Antithrombotic properties of pravastatin reducing intra-thrombus fibrin deposition under high shear blood flow conditions

Abstract

In addition to lowering cholesterol, the 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a range of pleiotropic effects that help reduce the risk of adverse cardiovascular events. We sought to understand the molecular mechanisms by which statins could exert anti-platelet actions under physiologic whole blood flow conditions. Using an in vitro perfusion chamber system, we examined the anti-platelet effects of pravastatin under whole blood flow conditions with high or low shear rates. We determined that pravastatin significantly suppressed platelet activation-dependent procoagulant activity, decreasing P-selectin membrane expression, tissue factor accumulation, and thrombin binding within platelet thrombi generated on a von Willebrand factor-surface under high shear rate conditions. These effects resulted in reductions of intra-thrombus fibrin deposition. These antithrombotic properties of pravastatin, which were comparable to those of atorvastatin, could be abrogated by mevalonate. Our experimental approach revealed a novel mechanism mediating the anti-platelet action of statins. Shear rate-dependent antithrombotic activity may explain the favourable effect of pravastatin on the reduction in cardiovascular events that typically occur in vivo under whole blood flow conditions with high shear rates.

Pravastatin and simvastatin improves acetylsalicylic acid‐mediated in vitro blood platelet inhibition

“…Various pleiotropic effects of statins concerning the molecular mechanisms of their antithrombotic effects, and especially their antiplatelet actions, are still under discussion. However, we consider that our results, convergent also with literature data [8,9,23,24], support the evidence showing that statins may modulate platelet function via direct interactions with platelet membranes (though these interactions do not include statins' effects on membrane cholesterol or membrane permeability) or by the influence on signalling pathways (pleiotropic effects of statins). It is possible that the statin effect on CD36 expression and ASA-mediated protein acetylation, especially the acetylation of COX-1, can be reached by the modulation of a distribution or a function of membrane-associated proteins.…”

“…Also, cerivastatin is able to reduce thrombin generation via a direct interaction with platelets [24]. Hamada et al [8] determined that pravastatin significantly suppressed platelet activation-dependent procoagulant activity and these effects resulted in reductions in intra-thrombus fibrin deposition within thrombin generated on a vWF surface under high shear rate conditions. This effect was observed without any apparent inhibition of platelet adhesion or aggregation.…”

Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

“…Statins have antiplatelet effects in vitro, ex vivo, in animal models and in patients293239. Therefore, in order to distinguish their effects on endothelial cells from those on platelets, we used washed platelets from healthy non-medicated volunteers for our experiments.…”

High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis

“…The haemostatic system is a modulator of atherosclerosis [ 135 ]. HSS induces intra-thrombus fibrin deposition and platelet adhesion to the arterial wall [ 136–138 ]. HSS also promotes platelet aggregation [ 139 ].…”