Shear-Induced Platelet Dysfunction Relevant to Prosthetic Cardiovascular Devices
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Date
2018-01-01
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Department
Mechanical Engineering
Program
Engineering, Mechanical
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Access limited to the UMBC community. Item may possibly be obtained via Interlibrary Loan thorugh a local library, pending author/copyright holder's permission.
This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
Abstract
Thrombosis and bleeding are two major clinical complications in prosthetic cardiovascular device (PCD) patients. Non-physiological shearing conditions (NPSCs) in these devices are believed to induce platelet activation (PA), leading to thrombosis. There have been limited quantitative data on how the NPSCs cause PA. In the first project, shear-induced PA was characterized under PCD-related well-defined NPSCs generated by two Hemolyzers. Four PA markers were measured by flow cytometry and ELISA. PA can be reliably identified with surface P-selectin, and, to a lesser extent, platelet-derived microparticles rather than soluble P-selectin. Platelet-monocyte aggregation was a highly sensitive indirect PA marker. The relationship between PA expressed by surface P-selectin and shear stress/exposure time fitted a power law model well. The model can be used in computational fluid dynamics simulation for comparing platelet activation potential of PCDs. As the initial step of hemostasis, platelet adhesion is involved with several proteins (fibrinogen, VWF, and collagen) and platelet receptors (GPIIb/IIIa, GPIb?, and GPVI). NPSCs were known to lead to GPIb? and GPVI shedding. Few studies used sheared platelets for platelet adhesion to those three immobilized proteins. In the second project, with sheared blood perfused at two shear rates (500 and 2000 s-1), platelet adhesion to the three proteins was quantified using fluorescence microscopy. GPIb? and GPVI shedding was measured by flow cytometry. Agonist-induced platelet aggregation (AIPA) was also tested. At 500 s-1, NPSCs impaired platelet adhesion to VWF and collagen by receptor shedding of GPIb? and GPVI, respectively, increasing bleeding potential in PCD patients. However, NPSCs enhanced platelet adhesion to fibrinogen by increasing GPIIb/IIIa activation, elevating their thrombotic risk. NPSCs also reduced AIPA. With the shear rate increasing from 500 to 2000 s-1, platelets adhered less to VWF and fibrinogen but more to collagen. This study explains the potential connection among clinical complications, cellular level changes, and in-vitro observations. To overcome thrombosis, PCD patients need to take antiplatelet drugs. However, overdosing causes bleeding. Interaction between NPSCs and eptifibatide (a common antiplatelet drug) is not clear. In third project, the combined effect of shear stress and eptifibatide was investigated by quantifying platelet adhesion to fibrinogen, collagen, and VWF. PA and AIPA were also measured. NPSCs and eptifibatide additively inhibit platelet adhesion to VWF and collagen. NPSCs increased the adhesion to fibrinogen, but eptifibatide inhibited it. Higher eptifibatide concentration decreased platelet adhesion to all proteins. Eptifibatide suppressed thrombosis by inhibiting PA and might cause bleeding at high concentration by inhibiting platelet adhesion. This platelet adhesion assay is reliable in testing patient's sensitivity to eptifibatide and may be extended to other antiplatelet and anticoagulant drugs. The assay is helpful to enable reasonable management of eptifibatide for PCD patients.