Abstract
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.
Highlights
Platelets are very small circulating blood cells, that play pivotal roles in hemostasis and blood coagulation
We used a novel approach, where we have considered the entire platelet aggregation signature as the outcome and which has been facilitated by the use of a recent class of methods known as Functional Data Analysis (FDA) (Ramsay and Silverman, 2005)
Platelet aggregation kinetics was studied in presence of adenosine 5′-diphosphate (ADP) while in the second set, alterations in ADP induced platelet kinetics were measured in presence of the gold nanoparticles (AuNPs)
Summary
Platelets are very small circulating blood cells, that play pivotal roles in hemostasis and blood coagulation. Platelet aggregation is an inter-cellular phenomenon instead of an intra-cellular phenomenon, and has a faster kinetic rate than other physiological events such as cell division, apoptosis etc It requires the presence of permissive plasma physiological conditions to ensue, it is hard to monitor any inter-platelet modulation during aggregation under laboratory conditions. A deeper understanding of ADP induced platelet aggregation is a pre-requisite for a better interpretation of the effects during disease conditions and/or during estimation of the drug efficacy on platelet function. Insights in this area would help clinicians in treating patients according to the individual’s drug response profile
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