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45 Cards in this Set
- Front
- Back
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Sequence of events in hemostatis
Intro |
The hemostatic process can be divided into four stages - vasconstriction, primary hemostasis, secondary hemostasis, and resolution - although recent evidence suggests that these stages are temporally overlapping and may be nearly simultaneous.
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Sequence of events in hemostatis
Part A: Vasoconstriction |
Vascular injury causes endo thelial denudation. Endothelin, released by activated endothelium, and neurohumoral factor(s) induce transient vasoconstriction.
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Sequence of events in hemostatis
Part B: Primary Hemostatis |
Injury-induced exposure of the subendothelial matrix provides a substrate for platelet adhesion and activation. In the granule release reaction, activated platelets secrete TxA2 and ADP. TxA2 and ADP released by activated platelets undergo shape change and are recruited to the site of injury. The aggregation of activated platelets at the site of injury forms a primary hemostatic plug.
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Sequence of events in hemostatis
Part C: Secondary Hemostatis |
Tissue factor expressed on activated endothelial cells and leukocyte microparticles, together with acidic phospholipids expressed on activated platelets and activated endothelial cells, initated the steps of the coagulation cascade, culminating in the activation of thrombin. Thrombin proteolytically activates fibrinogen to form fibrin, whic hpolymerizes around the site of injury, resulting in the formation of a definitive (secondary) hemostatic plug.
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Sequence of events in hemostatis
Part D: Resolution |
Natural anticoagulant and thrombolytic factors limit the hemostatic process to the site of vascular injury. These factors include tissue plasminogen activator , which activates the fibrinolytic system; thrombomodulin, which activates inhibitors of the coagulation cascade, prostacyclin, which inhibits both platelet activation and vasoconstriction; and surface heparin-like molecules, which catalyze the inactivation of coagulation factors.
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Sequence of events in hemostatis
Platelet adhesion and aggregation |
von Willebrand factor mediates platelet adhesion to the subendothelium by binding both the platelet membrane glycoprotein GPIb and to exposed endothelial collagen. Platelet adhesion to the subendothelial matrix also requires a direct binding interaction between platelet membrane glycoprotein GPVI and subendothelial collagen. During platelet aggregation, fibrinogen cross-links platelets to one another by binding to GPIIb-IIIa receptors on platelet membranes.
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Sequence of events in hemostatis
Platelet Activation |
Platelet activation is initiated at the site of vascular injury when circulating platelets adhere to exposed subendothelial collagen and are activated by locally generated mediators. Activated platelets undergo shape change and granule release, and platelet aggregates are formed as additional platelets are recruited and activated. Platelet recruitment is mediated by the release of soluble platelet factors, including ADP and TxA2. Tissue factor, expressed on activated endothelium, is a critical initiating component in the coagulation cascade. The membranes of activated platelets provide a surface for a number of critical reactions in the coagulation cascade, including the conversion of prothrombin to thrombin.
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Antiplatelet Agents:
Their purpose and clinical use |
Inhibition of platelet function is a useful prophylactic and therapeutic strategy against MI and stroke caused by thrombosis in coronary and cerebral arteries, respectively. The classes of antiplatelet agents in current clinical use including COX inhibitors, PDE Inhibitors, ADP receptor pathway inhibitors and GPIIb/IIIa antagonists.
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MOA:
Aspirin |
Aspirin:
Binds Irreversibly |
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MOA: Clopidogrel
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Clopidogrel
Binds irreversibly Pro Drug Metabolized by 2C19 |
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MOA: Ticlopidine
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Ticlopidine
Binds irreversibly Pro Drug Causes thrombocytopenia, neutropenia |
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MOA: Dipyridamole
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Dipyridamole
Very weak platelet inhibitor |
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MOA: Abciximab
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Abciximab
Binds irreversibly Causes thrombocytopennia Inhibit the final step in platelet aggregation |
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MOA: Eptifibatide, Tirofiban
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Eptifibatide, Tirofiban
Causes thrombocytopenia Insufficiently reversed with platelet infusion Inhibit the final step in platelet aggregation |
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Coag Factors: Unfractionated Heparin
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Unfractionated Heparin
IIa (Thrombin), Xa |
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Coag Factors: Enoxaparin (LMWH)
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Enoxaparin (LMWH)
Xa > IIa (Thrombin) 3:1 |
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Coag Factors: Argatroban
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Argatroban
IIa (Thrombin) |
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Coag Factors: Fondaparinux
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Fondaparinux
Xa |
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Coag Factors: Dabigatran
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Dabigatran
IIa (Thrombin) |
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Coag Factors: Warfarin
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Warfarin
II, VII, IX, X |
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Why does warfarin can cause skin necrosis? Prevention?
