When platelets are activated, they acquire enhanced capacity to catalyze interaction between activated coagulation on factors [Hirsh J, et al, 1994]. These factors circulated in the form of inactive precursors (zymogens). Rupture of the atherosclerotic plaque leads to activation of the coagulation cascade: each zymogen is converted into an activated coagulation factor, which in turn activates the next zymogen in the sequence. This process culminates in the generation of thrombin, an enzyme that converts the soluble protein fibrinogen to insoluble fibrin, forming a blood clot.
The clotting cascade consists of two separate initial pathways (“intrinsic” and “extrinsic”) that ultimately converge on the “common” pathway [Colman RW, et al, 1994; Rapaport SI. Western J Med. 1993;158:153]. The intrinsic and extrinsic pathways essentially serve to activate the precursor protein prothrombin to the active enzyme thrombin. The intrinsic pathway includes the “contact” activation system (see below).
The extrinsic system, the principal initiating pathway of in vivo blood coagulation, involves both blood and vascular elements. The critical component is tissue factor (TF, sometimes referred to as thromboplastin), a glycoprotein embedded in association with phospholipid (PL) in the surface membrane of fibroblasts within and around blood vessels and in various other tissue cells. Under physiologic conditions, tissue factor is not exposed to blood, but with vascular or endothelial cell injury, this substance acts in concert with activated Factor VIIa and phospholipid to convert Factor IX (from intrinsic system) to IXa and Factor X (from the extrinsic system) to Xa. The coagulant activity of Factor VII, the major plasma component of the extrinsic pathway, is increased by Factor IXa of Factor XIIa of the contact system. These events take only about 15 seconds.
The intrinsic pathway can be viewed as coagulation initiated by components entirely contained within the vasculature. This pathway results in the activation of Factor IX by Factor XIa, providing a pathway independent of Factor VII for blood coagulation. A major difference between the intrinsic and extrinsic pathways is that whereas the activation of Factor IX by IXa requires only the presence of ionized calcium, the activation of Factor IX by VIIa (in the extrinsic system) requires both calcium and tissue factor. Importantly, Factor XIa converts Factor X (in the extrinsic system) to Factor Xa in concert with the “tenase” complex (PL/VIIIa) [see below].
Included in the intrinsic pathway is the contact system by which skin, muscle, connective tissue, and a variety of other surfaces may act as activators. However, a number of other surfaces, especially vascular endothelium, are ineffective as activators. Among the events associated with the contact system are activation of Factor XI by the XIIIa/activated high molecular with kinogen (HKa) complex. The role of contact system proteins in initiation of the intrinsic pathway of coagulation in hemostasis is questionable, but these proteins do participate in a number of other events (eg, inflammatory response, complement activation, fibrinolysis, and kinin formation) and are also critical when blood interacts with a foreign surface as in cardiopulmonary bypass [Colman RW, et al, 1994].
Factor Xa, regardless of how it is formed, is the active catalytic component of the “prothrombinase” complex, which converts prothrombin to thrombin. Thrombin cleaves fibrinopeptides (FPA, FPB) from fibrinogen, allowing the resultant fibrin monomers to polymerize, and converts Factor XIII to XIIIa, which crosslinks (XL) the fibrin clot. Thrombin accelerates the process (interrupted lines) by its potential to activate Factors V and VIII. A number of natural plasma inhibitors retard clotting, including C1-inhibitor (C1 INH), tissue factor pathway inhibitor (TFPI), and antithrombin II (ATIII).
The fibrin molecules aggregate together, trapping platelets, erythrocytes, and leukocytes to form the clot. The clot then contracts, pulling together the edges of the injured surface.
An internal clot that remains in the area in which it is formed is called a thrombus, and the general condition is called thrombosis. In an area where a small thrombus has formed, there is a tendency for the clot to enlarge for the following reason: as blood flow slows around the clot, clot-forming elements (e.g., platelets, red blood cells, and clotting factors) are deposited, producing an enlarging, or propagating thrombus.
Acute Ischemic Stroke: New Concepts of Care
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