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Thrombosis
Introduction
Thrombosis resulting from various pathologies is the underlying cause of the majority of ischemic strokes. Hemostasis is the complex and highly regulated system that helps to maintain the integrity of blood and the vasculature. Maintenance of blood flow depends upon an intact and fully functional vascular endothelium. Thrombosis is one of the pathological consequences when the hemostatic system is activated within the circulation itself often as a result of disruption or derangements in the vascular endothelium. Although the concept dates back at least 250 years to the time of the Scottish surgeon John Hunter, the current understanding of how thrombotic events happen increasingly links inflammatory mechanisms with thrombosis .
Physiology: Homeostatic System
The hemostasis system functions to limit bleeding when blood vessels are injured or broken. Thrombosis is the formation of a clot within a blood vessel or the heart that results in obstruction of blood flow within the vessel or downstream by embolization. With vascular injury there is a rapid multiphase chain-reaction response initiated by platelet activation and fibrin deposition . The thrombotic reactions begin with a series of initiation events that are quickly followed by amplification and propagation of the clotting process. The initiation step can be triggered by mechanical or inflammatory injury to the vascular endothelium that changes the surface into a prothrombotic state or disrupts the endothelium altogether thereby exposing subendothelial prothrombotic molecules including collagen and tissue factor (TF). These events induce circulating platelets to change shape, express activated surface markers, and adhere to the collagen via von Willebrand factor (vWF) binding. At the location of vascular injury vWF is released from platelets and from stores in endothelial Weibel–Palade bodies. Thrombin is generated in this phase by release from the activated platelets and from the exposure of TF and extrinsic pathway activation as shown in Fig. 21.1 . The amplification phase is instigated by a great increase in the available surface area for the clotting cascade to become active. This process is driven by thrombin generation that further activates surrounding circulating platelets causing them to adhere to the site of injury thereby providing increased membrane surface areas for the clotting cascade assembly. In the propagation phase sometimes described as a traveling wave, thrombin generation is massively increased as a result of a positive feedback effect of thrombin on the activation of coagulation factors V and VIII, principal participants in the “prothrombinase complex” composed of factors Va, Xa, Ca + , and phospholipid that converts prothrombin to thrombin . As outlined in Fig. 21.1 the “contact” or intrinsic pathway plays an important role in both the amplification and especially the propagation phases of thromboses. It bears emphasis that these clotting reactions take place on membrane surfaces that not only include activated platelets but may also include shed cellular microvesicles that have phosphatidylserine exposed on their outer surfaces. Factor XIIIa, which is activated by thrombin, cross-links fibrin and helps to stabilize the clot.
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