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Blood Cells Mol Dis. 2020 Mar 10;83:102424. doi: 10.1016/j.bcmd.2020.102424. [Epub ahead of print]

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

Author information

1
Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
2
Department of Hematology and Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Department of Hematology and Oncology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
4
Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: umut@case.edu.

Abstract

Upregulated expression of P-selectin on activated endothelium and platelets significantly contributes to the initiation and progression of vaso-occlusive crises (VOC), a major cause of morbidity in sickle cell disease (SCD). Crizanlizumab (ADAKVEO®), a humanized monoclonal antibody against P-selectin, primarily inhibits the interaction between leukocytes and P-selectin, and has been shown to decrease the frequency of VOCs in clinical trials. However, the lack of reliable in vitro assays that objectively measure leukocyte adhesion to P-selectin remains a critical barrier to evaluating and improving the therapeutic treatment in SCD. Here, we present a standardized microfluidic BioChip whole blood adhesion assay to assess leukocyte adhesion to P-selectin under physiologic flow conditions. Our results demonstrated heterogeneous adhesion by leukocytes to immobilized P-selectin, and dose-dependent inhibition of this adhesion following pre-exposure to Crizanlizumab. Importantly, treatment with Crizanlizumab following adhesion to P-selectin promoted detachment of rolling, but not of firmly adherent leukocytes. Taken together, our results suggest that the microfluidic BioChip system is a promising in vitro assay with which to screen patients, monitor treatment response, and guide current and emerging anti-adhesive therapies in SCD.

KEYWORDS:

Adhesion; BioChip; Crizanlizumab; Microfluidics; P-selectin; SEG101; Sickle cell disease

PMID:
32208292
DOI:
10.1016/j.bcmd.2020.102424

Conflict of interest statement

Declaration of competing interest YM, UG, EK, JAL, and UAG are inventors of intellectual property (PCT/US2018/022888 filed on March 16, 2018 and provisional patent application 62/928,109 filed on November 1, 2019) on the microfluidic BioChip technology presented in this manuscript. Competing interests of Case Western Reserve University employees are overseen and managed by the Conflict of Interests Committee according to a Conflict of Interest Management Plan.

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