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46 Cards in this Set
- Front
- Back
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In order for hemostasis to occur, platelets must adhere to exposed collagen, release the contents of their granules, and aggregate. The adhesion of platelets to the collagen exposed on endothelial cell surfaces is mediated by this.
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vWF
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What is the other function of vWF?
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It binds to and stabilizes coagulation factor 8 in the plasma.
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Describe the initial cascade of coagulation.
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1. Vasoconstriction
2. Platelets activated by thrombin and aggregate to form a loose plug. Platelet activation causes degranulation and release of ADP, Thromboxane A2 and serotonin. These compounds activate additional platelets. Platelets will also change shape to facilitate clot formation. |
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What causes platelets to change shape?
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Thromboxane A2 and ADP due to activation of integrin alpha IIb-beta 3
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How do endothelial cells normally keep platelets quiet?
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By raising intracellular cyclic nucleotides such as cAMP and cGMP. cAMP production is stimulated by PGI-2 which is inhibited by COX-2 inhibitors
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Describe how platelets are activated?
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Thromboxane and ADP bind a GPCR which increases intracellular signaling and leads to the eventual activation of integrin alpha 2b beta 3. It can now bind fibrinogen
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What are the 3 primary sites of actions for platelets?
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1. Receptor antagonists
2. Signaling blockers 3. Integrin alpha 2b beta 3 blockers |
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Name 2 receptor antagonists
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ticlopidine
clopidogrel |
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Name 2 signal blockers
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aspirin
dipyridamole |
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Name 3 integrin blockers
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Abeiximab
integrilin tirofiban |
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How does dipyramidole work?
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PDE degrades cAMP to AMP
cAMP inhibits platelet activation Dipyramidole inhibits this conversion therefore increasing cAMP levels in the cell. |
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What are the 2 receptors for collagen on platelets?
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alpha 2 beta 1 - integrin
GPVI - immunoglobulin superfamily |
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What are the 2 receptors for vWF?
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GP1b/V/IX complex
alpha 2b beta 3 - integrin |
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Collagen/vWF binding to platelets causes this cascade.
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Calcium influx --> PLA2 --> TxA2
PKC --> Platelet dense granules --> ADP secretion |
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How does aspirin work?
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Thromboxane A2 is formed from Arachidonate inside platelets. Aspirin irreversibly binds to COX -1 which inhibits this conversion.
TxA2 helps recruit platelets to the plug. |
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Name the 3 main ligands that bind GPCRs on platelets to activate integrin alpha 2b beta 3
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Thrombin
TxA2 ADP |
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How does plavix work?
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It inhibits the receptor P2Y12 therefore inhibiting activation of integrin and cAMP suppression.
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How do direct thrombin inhibitors work?
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They bind to and inhibit thrombin binding to the PAR 1 and PAR 4 platelet receptor.
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What is the role of fibrinogen in platelet aggregation?
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It link proteins via integrin alpha 2b beta 3
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Name the 3 drugs that inhibit this integrin-fibrinogen-integrin interaction.
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Abciximab
Integrilin Tirofiban |
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How is fibrin formed from fibrinogen?
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thrombin cleaves fibrinogen to form fibrin. Fibrin is then cross linked by Factor 13 (transglutaminase)
Thrombin activates Factor 13 to Factor 13a Thrombin inhibitors inhibit these two processes |
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What are the 5 indications for anti-platelet drugs?
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1. Coronary artery disease
2. Heart Attack 3. Angina 4. Stroke and TIA 5. Peripheral artery disease |
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Describe the difference between COX-1 and COX-2 inhibitors.
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COX-1 Inhibitors decrease the formation of Thromboxane A2. Decreased Thromboxane which decreases platelet aggregation via integrin
COX-2 Inhibitors inhibit PGI-2 formation. Decreased PGI-2 leads to decreased cAMP in the cell and therefore makes it difficult to repress platelet activation and increases cardiovascular risk. |
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Name the 2 ADP receptor inhibitors.
What are they used for? |
Clopidogrel - prevention of MI, stroke or peripheral vascular disease
Ticlopidine - secondary stroke prevention in aspirin resistant patients, prevention of stent thrombosis |
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Name the alpha 2b beta 3 integrin antagonists.
State whether they are reversible or irreversible. |
Abciximab - irreversible
Eptifibatide - reversible Tirofiban - reversible |
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What are the clinical applications of aspirin?
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Prophylaxis for TIA, MI,Thomboembolism
ACS Stent Implantation |
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What are the common adverse side effects?
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GI bleeding
Reye's syndrome |
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What are the contraindications?
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NSAID induced sensitivity reactions
Children with chickenpox or flu like syndromes G6PD deficiency Bleeding disorders |
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What are the therapeutic considerations?
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Inhibits COX-1 and COX-2 nonselectively
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What are the clinical applications for Dipyridamole?
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Prophylaxis against thromboembolic disorders
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What are the common adverse effects?
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Exacerbation of angina
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What are the therapeutic considerations?
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Weak anti-platelet effect
Usually administered in combination with warfarin and aspirin Has vasodilatory properties |
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What are the clinical applications for Ticlopidine?
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Secondary prevention of thrombotic strokes in patients intolerant to aspirin
Stent implantation |
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Common adverse reactions?
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Aplastic anemia
neutropenia thrombotic thrombocytopenic purpura |
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Contraindications?
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Active bleeding disorder
Neutropenia Thrombocytopenia Severe liver dysfunction |
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Therapeutic considerations?
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Use is limited by associated myelotoxicity
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What are the clinical applications of Clopidogrel?
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Prophylaxis against thromboembolic disorders
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Adverse effects?
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Exacerbation of angina
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Contraindications?
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Active bleeding disorder
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Therapeutic considerations?
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More favorable adverse effect profile than ticlopidine
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What are the Clinical applications for Eptifibatide?
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ACS
PCI |
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What are the clinical applications for Abciximab?
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Prevention of ischemic event during or after PCI
Unstable angina in non-responders |
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What is the clinical application of Tirofiban?
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ACS
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What are the adverse reactions for these 3 drugs?
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Major bleeding
Intracerebral hemorrhage Thrombocytopenia Hypotension |
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What are the contraindications for these three drugs?
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Bleeding diathesis
Recent surgery or stroke |
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What are the therapeutic considerations for these 3 drugs?
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Avoid co-administration with a second GP IIb-IIIa antagonist
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