High shear stress marks: the vulnerable target with von Willebrand factor for platelet deployment -letter-.

Abstract

The original work of Maalej et al. “Effects of shear stress on acute platelet thrombus formation in canine stenosed carotid arteries: an in vivo quantitative study” [1] is an elegant study that contributes considerably to the knowledge concerning the dynamics of platelet deposition in fresh thrombus formation. However, this study raises a few problems that should be addressed. This study which intends to present “in vivo” data does not take into consideration the potential effect of extracorporeal study protocols on platelets. For example, platelets were shown to be activated when centrifuged and found to be vulnerable to damage by this mechanical manipulation, even more than erythrocytes [2,3]. It is important to remember that such activation may lead to tiny cell aggregates, setting the stage for the “inversion phenomenon” to occur. According to this biophysical rule, the presence of cell aggregates increases blood viscosity in the microcirculation and would cause a steep rise of resistance to blood _ow, possibly to the point of no-_ow and stasis [4]. Measuring post transfusion platelet activity and ruling out the presence of platelet aggregates would have given more validity to the results. Other effects of high shear stress on platelet biology and functional should be taken into consideration for a comprehensive understanding of thrombotic balance. High shear stress also induces deactivation of platelets through at least two mechanisms. In platelets, arachidonic acid is metabolized by the 12-lipoxygenase pathway to the formation of 12-hydroperoxyeicosa-tetraenoic acid (12HPETE), which is further metabolized to hepoxilin A3 (Hx-A3) [5]. High shear stress such as that which exists in stenotic coronary artery regions [6] also induces Hx-A3 production [7] that was recently reported to inhibit platelet aggregation induced by thrombin [8]. These ~ndings probably have clinical implications, as high risk patients were shown by our group to be low Hx-A3 producers [9]. Another downregulation mechanism is nitric oxide (NO) which is produced by endothelial cells ampli~ed under high shear stress. Nitric oxide attenuates human platelet activation [10], shown to be at lower levesl in patients with risk factors for cardiovascular disease than in normal population. These two mechanisms could function as a negative feedback that inhibits downstream aggregability of those platelets traveling in the vicinity of a lesion, but not being trapped in a thrombus. It was demonstrated previously that in a stenotic vessel, thrombi were composed primarily of platelets and occurred 1.0 mm downstream from the apex of the constriction, propagating distally [6]. It is probable that the positive and negative thrombotic effects of these metabolites are primarily a downstream event. If this is the case, than I would like to present an alternative interpretation of the Maalej study’s results. The importance of shear stress-induced platelet activation by von Willebrand factor (vWF) has been emphasized recently [11]. When high shear stress is applied to vWF, this molecule changes its round shape to a linear one, and then binds to an extracellular matrix such as collagen type I or III [12]. This complex initial platelet adhesion without agonist stimulation, followed by activation of GPIIb/IIIa receptor. The binding of platelets via vWF is further strengthened to sustain the opposing effect of high shear forces in coronary artery [10]. Thus, it is reasonable to hypothesize that intraluminal regions of damaged arterial wall that are under high shear stress are being “paved” with the linear form of vWF adhering platelets some of which may have been previously activated in the circulation by catecholamines [13] or other factors. If this is true, then the importance of shear stress is to “mark the target” with vWF for the preconditioned platelet “missiles”. This could be an alternative explanation both to the effect of shear stress on platelet adhesion to the stenotic region and to the passivation achieved by IIb/IIIa.