of which are prolonged in patients with SCD. This may reflect delayed or impaired endothelial responses to shear stress and/or greater viscosity of blood. Time to maximal blood flow might represent a useful physiological biomarker as a proxy for clinical severity of sickle cell anemia, and a potential surrogate marker in early phase clinical trials. This technique merits additional characterization and validation. Disclosures: No relevant conflicts of interest to declare.

Effect Of Purified Poloxamer 188  and Various Dextrans On Erythrocyte Sedimentation Rate In Healthy Subjects and Patients With Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4764-4764
Author(s):  
Debra Hoppensteadt ◽  
Martin Emanuele ◽  
Joann Molnar ◽  
Omer Iqbal ◽  
Jawed Fareed
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Erythrocyte Sedimentation Rate ◽  
Sickle Cell ◽  
Sedimentation Rate ◽  
Healthy Subjects ◽  
Microvascular Blood Flow ◽  
Cell Protein ◽  
Cell Disease ◽  
Erythrocyte Sedimentation

Introduction Purified poloxamer188 (P188) (Mast Therapeutics) is a non-ionic, linear block copolymer composed of a central chain of hydrophobic polyoxypropylene and two flanking chains of hydrophylic polyoxyethylene (MW 8.5 kDa). This agent has hemorheologic properties which result in improved microvascular blood flow. P188 has been investigated in a number of indications and is currently under study in an international phase 3 clinical trial in sickle cell patients with vaso-occlusive crisis. Dextrans represent branched polysaccharides of 10-70 kDa that have been used as antithrombotic agents and plasma expanders. Sickle cell disease (SCD) represents a complex hemorheologic condition due to RBC aggregation and cell-fibrin/fibrinogen interactions. The erythrocyte sedimentation rate (ESR) is reflective of RBC and plasma interactions. This study was designed to compare the effect of P188 and dextrans on ESR’s in blood obtained from healthy subjects and patients with sickle cell disease who were seen at Loyola University Medical Center clinics. Material and Methods Whole EDTA blood collected from normal individuals (n=8) and sickle cell patients confirmed by electrophoresis (n=11) were supplemented with P188 or dextran 10K, 18K , 40K and 70K at various concentrations (or saline control). ESR was measured using standard laboratory technique. Results The ESR’s for sickle cell patients (26.4 ± 7.1 mm/hr) were significantly higher in comparison to the ESR’s for healthy subjects (14.6 ± 2.1 mm/hr). Supplementation of P188 decreased ESR’s in both populations. Normal blood ESR’s decreased to 9.1 ± 1.3 mm/hr (38%), whereas the sickle cell patient values decreased to 14.1 ± 4.6 mm/hr (47%).  At comparable concentrations, none of the dextrans changed ESR’s in healthy subjects or patients with sickle cell disease. Discussion These results demonstrate that ESR in SCD patients are elevated compared to healthy subjects. P188 supplementation decreased (up to 50%) ESR’s in both the healthy subjects and sickle cell patients. This may be due to the inhibition of rouleaux formation resulting from P188 effects on RBC membranes or cell-protein interactions. None of the dextrans produced a similar decrease, suggesting that the observed lowering of ESR by P188 is unlikely to be due to a non-specific effect related to polymer molecular weight. Clinical Implications P188 is a potential therapeutic agent which may facilitate blood flow and reduce cell-fibrin/fibrinogen interactions in a variety of hemorrheologic disorders. The observed decrease in ESR both in normal and sickle cell blood samples by P188 may primarily be due to increased membrane hydration, fibrinogen dispersion and anti-adhesive effects of this agent. Disclosures: Emanuele: Mast Therapeutics: Employment. Fareed:Mast Therapeutics: Research Funding.

scholarly journals Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

2019 ◽  
Vol 8 (10) ◽  
pp. 1690 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Christopher Denton ◽  
Patjanaporn Chalacheva ◽  
Michael Khoo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Critical Role ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

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