David Ku, M.D., Ph.D., Advisor

Committee:  
Gilda Barabino, Ph.D., Georgia Tech
Hans Deckmyn, Ph.D., Leuven University
Shannon Meeks, M.D., Emory University
Todd Sulchek, Ph.D., Georgia Tech

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 3,500s-1.  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 activation and GPIIb/IIIa have been proposed, but their efficacy in patients remain mixed. The overall objective 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 are necessary for thrombosis, and that higher concentrations of vWF in the plasma will increase thrombosis.

To this end, we developed a new high shear hemodynamic 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 that increasing plasma vWF levels in high shear regions increased thrombus thickness.  The results clarify the need for activation of mural platelets for long term thrombus accumulation without the activation of circulating platelets.