Abstract 19810: Oxidized LDL Exposure Enhances Baseline Platelet Activation and Amplifies Shear-mediated Activation

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Abstract

Introduction: Atherosclerotic heart disease is the leading cause of advanced cardiac failure. For end-stage patients, mechanical circulatory support is essential. While live-saving, it is often limited by device-related thrombosis. Blood is exposed to abnormal flow and high levels of shear stress within these devices, and shear has been associated with platelet activation. These patients exhibit hypercholesterolemia, and the deposition of oxidized low density lipoprotein (oxLDL) along arteries foreshadows cardiac failure. It remains unknown if there is a mechanistic link between atherogenic lipids and shear-mediated platelet activation.

Hypothesis: We hypothesize that oxLDL and shear exhibit synergistic effects on platelet activation, creating an environment susceptible to thrombosis.

Methods: Human gel filtered platelets (GFP) isolated from 8 donors were incubated with 0.5ug oxLDL or non-oxidized LDL (nLDL) for 15 minutes, and then exposed to uniform shear flow in a hemodynamic shearing device (HSD) at 37 °C. Samples were collected at 0 (no shear exposure), 2, and 5 minute time points during shear exposure of 70 dynes/cm2. Platelet activity was measured using a prothrombinase based platelet activation assay.

Results: GFP incubated with oxLDL had a twofold increase in platelet activation levels compared to baseline controls (p < .001). GFP- nLDL showed no statistical difference from baseline. GFP- nLDL or GFP alone showed typical activation curves in response to shear, reaching maximum activation between 5-10 minutes. OxLDL-incubated GFP exposed to the same shear conditions demonstrated an accelerated rate of activation, achieving greater than a twofold increase in thrombin generation by 2 minutes (p < .005), plateauing thereafter.

Conclusions: Exposure of platelets to oxLDL significantly increased their susceptibility to shear-mediated activation - with a net higher level of activation as well as an acceleration of activation. Our findings suggest that persistent hyperlipidemia in mechanical circulatory support patients may be a further risk factor amplifying device-related thrombosis. Further studies are warranted as to the mechanisms operative in oxLDL amplified platelet activation and their contribution to thrombotic risk.

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