Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Nonanticoagulant Heparin Derivative

Alshaiban, Abdulelah; Muralidharan‐Chari, Vandhana; Nepo, Anne; Mousa, Shaker A.

doi:10.1177/1076029614565880

Cited by 15 publications

(13 citation statements)

References 34 publications

(49 reference statements)

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“…In recent years, great advances have been made in the development of translational therapies targeting abnormal cellular adhesion in SCD. For targeting abnormal adhesion of RBCs to activated endothelium, several therapies have been developed, including small molecules (αVβ3), low molecular weight heparin (P‐Selectin), and an oral agent in phase I/II studies in humans (P‐selectin) . A recent publication in the New England Journal of Medicine described a successful randomized trial of P‐selectin blockade in patients with SCD .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐enhanced adhesion of red blood cells in microscale flow

et al. 2017

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Objectives The advancement of microfluidic technology has facilitated the simulation of physiological conditions of the microcirculation, such as oxygen tension, fluid flow, and shear stress in these devices. Here, we present a micro-gas exchanger integrated with microfluidics to study red blood cell (RBC) adhesion under hypoxic flow conditions mimicking post-capillary venules. Methods We simulated a range of physiological conditions and explored RBC adhesion to endothelial or sub-endothelial components (fibronectin, FN, or laminin, LN). Blood samples were injected into microchannels at normoxic or hypoxic physiological flow conditions. Quantitative evaluation of RBC adhesion was performed on 35 subjects with homozygous sickle cell disease (SCD). Results Significant heterogeneity in RBC adherence response to hypoxia was seen among SCD patients. RBCs from a hypoxia enhanced adhesion population showed a significantly greater increase in adhesion compared to RBCs from a hypoxia non-enhanced adhesion population, for both FN and LN. Conclusions The approach presented here enabled the control of oxygen tension in blood during microscale flow and the quantification of RBC adhesion in a cost-efficient and patient-specific manner. We identified a unique patient population in which RBCs showed enhanced adhesion in hypoxia in vitro. Clinical correlates suggest a more severe clinical phenotype in this subgroup.

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐enhanced adhesion of red blood cells in microscale flow

et al. 2017

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“…148 Beta-adrenergic receptor blockade, which targets epinephrine-mediated red cell adhesion, 95,149-152 has been used in patients, using an U.S. Food and Drug Administration (FDA) approved medication (propranolol). 153 Red cell adhesion to an activated endothelium has specifically been targeted with small molecules ( α V β 3 ), 154 low-molecular-weight heparin (P-Selectin), 155,156 and an oral agent in phase I/II studies in humans (P-selectin). 125,157,158 Abnormal interactions between leukocytes and activated endothelium and endothelial selectins have been targeted in vitro and in vivo with antibodies and small molecules 159-162 and are now the focus of phase II and III clinical studies in SCD.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease

Alapan

Kim

Adhikari

et al. 2016

Translational Research

105

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Sickle cell disease (SCD) afflicts millions of people worldwide and is associated with considerable morbidity and mortality. Chronic and acute vaso-occlusion are the clinical hallmarks of SCD and can result in pain crisis, widespread organ damage, and early movtality. Even though the molecular underpinnings of SCD were identified more than 60 years ago, there are no molecular or biophysical markers of disease severity that are feasibly measured in the clinic. Abnormal cellular adhesion to vascular endothelium is at the root of vaso-occlusion. However, cellular adhesion is not currently evaluated clinically. Here, we present a clinically applicable microfluidic device (SCD biochip) that allows serial quantitative evaluation of red blood cell (RBC) adhesion to endothelium-associated protein-immobilized microchannels, in a closed and preprocessing-free system. With the SCD biochip, we have analyzed blood samples from more than 100 subjects and have shown associations between the measured RBC adhesion to endothelium-associated proteins (fibronectin and laminin) and individual RBC characteristics, including hemoglobin content, fetal hemoglobin concentration, plasma lactate dehydrogenase level, and reticulocyte count. The SCD biochip is a functional adhesion assay, reflecting quantitative evaluation of RBC adhesion, which could be used at baseline, during crises, relative to various long-term complications, and before and after therapeutic interventions.

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“…Anti-SCD RBC adhesion therapy has been validated pre-clinically, and, importantly, these targets are beginning to reach clinical trial, including VLA-4 blocking antibodies 109 , and beta-adrenergic receptor blockade (via an FDA-approved medication, propranalol 110 ) targeting epinephrine-mediated red cell adhesion 92, 99, 106, 111, 112 . Small molecules (αVβ3 integrin) 113 and low molecular weight heparin (P-Selectin) 59, 114 were utilized to target RBC adhesion to an activated endothelium specifically, and an oral agent for this purpose is in phase I/II studies in humans (P-selectin) 58, 115, 116 .…”

Section: Scd Pathophysiologymentioning

confidence: 99%

Emerging point-of-care technologies for sickle cell disease screening and monitoring

Alapan

Fraiwan

Kucukal

et al. 2016

Expert Review of Medical Devices

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Introduction Sickle Cell Disease (SCD) affects 100,000 Americans and more than 14 million people globally, mostly in economically disadvantaged populations, requires early diagnosis after birth and constant monitoring throughout the life-span of the patient. Areas Covered Early diagnosis of SCD still remains a challenge in preventing childhood mortality in the developing world due to requirements of skilled personnel and high-cost of currently available modalities. On the other hand, SCD monitoring presents insurmountable challenges due to heterogeneities among patient populations, as well as in the same individual longitudinally. Here, we describe emerging point-of-care micro/nano platform technologies for SCD screening and monitoring, and critically discuss current state-of-the-art, potential challenges associated with these technologies, and future directions. Expert Commentary Recently developed microtechnologies offer simple, rapid, and affordable screening of SCD and have the potential to facilitate universal screening in resource-limited settings and developing countries. On the other hand, monitoring of SCD is more complicated compared to diagnosis and requires comprehensive validation of efficacy. Early use of novel microdevices for patient monitoring might come in especially handy in new clinical trial designs of emerging therapies.

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Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Nonanticoagulant Heparin Derivative

Cited by 15 publications

References 34 publications

Hypoxia‐enhanced adhesion of red blood cells in microscale flow

Hypoxia‐enhanced adhesion of red blood cells in microscale flow

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease

Emerging point-of-care technologies for sickle cell disease screening and monitoring

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