Platelets.

Under normal conditions, 1 10 platelets continuously flow along 1000 m of vascular surface in the human body without adhering or aggregating. However, on disruption of the integrity of the vessel wall, a swift and complex interaction occurs between circulating platelets, endothelial cells, and subendothelial structures (1). The result of this interaction is that platelets adhere to the vessel wall and form aggregates with each other, thereby materializing a first line of defense against blood loss. The interaction between platelets and the vessel wall is mediated by cellular receptors on the surface of platelets and endothelial cells, such as integrins and selectins, and by adhesive proteins, such as von Willebrand factor and fibrinogen. Platelet Adhesion, Aggregation, and Activation. After disruption of the integrity of the vessel wall, subendothelial collagen is exposed to the blood. This collagen can then bind to the circulating protein von Willebrand factor, and von Willebrand factor will subsequently bind to the platelet membrane receptor glycoprotein Ib, which is part of a larger receptor complex on the platelet surface (Fig. 1) (2, 3). Von Willebrand factor is large polymer of disulfide-linked subunits, each comprising 2050 amino acid residues and up to 22 carbohydrate chains (3). The molecular mass of the multimers ranges from about 500 kDa to 10,000 kDa. The multimers may form coiled molecules or thin filaments up to 1250 nm long (which means as large as a platelet). Data from clinical studies indicate that large von Willebrand factor multimers may be hemostatically more active than smaller molecules (4). The biochemical basis for this observation probably relies on the fact that they contain a relatively large number of the domains that will support multiple interactions between the vessel wall, subendothelial matrix, and cellular receptors on platelets. Binding of von Willebrand factor to both subendothelial structures and platelet glycoproteins is dependent of blood flow-associated shear stress, which causes stretching of the large von Willebrand factor multimers, thereby exposing adhesive binding sites (5). When binding of von Willebrand factor to glycoprotein Ib occurs, platelets become activated and change their shape (Fig. 2). The shape change will also result in the expression of active glycoprotein IIb/IIIa on the platelet surface. Subsequently, platelets may aggregate with each other through this receptor, using circulating fibrinogen as a ligand (Fig. 1). During activation of the platelets and via a series of enzymatic reactions involving the enzyme cyclooxygenase, arachidonic acid (from the platelet membrane) is converted into several eicosanoids, such as thromboxane A2 and various prostaglandins, which may exert a vasoconstricting action and may promote further activation of primary hemostasis. Pharmaceutical agents, such as aspirin or other nonsteroidal anti-inflammatory drugs, are inhibitors of cyclooxygenase, which explains their antiplatelet effect. Another consequence of platelet activation is the release of various proteins from platelet storage granules, including a) several platelet agonists (such as adenosine diphosphate and serotonin); b) coagulation factors (such as von Willebrand factor and coagulation factor V); c) heparin-binding proteins (such as platelet factor 4 and -thromboglobulin); and d) proteins with an activity as a growth factor or chemokine (such as plateletderived growth factor, platelet transforming growth factor 1, epidermal growth factor, or thrombopoietin). Last, the phospholipid membrane of the activated platelet provides an excellent surface on which the generation of thrombin and subsequent fibrin formation may take place (1). Platelet Aggregation Under Pathologic Conditions. Platelets play a pivotal role in the pathogenesis of acute atherothrombosis, which is the pathologic substrate of acute vascular events, such as acute myocardial infarction and stroke. Although the mechanism by which platelets adhere to the vessel wall to achieve hemostasis is fairly well understood, the exact pathways that contribute to platelet adhesion and activation in thrombosis (e.g., on rupture of an atherosclerotic plaque) are still unclear (6). The essential aspects of platelet activation and aggregation are for the mast part the same as those in response to hemorrhage. However, in case of pathologic thrombus formation, there may be modifying factors, such as increased shear stress around atherosclerotic plaques and local dysfunction of endothelial cells, potentially in association with inflammatory mechanisms, that are probably important in pathologic thrombus formation (6, 7). Besides playing a role in thrombus formation on a ruptured atherosclerotic plaque, platelets also play a role in the formation of the atherosclerotic plaque itself. Platelets can release adhesive ligands, such as Pselectin, and may, on activation, provide a suitable phospholipid surface for the recruitment of mononuclear cells and lymphocytes, which contribute to the local inflammatory processes associated with atherosclerosis (8, 9). In addition, platelet granules contain growth factors, such as platelet-derived growth factor, which is important for cellular proliferation in the expanding atherosclerotic lesion. From the Department of Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. The author has no financial interests to disclose. Address requests for reprints to Marcel Levi, MD, Department of Internal Medicine (F-4), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: m.m. levi@amc.uva. nl Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins