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Probing ADP Induced Aggregation Kinetics During Platelet-Nanoparticle Interactions: Functional Dynamics Analysis to Rationalize Safety and Benefits
GlaxoSmithKline Asia Pvt. Ltd., Bangalore, India.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten.
Department of Biochemistry, University of Calcutta, Kolkata, India.
Department of Statistics, University of Calcutta, Kolkata, India.
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2019 (Engelska)Ingår i: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, s. 163-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Platelets, one of the most sensitive blood cells, can be activated by a range of external and internal stimuli including physical, chemical, physiological, and/or non-physiological agents. Platelets need to respond promptly during injury to maintain blood hemostasis. The time profile of platelet aggregation is very complex, especially in the presence of the agonist adenosine 5′-diphosphate (ADP), and it is difficult to probe such complexity using traditional linear dose response models. In the present study, we explored functional analysis techniques to characterize the pattern of platelet aggregation over time in response to nanoparticle induced perturbations. This has obviated the need to represent the pattern of aggregation by a single summary measure and allowed us to treat the entire aggregation profile over time, as the response. The modeling was performed in a flexible manner, without any imposition of shape restrictions on the curve, allowing smooth platelet aggregation over time. The use of a probabilistic framework not only allowed statistical prediction and inference of the aggregation signatures, but also provided a novel method for the estimation of higher order derivatives of the curve, thereby allowing plausible estimation of the extent and rate of platelet aggregation kinetics over time. In the present study, we focused on the estimated first derivative of the curve, obtained from the platelet optical aggregometric profile over time and used it to discern the underlying kinetics as well as to study the effects of ADP dosage and perturbation with gold nanoparticles. In addition, our method allowed the quantification of the extent of inter-individual signature variations. Our findings indicated several hidden features and showed a mixture of zero and first order kinetics interrupted by a metastable zero order ADP dose dependent process. In addition, we showed that the two first order kinetic constants were ADP dependent. However, we were able to perturb the overall kinetic pattern using gold nanoparticles, which resulted in autocatalytic aggregation with a higher aggregate mass and which facilitated the aggregation rate.

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Frontiers Media S.A., 2019. Vol. 7, s. 163-
Nyckelord [en]
platelet aggregation, functional data analysis, ADP, nanoparticle, Bi-stable system
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:liu:diva-159096DOI: 10.3389/fbioe.2019.00163ISI: 000476955900001PubMedID: 31380358Scopus ID: 2-s2.0-85069987718OAI: oai:DiVA.org:liu-159096DiVA, id: diva2:1338738
Anmärkning

Funding agencies: SERB, India [YSS/2015/002101]; EU H2020 Marie Sklodowska-Curie Individual Fellowship [706694]; MIIC Seed Grant at Linkoping University (LiU), Sweden; Wolfson College, University of Cambridge (UK)

Tillgänglig från: 2019-07-24 Skapad: 2019-07-24 Senast uppdaterad: 2019-08-23Bibliografiskt granskad

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Azharuddin, Mohammad

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