Experimental and mathematical analyses of mural thrombogenesis under flow

[摘要] An epifluorescence video microscopy system, coupled with digital image processing techniques, and a computerized microphotometric measurement system were used to analyze the effects of two antithrombotic agents on surface platelet aggregation induced by collagen and to investigate the relative thrombogenicity of the various human collagen subtypes found in the vasculature as a function of wall shear rate. A parallel plate flow chamber, 200 $mu$m-thick, served as the model blood vessel in those studies.Our measurements revealed that increasing concentrations of GT-12 (an antiplatelet agent) correspondingly decreased the reaction rate between platelets at the surface, thereby reducing thrombus rate of growth at the surface. In the presence of GT-12 average thrombus size and number of platelets per thrombus were both strikingly lowered. Similarly, ATA (an anti-von Willebrand Factor agent) was found to reduce significantly both thrombus rate of growth and size, when compared to controls, in a dose-dependent manner.In native-fibrillar form, type I collagen was the most thrombogenic of the collagens at high wall shear rate, while type III was the most reactive at low and intermediate wall shear rates. Whereas platelet surface deposition continually increased on type I and VI collagen fibrils with increasing wall shear rates, it reached a maximum value at 800 sec$sp{-1}$ on types III, IV and V fibrils. Type V fibrillar collagen was found to be the least thrombogenic among the collagens of the vasculature.The concentration profiles of adenosine diphosphate, thromboxane A$sb2$, thrombin, and von Willebrand factor released extracellularly during thrombus growth, were estimated using finite element simulation of blood flow over model thrombi of various shapes and dimensions. It was found that thrombin concentrations were large enough to cause irreversible platelet aggregation, even in presence of heparin. While ADP concentrations were large enough to cause irreversible platelet aggregation at low shear rates and for small aggregate sizes, TxA$sb2$ concentrations were only sufficient to induce platelet shape change. The local concentration of vWF multimers released from the platelet $alpha$-granules may be sufficient to modulate platelet aggregation at low and intermediate wall shear rates ($<$1000 sec$sp{-1}$).

[发布机构] Rice University

[效力级别] engineering