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Detection of platelet sensitivity to inhibitors of COX-1, P2Y?, and P2Y?? using a whole blood microfluidic flow assay.

ABSTRACT: Microfluidic devices recreate the hemodynamic conditions of thrombosis.Whole blood inhibited with PPACK was treated ex vivo with inhibitors and perfused over collagen for 300 s (wall shear rate=200 s(-1)) using a microfluidic flow assay. Platelet accumulation was measured in the presence of COX-1 inhibitor (aspirin, ASA), P2Y? inhibitor (MRS 2179), P2Y?? inhibitor (2MeSAMP) or combined P2Y1 and P2Y?? inhibitors.High dose ASA (500 ?M), 2MeSAMP (100 ?M), MRS 2179 (10 ?M), or combined 2MeSAMP and MRS 2179 decreased total platelet accumulation by 27.5%, 75.6%, 77.7%, and 87.9% (p<0.01), respectively. ASA reduced secondary aggregation rate between 150 and 300 s without effect on primary deposition rate on collagen from 60 to 150 s. In contrast, 2MeSAMP and MRS 2179 acted earlier and reduced primary deposition to collagen between 60 and 105 s and secondary aggregation between 105 and 300 s. R(COX) and R(P2Y) (defined as a ratio of secondary aggregation rate to primary deposition rate) demonstrated 9 of 10 subjects had R(COX)<1 or R(P2Y)<1 following ASA or 2MeSAMP addition, while 6 of 10 subjects had R(P2Y)<1 following MRS 2179 addition. Combined MRS 2179 and 2MeSAMP inhibited primary platelet deposition rate and platelet secondary aggregation beyond that of each individual inhibitor. Receiver-Operator Characteristic area under the curve (AUC) indicated the robustness of R(COX) and R(P2Y) to detect inhibition of secondary platelet aggregation by ASA, 2MeSAMP, and MRS 2179 (AUC of 0.874 0.966, and 0.889, respectively).Microfluidic devices can detect platelet sensitivity to antiplatelet agents. The R-value can serve as a self-normalized metric of platelet function for a single blood sample.

SUBMITTER: Li R

PROVIDER: S-EPMC3932538 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Detection of platelet sensitivity to inhibitors of COX-1, P2Y₁, and P2Y₁₂ using a whole blood microfluidic flow assay.

Li Ruizhi R Diamond Scott L SL

Thrombosis research 20131106 2

<h4>Background</h4>Microfluidic devices recreate the hemodynamic conditions of thrombosis.<h4>Methods</h4>Whole blood inhibited with PPACK was treated ex vivo with inhibitors and perfused over collagen for 300 s (wall shear rate=200 s(-1)) using a microfluidic flow assay. Platelet accumulation was measured in the presence of COX-1 inhibitor (aspirin, ASA), P2Y₁ inhibitor (MRS 2179), P2Y₁₂ inhibitor (2MeSAMP) or combined P2Y1 and P2Y₁₂ inhibitors.<h4>Results</h4>High dose ASA (500 μM), 2MeSAMP (1 ...[more]

PMID: 24365044

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Project description:Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes, and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls, whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a nonmonotonic variation with the highest near-wall concentration corresponding to platelets with a moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tends to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.

Dataset Information

Detection of platelet sensitivity to inhibitors of COX-1, P2Y?, and P2Y?? using a whole blood microfluidic flow assay.

Publications

Detection of platelet sensitivity to inhibitors of COX-1, P2Y₁, and P2Y₁₂ using a whole blood microfluidic flow assay.

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