Biomechanical thrombosis: the dark side of force and dawn of mechano-medicine

Abstract

<jats:p>Arterial thrombosis is in part contributed by excessive platelet aggregation, which can lead to blood clotting and subsequent heart attack and stroke. Platelets are sensitive to the haemodynamic environment. Rapid haemodynamcis and disturbed blood flow, which occur in vessels with growing thrombi and atherosclerotic plaques or is caused by medical device implantation and intervention, promotes platelet aggregation and thrombus formation. In such situations, conventional antiplatelet drugs often have suboptimal efficacy and a serious side effect of excessive bleeding. Investigating the mechanisms of platelet biomechanical activation provides insights distinct from the classic views of agonist-stimulated platelet thrombus formation. In this work, we review the recent discoveries underlying haemodynamic force-reinforced platelet binding and mechanosensing primarily mediated by three platelet receptors: glycoprotein Ib (GPIb), glycoprotein IIb/IIIa (GPIIb/IIIa) and glycoprotein VI (GPVI), and their implications for development of antithrombotic ‘mechano-medicine’ .</jats:p>

Hemodynamic analysis for stenosis microfluidic model of thrombosis with refined computational fluid dynamics simulation

“…The follow-up studies suggested that γ 0 , S and α affect platelet aggregation in terms of kinetics, stability and sizes of aggregates 38 . The underlying platelet mechanobiology at molecular and cellular levels is exciting yet incompletely understood 5 . One possibility is that a γ ′ threshold exists for VWF elongation, and its subsequent conformational activation 6 , 13 , 60 , 64 .…”

“…They become dangerous when they grow large and occlude blood vessels in the heart, brain and peripheral vascularized organs, leading to heart attack, stroke and deep vein thrombosis respectively 2 . While it is well known that platelet adhesion, activation, and subsequent aggregation play a central role in thrombosis, the interplay of biochemical and biomechanical factors regulating platelet thrombosis remains incompletely understood 3 – 5 .…”

“…It has been recognized that a high shear rate and its gradient may activate mechanosensitive proteins such as von Willebrand factor (VWF) 8 , 9 and platelet glycoprotein Ib receptor 10 – 12 , leading to subsequent platelet activation and aggregation 7 , 13 . Nevertheless, the relationship between the microfluidic boundary conditions ( γ 0 , S , α ,) and hemodynamic parameters of flow disturbance, such as the peak shear rate ( γ max ), peak WSS ( τ max ) and shear rate gradient ( γ ′ ) at the stenotic (narrowing) region, remains incompletely defined 5 , 14 , 15 . Furthermore, it has been hypothesized that biomechanical platelet aggregation is not simply attributed to elevated shear and elongational force at the narrowing apex alone 4 , but the entire ‘shear history’ where the platelet experiences accumulated mechanical stimuli and concomitant cellular interactions 15 , 16 .…”

“…Furthermore, it has been hypothesized that biomechanical platelet aggregation is not simply attributed to elevated shear and elongational force at the narrowing apex alone 4 , but the entire ‘shear history’ where the platelet experiences accumulated mechanical stimuli and concomitant cellular interactions 15 , 16 . Thus, it is important to map the hemodynamic distribution at both the pre- and post-stenosis regions 5 .…”

Blood Clot Phenotyping by Rheometry: Platelets and Fibrinogen Chemistry Affect Stress-Softening and -Stiffening at Large Oscillation Amplitude

“…In arteries, red blood cells (RBCs) migrate to the centerline whereas platelets migrate towards the vessel wall, where they bind to the von Willebrand factor (vWF)-collagen cluster on top of a vessel lesion [ 3 ] or a ruptured atherosclerotic plaque. This process is supported by the irregular shape of platelets (which creates a surface that can be subjected to tangential shearing forces), by platelets sensing their mechanical environment [ 4 ], and by the linear conformation of vWF in high shear flow. This is also supported by RBCs pushing the platelets to aggregate closer together [ 5 , 6 ].…”