Initiation Of Thrombosis

The initiation of thrombosis is dependent on two critical steps: vessel wall injury and the adherence of platelets on this disrupted surface. When there is a dysfunctional surface or a breach in the endothelial surface, a series ofbiochemical events is triggered that leads to the rapid deposition of platelets and insoluble fibrin as an initial plug that is the start of the repair process. In a cell-based model of arterial thrombosis, the integrity and state of the endothelium are the basis for the initiation of thrombosis (3). The pivotal step in transforming the endothelium into a procoagulant surface is the production of tissue factor (4,5) (Fig. 1). Tissue factor is an integral membrane glycoprotein that must be anchored to a phospholipid membrane to be active (6). Activated monocytes, attracted to sites of vascular injury by tumor necrosis factor (TNF)-a and interleukin-1, also elaborate tissue factor (7,8). Tissue factor forms a complex with factor VII and activated factor VII (VIIa), a powerful procoagulant complex that cleaves its substrates, factor IX and factor X, and starts the coagulation cascade (6,9).

In addition to elaborating tissue factor when activated, the endothelium participates in the second component of thrombus initiation—platelet deposition. The primary molecule responsible for platelet adhesion is von Willebrand factor (vWF), especially in vessels with high shear stress such as coronary vessels (10,11). This molecule is synthesized by the endothelium. Activated or injured endothelial cells (ECs) can also release vWF and P-selectin, molecules also involved in platelet and leukocyte adhesion (12). Storage granules, called Weibel-Palade bodies, contain P-selectin and vWF within the EC and fuse with the cell membrane on activation to present these molecules on the EC surface (13,14). In this manner, through either activation or severe injury leading to deendo-thelialization, the molecular signals for both the initiation of coagulation and platelet adhesion are initiated at the vessel wall.

Fig. 1. Cell-based model ofarterial thrombosis. Monocyte-derived tissue factor is provoked by inflammatory cytokines and contributes to thrombin generation in atherothrombotic CAD, a prothrombotic disorder characterized by endothelial dysfunction. Impaired thromboresistance and attenuated fibrinolytic potential TF, tissue factor; Vila, factor Vila; Xa, factor Xa; TAFI, thrombin-activated fribrino-lytic inhibitor. (Adapted from ref. 112.)

Fig. 1. Cell-based model ofarterial thrombosis. Monocyte-derived tissue factor is provoked by inflammatory cytokines and contributes to thrombin generation in atherothrombotic CAD, a prothrombotic disorder characterized by endothelial dysfunction. Impaired thromboresistance and attenuated fibrinolytic potential TF, tissue factor; Vila, factor Vila; Xa, factor Xa; TAFI, thrombin-activated fribrino-lytic inhibitor. (Adapted from ref. 112.)

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