Leukocyte adhesion to P-selectin and the inhibitory role of Crizanlizumab in sickle cell disease: A standardized microfluidic assessment

Man, Yuncheng; Goreke, Utku; Kucukal, Erdem; Hill, Ailis; An, Ran; Liu, Shichen; Bode, Allison; Solis-Fuentes, Ambar; Nayak, Lalitha; Little, Jane A.; Gürkan, Umut A.

doi:10.1016/j.bcmd.2020.102424

Cited by 37 publications

(40 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, medication like the newly approved crizanlizumab-tmca, which has shown efficacy in the reduction of VOC frequency in SCD patients, could be included in the management of SCD patients. 33 This may help alleviate the burden of frequent VOCs in SCD patients.…”

Section: Discussionmentioning

confidence: 99%

Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study

Shah¹,

Bhor²,

Xie³

et al. 2020

JHEOR

View full text Add to dashboard Cite

Background: The study investigated the economic burden of vaso-occlusive crisis (VOC) among sickle cell disease (SCD) patients, through assessment of overall utilization and costs and costs per VOC episode (regarding the number of VOC episodes and health care setting, respectively). Methods: Using the Medicaid Analytic Extracts database, the first SCD-related diagnosis claim (index claim) between June 1, 2009–December 31, 2012 was identified among eligible adults. Patients were required to have continuous medical and pharmacy benefits for 6 months pre- and 12 months post-index. Discrete VOC claims identified within a 3-day gap were combined as a single VOC episode. Annual all-cause and SCD-related medical resources and costs were identified and stratified by number of VOC episodes during the 1-year follow-up period. Health care costs per VOC episode were also examined, stratified by care setting. Results: Enrollees included 8521 eligible patients with a mean age of 32.88 years (SD=12.21). Of these, 66.5% had a Charlson Comorbidity index (CCI) score of 0 (no comorbidities) and 67.3% were female. The average total medical costs were US$34 136 (median=US$12 691) annually, and SCD accounted for 60% of the total costs (mean=US$20 206, median=US$1204). Patients with >3 episodes had the highest annual SCD-related costs (mean=US$58 950) across all settings. Health care resource utilization (HCRU) and costs increased substantially as the number of VOC episodes increased. This study was limited to observation of associations rather than causal inference, and by possible coding and identification discrepancies and the restricted generalizability of the population. Conclusions: VOC has a severe impact on medical resource use and costs among the adult SCD population. Further research among broader study populations is needed to facilitate the reduction of VOC episodes and thereby improve clinical and economic outcomes for SCD patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study

Shah¹,

Bhor²,

Xie³

et al. 2020

JHEOR

View full text Add to dashboard Cite

show abstract

“…The microfluidic assay described in this study holds promise as a translatable system that could be utilized for simultaneous assessment of WBV and RBC adhesion in a wide spectrum of clinical scenarios as clinically relevant biomarkers, and in assessment of emerging targeted and curative therapies that aim to improve blood rheology and cellular adhesion. [73][74][75][76] For instance, WBV and RBC adhesion levels can be assessed before and after therapeutic interventions targeted at HCT augmentation, adhesion mitigation, and/or before and after curative therapies, in order to assess improvements in blood rheology and RBC properties with therapy.…”

Section: Discussionmentioning

confidence: 99%

Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

Sickle cell disease (SCD) is a recessive genetic blood disorder exhibiting abnormal blood rheology. Polymerization of sickle hemoglobin, due to a point mutation in the β-globin gene of hemoglobin, results in aberrantly adhesive and stiff red blood cells (RBCs). Hemolysis, abnormal RBC adhesion, and abnormal blood rheology together impair endothelial health in people with SCD, which leads to cumulative systemic complications. Here, we describe a microfluidic assay combined with a micro particle image velocimetry technique for the integrated in vitro assessment of whole blood viscosity (WBV) and RBC adhesion. We examined WBV and RBC adhesion to laminin (LN) in microscale flow in whole blood samples from 53 individuals with no hemoglobinopathies (HbAA, N = 10), hemoglobin SC disease (HbSC, N = 14), or homozygous SCD (HbSS, N = 29) with mean WBV of 4.50 cP, 4.08 cP, and 3.73 cP, respectively. We found that WBV correlated with RBC count and hematocrit in subjects with HbSC or HbSS. There was a significant inverse association between WBV and RBC adhesion under both normoxic and physiologically hypoxic (SpO 2 of 83%) tests, in which lower WBV associated with higher RBC adhesion to LN in subjects with HbSS. Low WBV has been found by others to associate with endothelial activation. Altered WBV and abnormal RBC adhesion may synergistically contribute to the endothelial damage and cumulative pathophysiology of SCD. These findings suggest that WBV and RBC adhesion may serve as clinically relevant biomarkers and endpoints in assessing emerging targeted and curative therapies in SCD. 1 | INTRODUCTION Sickle cell disease (SCD) is one of the most common inherited diseases in the world. 1,2 It is caused by a single-point mutation in the β-globin gene of hemoglobin. Sickle hemoglobin (HbS) polymerizes into long and stiff chains within the red blood cell (RBC) under low-oxygen conditions. 3,4 As a result, HbS-containing RBCs (sickle RBCs) become abnormally stiff and adherent (impairing microcirculatory blood flow), and fragile (resulting in hemolysis). Microvascular occlusion causes episodic and unpredictable vaso-occlusive events (VOE), pain, and Erdem Kucukal and Yuncheng Man contributed equally to this study.

