N5315 Advanced Pathophysiology Hematologic System Core Concepts and Objectives with Advanced Organizers Hemostasis 1. Analyze the process of hemostasis: a. Analyze the platelet structure and the 4 phases of platelet plug formation: Platelet Structure Function peripheral zone-cell membrane OCS channel for substances to be released, thromboxane a2 formed on phospholipid membrane via arachidonic acid pathway; site for coagulation proteins and adhesive proteins to bind; receptors responsible for adhesion/aggregation sol-gel zone-structural support Middle layer Organelle Zone Mitochondria, tubular system, dense granules, alpha granules 1. The first receptor is the thromboxane receptor. The COX-1 arm of the arachidonic acid pathway produces thromboxane A 2 . TXA 2 binds to this receptor and is responsible for binding platelets to one another. This process is called platelet aggregation. Aspirin inhibit the formation of TXA 2 by blocking the COX-1 pathway of the arachidonic acid pathway. 2. GPIIb/IIIa receptor is the main receptor responsible for platelet aggregation. Fibrinogen(I), 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 P2Y 12 receptor. When ADP binds to this receptor it stimulates platelet activation a process which involves calcium influx and TXA 2 formation. Adenylate cyclase is responsible for the generation of cyclic adenosine monophosphate (cAMP). cAMP prevents platelets from adhering to one another. When the P2Y 12 receptor is stimulated by ADP it inhibits the action of cAMP. The P2Y 12 receptor is the site of inhibition of the drugs clopidogrel & prasugrel. These drugs block ADP from binding to the P2Y 12 receptor thus allowing cAMP to exert its action and prevent platelet aggregation. Four Phases of Platelet Plug Formation Function Activation Injury to endothelium expose vWF, fibronectin, COLLAGEN, thrombospondin—collagen potent plt
activator—charge plts AKA activated—undergo shape change (allow to adhere to site) Adherence Plt attach to injured endothelium—begins with vWF—vWF circulating binds to exposed subendothelial collagen and GpIb/IX/V receptors on plts—collagen binding with GP VI receptor activates GPIIb/IIa & GPIa/IIa receptor—vWF binds with GPIIb/IIIa receptors and collagen binds with GPIa/IIa (collective binding)—achors plts in place Aggregation
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- Fall '15
- Platelet, Folate deficiency