Role of von Willebrand factor in shear induced platelet accumulation in a microfluidic device

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Casa, Lauren D. C.
Ku, David N.
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Thrombus formation under high fluid shear rates at the site of atherosclerotic plaque rupture leads to myocardial infarction and stroke. At high shear rates, thrombus is formed by platelets adhering via the glycoprotein von Willebrand factor (vWF). To investigate the relative contributions of vWF and platelets in high shear thrombosis, the present work developed a microfluidic thrombosis assay to meet low blood volume requirements and fluid shear conditions (3500-6000 s-1). Microfluidic conditions were selected to mimic the high shear environment of a diseased coronary artery, with the long-term objective of developing a clinically relevant assay for the assessment of thrombosis risk and treatment efficacy. The microfluidic design also addressed the requirement for volumetric thrombus formation rather than only surface platelet adhesion. As part of the design of the microfluidic assay, the effect of flow pulsatility on high shear thrombosis was investigated. It was found that steady wall shear rate matched to the mean pulsatile wall shear rate reproduced bulk thrombus formation characteristics of occlusion time, lag time, and thrombus growth rate, allowing subsequent experiments and future device design to utilize steady flow. The microfluidic assay was implemented to study the roles of vWF and platelets to thrombus formation using blood analogs produced from whole human blood diluted with normal saline at 90% and 99%. Hematocrit was restored to normal in all cases with the addition of red blood cells, and vWF and platelets were selectively restored to normal levels. Results showed that 90% dilutions with only vWF restored to normal levels occluded in 6/7 subject tested. The addition of platelets accelerated thrombus formation, but blood analogs with only platelets restored to normal levels occluded in only 2/5 subjects, indicating that vWF is more contributory in high shear occlusive thrombosis. At 99% dilutions, large thrombus formed with the addition of both platelets and vWF but was unstable and did not fully occlude the channel, indicating the possible requirement of an additional stabilizing factor(s) in occlusive thrombosis. Results of this study may lead to the development of improved anti-thrombotic treatments and improve patient care by providing a potential assay to evaluate treatment effectiveness and predict thrombosis risk.
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