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Microvascular thrombosis via inhibition of Protein C&S (natural anticoag), particularly in pts with Protein C def (8 hours).
Prevention - briding with Heparin |
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Why do you have to wait 3-4 days before checking INR for dose adjustment of warfarin?
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Onset: 24 hours
Peak: 72-96 hours Future factors need to let existing factors expire |
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Why does warfarin have so many drug interactions? Discuss the various mechanisms and drug interactions.
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CYP2C9, Vit K availability, Antibiotics (decrease VitK in GI tract)
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UFH vs LMWH
Monitoring |
UFH: aPTT
LMWH: not necessary - can measure Xa activity |
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UFH vs LMWH
Route of Administration |
UFH: IV
LMWH: SQ |
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UFH vs LMWH
Half-life |
UFH: 1 hour
LMWH: 4 hour |
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UFH vs LMWH
AE & End Organ Damage |
UFH: Higher risk of HIT (protamine - reverse bleeding), thrombocytopenia, hypersensitivity reactions. Liver??
LMWH: Lower risk of HIT (not completely reversible with protamine), same risks - not good for renally impaired pts. |
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UFH vs LMWH
Clinical Use |
UFH: Immediate use - NSTEMI, unstable Angina, prophylaxis, DVT, PE
LMWH: More of a bridge - warfarin, prophylaxis |
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Clinical Use of Unfractionated Heparin
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*Traditionally the preferred anticoagulant in pregnancy because it is a larger molecule that does not cross the placenta
*It is the preferred agent when rapid onset of anticoagulant effects is desired *It can be chemically antagonized by protamine |
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What breaks up an EXISTING clot?
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Fibrinolytics
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How do Statins work?
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Statins competitively inhibit HMG-CoA reductase (enzyme that catalyzes the rate limiting step in cholesterol biosynthesis)
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When should statins be taken?
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At night - more cholesterol is made at night
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How are statins metabolized?
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By CYP3A4 (look for interactions)
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What labs should be monitored?
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ALT/AST (LFT)
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Which medications can be given to liver disease patients?
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Pravastatin and Rosuvastatin - both are renally excreted and NOT metabolized by C3A4 - but check CrCl
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How do Bile Acid Sequestrants work?
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Bind (noncovalent) to negatively charged bile acids in the small intestine
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Bile Acid Sequestrants AE and Interactions?
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AE: Bloating/Dyspepsia
Interactions: Binding of other drugs, decrease absorption of fat-soluble vitamins |
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Where does Ezetimibe affect cholesterol absorption?
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Reduction of cholesterol absorption by the small intestine
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Fibrates
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Gemfirbozil, Fenofibrate, Clofibrate
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What are Fibrates predominately used for?
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Decrease TG
but also Increase HDL |
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What the side effects of Fibrates?
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GI discomfort, Increase transaminases
RARE: myopathy, arrhythmias |
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How do fibrates work?
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PPAR alpha activation which increases apoA-1 and apoA-II synthesis in hepatocytes and increases HDL
Also increases fatty acid oxidation in hepatocytes which decrease triglyceride synthesis. Also decrease apoC-III synthesis in hepatocytes and increase lipoprotein lipase expression in muscle vascular beds which increases fatty acid uptake in muscle cells and increases fatty acid oxidation in muscle cells which decreases triglycerides in plasma |
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What are important DI's for Fibrates?
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*Displaces warfarin from albumin binding sites - increase free warfarin concentrations
*Increase cyclosporin clearance |
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What is Niacin most effective at improving?
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Increase HDL
also decreases TG and decreases LDL |
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What is the most common side effect of Niacin and how do you prevent it?
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Cutaneous flushing
Take an aspirin/NSAID about 30 minutes prior |