show abstract

“…In sickle research context, the use of already developed microfluidic techniques to investigate VOC, RBC adhesion, inflammation and/or blood cell-endothelium interactions coupled with approaches to generate concentration gradients to evaluate dosage values of a single drug; a conceptual device is shown in Figure 5 . Multiple devices have demonstrated utility in evaluating novel drug effects on HbS polymerization, RBC sickling, RBC membrane damage, microrheology and endothelial adhesion ( Du et al, 2015 ; Lu et al, 2019 ; Hansen et al, 2020 ; Man et al, 2020 ; Noomuna et al, 2020 ). Moreover, often sickle patients require combination therapeutics.…”

Section: Current Challenges and Promising Microfluidics To Better Undmentioning

confidence: 99%

Microfluidics in Sickle Cell Disease Research: State of the Art and a Perspective Beyond the Flow Problem

Aich

Lamarre

Sacomani

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Sickle cell disease (SCD) is the monogenic hemoglobinopathy where mutated sickle hemoglobin molecules polymerize to form long fibers under deoxygenated state and deform red blood cells (RBCs) into predominantly sickle form. Sickled RBCs stick to the vascular bed and obstruct blood flow in extreme conditions, leading to acute painful vaso-occlusion crises (VOCs) – the leading cause of mortality in SCD. Being a blood disorder of deformed RBCs, SCD manifests a wide-range of organ-specific clinical complications of life (in addition to chronic pain) such as stroke, acute chest syndrome (ACS) and pulmonary hypertension in the lung, nephropathy, auto-splenectomy, and splenomegaly, hand-foot syndrome, leg ulcer, stress erythropoiesis, osteonecrosis and osteoporosis. The physiological inception for VOC was initially thought to be only a fluid flow problem in microvascular space originated from increased viscosity due to aggregates of sickled RBCs; however, over the last three decades, multiple molecular and cellular mechanisms have been identified that aid the VOC in vivo. Activation of adhesion molecules in vascular endothelium and on RBC membranes, activated neutrophils and platelets, increased viscosity of the blood, and fluid physics driving sickled and deformed RBCs to the vascular wall (known as margination of flow) – all of these come together to orchestrate VOC. Microfluidic technology in sickle research was primarily adopted to benefit from mimicking the microvascular network to observe RBC flow under low oxygen conditions as models of VOC. However, over the last decade, microfluidics has evolved as a valuable tool to extract biophysical characteristics of sickle red cells, measure deformability of sickle red cells under simulated oxygen gradient and shear, drug testing, in vitro models of intercellular interaction on endothelialized or adhesion molecule-functionalized channels to understand adhesion in sickle microenvironment, characterizing biomechanics and microrheology, biomarker identification, and last but not least, for developing point-of-care diagnostic technologies for low resource setting. Several of these platforms have already demonstrated true potential to be translated from bench to bedside. Emerging microfluidics-based technologies for studying heterotypic cell–cell interactions, organ-on-chip application and drug dosage screening can be employed to sickle research field due to their wide-ranging advantages.

show abstract

Leukocyte adhesion to P-selectin and the inhibitory role of Crizanlizumab in sickle cell disease: A standardized microfluidic assessment

Cited by 37 publications

References 19 publications

Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study

Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study

Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease

Microfluidics in Sickle Cell Disease Research: State of the Art and a Perspective Beyond the Flow Problem

Contact Info

Product

Resources

About