Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities

Abstract

Cardiovascular diseases (CVD) are the number one cause of morbidity and death worldwide. As estimated by the WHO, the global death rate from CVD is 31% wherein, a staggering 85% results from stroke and myocardial infarction. Platelets, one of the key components of thrombi, have been well-investigated over decades for their pivotal role in thrombus development in healthy as well as diseased blood vessels. In hemostasis, when a vascular injury occurs, circulating platelets are arrested at the site of damage, where they are activated and aggregate to form hemostatic thrombi, thus preventing further bleeding. However, in thrombosis, pathological activation of platelets occurs, leading to uncontrolled growth of a thrombus, which in turn can occlude the blood vessel or embolize, causing downstream ischemic events. The molecular processes causing pathological thrombus development are in large similar to the processes controlling physiological thrombus formation. The biggest challenge of anti-thrombotics and anti-platelet therapeutics has been to decouple the pathological platelet response from the physiological one. Currently, marketed anti-platelet drugs are associated with major bleeding complications for this exact reason; they are not effective in targeting pathological thrombi without interfering with normal hemostasis. Recent studies have emphasized the importance of shear forces generated from blood flow, that primarily drive platelet activation and aggregation in thrombosis. Local shear stresses in obstructed blood vessels can be higher by up to two orders of magnitude as compared to healthy vessels. Leveraging abnormal shear forces in the thrombus microenvironment may allow to differentiate between thrombosis and hemostasis and develop shear-selective anti-platelet therapies. In this review, we discuss the influence of shear forces on thrombosis and the underlying mechanisms of shear-induced platelet activation. Later, we summarize the therapeutic approaches to target shear-sensitive platelet activation and pathological thrombus growth, with a particular focus on the shear-sensitive protein von Willebrand Factor (VWF). Inhibition of shear-specific platelet aggregation and targeted drug delivery may prove to be much safer and efficacious approaches over current state-of-the-art antithrombotic drugs in the treatment of cardiovascular diseases.

Violin plot data: A concerto of crucial information on valve thrombogenicity categorized in vitro by valve motion and inferred flow velocity

“…At near valve closure, flow dynamics can be considered analogous to transient valve stenosis, whereby regurgitation is increasingly constrained until complete, motionless, closed-valve conditions occur. During brief crucial moments preceding valve closure, localized prothrombotic microenvironments may be relevant to generation of high velocity leakage jets, flow unsteadiness, valve flutter, cyclic variability of PDVA, turbulence, and excessive shear forces that may induce blood element damage [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. These influences may impact multiple valve types for:…”

Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study

“…In fact, due to the increase in RV pre-load, the increase in shear stress will induce endothelial damage [ 48 , 49 ]. Consequently, an impaired microcirculation [ 50 ] can trigger a PLT activation [ 51 ]. Moreover, since the growth differentiation factor-15 (GDF-15), a member of the TGF-beta family, has been described to be controlled by MAP kinase and amyloid, along with increased inflammation, oxidative stress, hypoxia and oncogene activation, it is reasonable to foresee the direct role played by GDF-15 in fueling the multiorgan and renal dysfunction in both AL [ 52 ] and non-AL amyloidosis.…”

Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study

“…In fact, due to the increase in RV pre-load, the increase in shear stress will induce endothelial damage 48,49 . Consequently, an impaired microcirculation 50 can trigger a PLTs activation 51 . Moreover, since the growth differentiation factor-15 (GDF-15), a member of the TGF-beta family, has been described to be controlled by MAP kinase and amyloid, along with increased inflammation, oxidative stress, hypoxia and oncogene activation, it is reasonable to foresee a direct role played by GDF-15 in fueling the multiorgan and renal dysfunction in both AL 52 and non-AL amyloidosis.…”