Now that we have gone over the coagulation cascade and its regulatory features, our next step is to integrate the pathway into the larger scheme of hemostasis, the Big Picture.
So far, have learned that the coagulation cascade is initiated in response to tissue or endothelial injury, which allows exposure of blood to Tissue Factor and thus activates the extrinsic pathway. This leads to formation of limited amounts of Factor IX , X and thrombin, which in turn propagate the cascade by activating the intrinsic pathway. Once thrombin is generated, it converts fibrinogen into fibrin, which then polymerizes into fibrin strands. We have also discussed how antithrombin III, protein C, protein S, thrombomodulin, TFPI and the fibrinolytic system influence the cascade to both limit the amount of fibrin formed, and to localize clot formation to the site of vessel injury. With this in mind, it must be understood that a clot does not contain only fibrin and that in order for fibrin to be created, another component of hemostasis must be present .... Platelets. So, how do platelets and fibrin interact in clot formation?
In our discussion of the coagulation cascade, one aspect that we have not addressed is the location where these reactions occur. It has been mentioned that the reactions require the presence of phospholipids and calcium. So, how can platelets, phospholipids, and the cascade be related? The current theory is that phospholipids are provided by platelets, i.e. much of the coagulation cascade occurs on the surface of platelets. Damaged endothelial cells also contribute phospholipids. Platelets exposing suitable membranes must be triggered to adhere at sites of tissue injury. Once there, they can promote protein complex formation and allow accumulation of other important cells such as polymorphonuclear lymphocytes (PMNs) and monocytes.
Overall, here is what happens. Vascular injury leads to the margination of platelets to the site of vessel injury. The platelets adhere to the damaged endothelial cells via vonWillebrand Factor. (Small amounts of fibrinogen assist in creating this platelet plug.) The platelets are then stimulated to degranulate and express receptors for Factors V and VIII as well as leukocytes. At this same time, blood is exposed to tissue factor and the clotting pathways are initiated. The necessary cofactors (V and VIII) bind to receptors on platelet surfaces and allow for efficient propagation of the cascade. This eventually leads to the formation of fibrin. Since fibrin strands are formed in the vicinity of platelets, the two can easily come together and form a clot. Leukocyte receptors on the platelets bind PMNs and monocytes. PMNs initiate inflammatory reactions, and monocytes produce tissue factor to help in generating the thrombus and allowing for the first steps in wound healing.
There are many instances when the clotting system becomes overproductive and leads to the formation of pathologic clots. This is further discussed in the Hypercoagulable States section.
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