Preventing rapid platelet accumulation under very high shear stress

Atherosclerosis;Thrombosis;Platelet activation;Rapid platelet accumulation;Shear stress

Para, Andrea N. ; Mechanical Engineering

University:Georgia Institute of Technology

Department:Mechanical Engineering

关键词: Atherosclerosis;    Thrombosis;    Platelet activation;    Rapid platelet accumulation;    Shear stress;   

Others  :  https://smartech.gatech.edu/bitstream/1853/44726/1/para_andrea_n_201208_phd.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

Atherosclerosis is a major cause of mortality in industrialized nations. Atherosclerosis is characterized by plaque deposition which decreases the lumen diameter into a stenosis. The creation of a restriction increases shear rates pathologic levels exceeding 3,500/s. Following plaque cap rupture, thrombus may form from the accumulation of millions of platelets, occluding the vessel, leading to heart attack and stroke. Studies of high shear thrombosis show that platelet activation, GPIIb/IIIa and vWF are involved.However, some recent studies also suggest that high shear aggregation is not dependent on activation or GPIIb/IIIa. Several antiplatelet pharmaceuticals against activationand GPIIb/IIIa have been proposed, but their efficacy in patients remains mixed. The overallobjective of this project is to determine the factors necessary for thrombosis to occlusion in very high shear regions seen in diseased arteries. Our central hypotheses are that platelet activation and the subsequent conformational change in GPIIb/IIIa arenecessary for thrombosis, and that higher concentrations of vWF in the plasma willincrease thrombosis.To this end, we developed a new high shearhemodynamic model utilizing 30mLs of whole blood and quantified thrombus thickness, volume accumulation and accumulation rates. We demonstrate that thrombosis to occlusion stems from a second phase of Rapid Platelet Accumulation (RPA). Thrombus accumulation is completely prevented by PGE1 inhibition of platelet activation. Similarly, GPIIb/IIIa blockade via abciximab prevented significant thrombus deposition and RPA. We also found thatincreasing plasma vWF levels in high shear regions increased thrombus thickness andsuggestively increased RPA rates. The results clarify the need for activation of muralplatelets for long term thrombus accumulation without the activation of circulating platelets.