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UT Arlington NURS 5315 - Hemostasis Part I Platelet Plug Formation

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1 N5315 Advanced Pathophysiology Hemostasis Part I Platelet Plug Formation Hemostasis is the termination of bleeding. It involves two processes which work independently of one another but yet have complimentary effects. The two arms of hemostasis are the platelet plug formation and the coagulation cascade. The platelet plug is formed on the damaged endothelium. Then fibrin and XIIIa (the two end products of the coagulation cascade) form a mesh over the platelet plug and to anchor it in place.2 It is essential to review the platelet structure to understand the process of platelet formation and the effects of antiplatelet agents. Platelets are disc shaped cells which circulate in the outer portion of the blood vessels. In physiologic conditions the red blood cells travel in the center of the blood vessel forcing platelets toward the edge of the vessel. In significant anemia there are less red blood cells circulating hence platelets will gravitate toward the center of the vessel. As a result, individuals with anemia may have a harder time clotting because the platelets cannot easily reach the damaged endothelium. A normal platelet count ranges from 150,000 to 450,000. Platelets have 3 layers, the peripheral zone, sol-gel zone and the organelle zone. The peripheral zone is the outer most portion of the cell and is the cell membrane. It is made of phospholipids. The open canalicular system (OCS) is a system of channels that runs from the inner most portion of the platelet and it opens to the outside of the platelet. Thus it provides a channel for substances produced by platelets to be released. Thromboxane A2 is formed on the phospholipid membrane via the arachidonic acid pathway. The phospholipid membrane provides a site for the coagulation proteins and adhesive proteins to bind. Additionally, the peripheral zone also contains many platelet receptors which are responsible for platelet adhesion and aggregation. The main platelet receptors are: 1. The first receptor is the thromboxane receptor. The COX-1 arm of the arachidonic acid pathway produces thromboxane A2. TXA2 binds to this receptor and is responsible for binding platelets to one another. This process is called platelet aggregation. Aspirin inhibit the formation of TXA2 by blocking the COX-1 pathway of the arachidonic acid pathway. 2. GPIIb/IIIa receptor is the main receptor responsible for platelet aggregation. Fibrinogen, von Willebrand Factor (vWF), Fibronectin, vitronectin & thrombospondin all bind to this receptor to cause platelet aggregation. The drug class Glycoprotein IIb/IIIa inhibitors prevent platelet aggregation by binding to this receptor thus preventing it from binding to the adhesive proteins listed above. These drugs include Abciximab, Tirofiban, Eptifibatide and are usually seen in the ICU settings to treat acute coronary syndrome or patients receiving a PCI. 3. GP Ia/IIa- is a receptor for collagen. 4. GP Ib/IX/V- is receptor for vWF. 5. GP VI- is receptor for collagen. 6. ADP receptors- There are two broad categories of these receptors, P1 and P2. They are further subdivided into many receptors. In physiologic conditions ADP binds with the P2Y12 receptor. When ADP binds to this receptor it stimulates platelet activation a process which involves calcium influx and TXA2 formation. Adenylate cyclase is responsible for the generation of cyclic adenosine monophosphate (cAMP). cAMP prevents platelets from adhering to one another. When the P2Y12 receptor is stimulated by ADP it inhibits the action of cAMP. The P2Y12 receptor is the site of inhibition of the drugs clopidogrel & prasugrel. These drugs block ADP from binding to the P2Y12 receptor thus allowing cAMP to exert its action and prevent platelet aggregation.3 The middle layer of the platelet is the sol-gel zone and it contains the structural support for the cell. The inner most layer of the platelet contains the organelles. The mitochondria, the dense tubular system (stores calcium & contains enzymes for prostaglandin synthesis), dense granules (contains ATP, ADP, serotonin, calcium, vWF, fibronectin, vitronectin, & thrombospondin) & alpha granules (contains platelet derived growth factor, platelet factor 4, Factor V, Kininogen, Factor XI, plasminogen activator inhibitor-1) are all located here. Now let us review the process of the platelet plug formation. Platelet plug formation has five steps: 1. Activation is the first step. In physiologic states platelets circulate without adhering to the intact endothelium. An injury to the endothelium exposes vWF, fibronectin, collagen and thrombospondin. Collagen is a potent platelet activator and when the subendothelial collagen is exposed by an injury the platelets become charged, AKA activated. Platelets then become aware of the injury and undergo a shape change which increases their ability to adhere to the site of injury. 2. Adherence is the process by which platelets attach to the injured endothelium. Adhesion begins with vWF. Circulating vWF binds to the exposed subendothelial collagen and to the GP Ib/IX/V receptors on circulating platelets. Collagen then binds with the GP VI receptor. The binding of collagen with the GP VI receptor results in the activation of the GPIIb/IIIa and GPIa/IIa receptors. vWF then binds with the GPIIb/IIIa receptors and collagen further binds with the GPIa/IIa receptors. This collective binding anchors the platelets in place. 3. Aggregation- is the process by which platelets bind to one other. There are multiple GPIIb/IIIa receptors on one platelet and when activated (as described above) they have a greater affinity for fibrinogen. Fibrinogen is able to bind to two GPIIb/IIIa receptors simultaneously and thereby bind platelets together. 4. Secretion- during this phase the platelet granules release their contents. a. ADP- enhances adhesion, activates platelets and recruits platelets b. Serotonin recruits platelets. c. Fibronectin and thrombospondin are proteins which stabilize platelets that are adhered to the site of injury. d. Thromboxane A2- is a product of the arachidonic acid pathway but is stored inside the platelet too. It causes vasoconstriction and enhances platelet aggregation. e. Growth factors promote tissue repair however they have a role in the development of atherosclerosis. 5. The platelet plug is stabilized by fibrin and XIIIa which are the end products of the coagulation


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