Platelets and shear stress.

C LINICAL BLEEDING or thrombosis results from a disturbance in the balance between a complex network of procoagulant and anticoagulant factors. This network involves three primary interactions, first described by the eminent pathologist Rudolph Virchow during the previous century, between blood (soluble and cellular constituents), the blood vessel (including fixed and dynamic responses), and blood flow. This review examines one increasingly recognized feature of this interplay that appears to affect both hemostasis and thrombosis. This feature is the effect on blood platelets of the mechanical forces of shear generated by flowing blood. Knowledge of the link between platelets and shear stress provides clues to general mechanisms governing physiologic and pathologic processes by re-emphasizing the importance of physical forces in regulating cellular function in vivo. Platelets have long been regarded as the preeminent cell involved in physiologic hemostasis and pathologic thrombosis. In both cases, the plasma protein von Willebrand factor (vWF) and the blood platelet work together to effect the biologic response. The versatility in biologic responses mediated by a single receptor-ligand coupling has been, and remains, one of the challenging conundrums placed before clinical investigators and practicing hematologists. It is all the more intriguing when one considers that mixing vWF with platelets in a static or stirred suspension evokes no response. The discovery that the mechanism of toxicity of the antibiotic ristocetin is its capacity to induce plasma vWF to bind to platelet glycoprotein (GP) Ib’ stimulated numerous important discoveries about the structure and function of vWF and its platelet receptors, including the nosology of von Willebrand (vWD) disease. ’-4 However, elucidation of mechanisms of hemostasis and thrombosis in vivo required the convergence of classical pathology with modem molecular biology. One hundred and forty years after it was proposed, Rudolf Virchow’s concept of the pathogenesis of thrombosis holds the key to understanding the relationship between platelets and shear stress. Virchow’s triad is a concept that is old but does not recidivate; rather, it confronts observations and their interpretation within a context of the interrelated pathophysiologic elements of blood, blood vessel, and blood flow. It is the application of Virchow’s principles to the puzzle of vWF-mediated platelet aggregation that ultimately led to the discovery that rheological factors mediate the binding of vWF to platelets in vivo, and that shear stress appears to be the physiologic, or pathophysiologic, equivalent of ri~tocetin. ’. ~ This review will attempt to summarize our current understanding of the molecular basis of Virchow’s triad operating in platelet-dependent arterial thrombosis, and to explore the mechanisms by which rheologic and vascular factors interact to effect platelet-dependent hemostasis. The scope of the problem of arterial thrombosis is staggering: at least 5 million adults in the United States alone suffer from related symptoms. About 50% of the annual nonaccident deaths in the United States are caused by thrombi predominantly composed of platelets in coronary or cerebral arteries. In addition, thrombosis of these and the peripheral arteries causes extensive morbidity. Antiplatelet agents presently available in clinical practice, which were originally tested predominantly in static or stirred systems, are only moderately effective in preventing the development or recurrence of thrombotic diseases of the coronary and cerebrovascular circulation. ’ To improve the therapy of arterial thrombotic disorders, therefore, it is imperative to establish basic mechanisms of platelet thrombus formation under conditions of arterial blood flow. In vitro systems capable of modeling flow-mediated platelet adhesion and aggregation have been developed to investigate the mechanisms by which mechanical forces affect platelet thrombus formation. The reconstitution in vitro of the components of Virchow’s triad operating in vivo in pathologically constricted arteries is likely to provide improved methods for the evaluation of