Term
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Definition
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Term
| Where do platelets come from and how long do they live? |
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Definition
Originate from megakaryocytes in bone marrow
life span: 10 days
Normal Lab Value: 150,000-450,000 /µL |
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Term
| What is the major trigger for all thrombotic events? |
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Definition
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Term
| What are the 3 steps of how a platelet functions? |
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Definition
Initiation
Activation
Aggregation |
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Term
| Components of platelet initiation.... |
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Definition
Underlying disease (weakened surface easy to break)
Endothelial injury (exposes collagen, vWF, tissue factor)
von Willebrand factor (in endothelial- important for binding)
GP Ib receptors (on platelets- important for binding) |
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Term
| Platelet activation begins with an agonist binding to platelet receptors to start the cascade. What are the potent and weak agonists for this process? |
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Definition
Potent Agonist
Adhesion to collagen after vascular damage
Adhesion to elements after plaque rupture
Thrombin
Weak Agonists
ADP
TXA2
Epinephrine
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Term
| After agonists bind to activate platelets, what actions does the cascade of signaling events result in? |
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Definition
1. Shape Change
2. Granule Release
3. Thomboxane A2 generation
4. Glycoprotein IIb/IIIa Receptor Activation |
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Term
| All of the agonist/cascade events are linked to what type of protein? |
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Definition
G-Protein coupled Receptors
Platelets are activated by Gq, Gi, and G12/13 families
Platelets are inhibited by Gs pathways |
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Term
|
Definition
Granules are released after platelet activation.
initiated by binding of agonists to platelets.
3 types: alpha, dense, and lysosomal |
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Term
| What is the major COX metabolite producted by platelets? |
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Definition
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Term
T/F
The final step in platelet activation is GP IIb/IIIa Receptor expression and activation |
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Definition
TRUE
This is the final step of platelet activation.
Increased expression on platelet surfaces
confromational change in the structure allows fibrinogen to bind |
|
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Term
| What is the final step in platelet funtion? |
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Definition
Platelet Aggregation
Fibrinogen binds to activated GPIIb/IIIa receptors
A hemostatis plug of platelets meshed in fibrin is formed |
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Term
| Indications for Antiplatelet Agents.... |
|
Definition
1. Cerebrovascular accident
2. Acute coronary syndrome
3. Angina
4. Vascular disease
5. Coronary artery bypass graft
6. Percutaneous coronary intervention |
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Term
| What are the antiplatelet agents? |
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Definition
1. Aspirin
2. Thienopyridines
3. GP IIb/IIIa
4. Phosphodiesterase inhibitors |
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Term
| What are the thienopyridines? |
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Definition
Ticlopidine (Ticlid)
Clopidogrel (Plavix)
Prasugrel (Effient) |
|
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Term
| What are Abciximad, Eptifibatide, and Tirofiban? |
|
Definition
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Term
T/F
Aspirin is a reversible inhibitor of platelets? |
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Definition
FALSE
Aspirin IRREVERSIBLY binds to platelets
Aspirin covalently inhibits platelets by transferring its acetyl group (acetylation) to inhibit COX-1 |
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Term
| Why are low doses of ASA effective? |
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Definition
1. Inhibition of platelet COX-1 occurs at lower doses than vessel wall COX-2
2. Platelets have no nucleus |
|
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Term
| What are the ADRs of aspirin? |
|
Definition
|
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Term
| Onset and duration of action for aspirin? |
|
Definition
Onset- 5 minutes (enhanced by chewing)
Duration- days |
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Term
|
Definition
Irreversible antagonists of platelet ADP receptors
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|
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Term
T/F
Thienopyridines are pro-drugs |
|
Definition
TRUE
All need to be converted the the active form in vivo
This leads to their delayed onset of action
(max effect 3-5 days)
and many drug interationas |
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Term
| Clopidogrel binds irreversibly to the ADP P2Y12 receptor to inhibit.... |
|
Definition
1. Platelet signaling events
2. Platelet granule release
3. GP IIb/IIIa receptor activation
4. Platelet aggregation |
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Term
| What is the onset and duration of Clopidogrel? |
|
Definition
Onset:
Initial response- 2 hours
Peak response- 3-7 days
Loading dose lowers time to onset
Duration:
Single dose- 72 hours
Multiple dose- 5-8 days |
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Term
| What leads to variability in Clopidogrel? |
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Definition
1. Compliance
2. Pharmacokinetics
3. Drug Drug interations
4. Down regulation or upregulation of important platelet signaling pathways
5. Genetic polymorphisms - CYP450 |
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Term
| Stategies to minimize Clopidogrel variability: |
|
Definition
1. increase clopidogrel dose
2. use alternative agents that produce greater inhibition |
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Term
| Who is Prasugrel different than Clodidogrel |
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Definition
| Prasugrel activations is a rapid single step process |
|
|
Term
| What is the newest ADP receptor antagonist? |
|
Definition
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Term
| What is Ticagrelor used for? |
|
Definition
Considered more efficacious for acute coronary syndromes than clopidogrel
NO activation required
Little inter-patient variability |
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Term
| How does Ticagrelor differ from the other thienopyridines? |
|
Definition
Reversibly binds platelet P2Y23
No metabolic activation |
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Term
|
Definition
Investigational antiplatelet agent
reversible P2Y12 antagonist
IV- onset within minutes
Plasma half life- 3 hours
Effects reversed quickly with stopping infusion
May be optimal for PCI setting |
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Term
| MOA of GP IIb/IIIa receptor antagonists |
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Definition
| Inhibits binding of fibrinogen to the activated GP IIb/IIIa receptor to prevent platelet aggregation |
|
|
Term
| What are the three GP Antagonists |
|
Definition
Abciximab- monoclonal antibody
Eptifibatide- reversible RGD mimetic peptide
Tirofiban- reversible, non-peptide RGD mimetic
Peptides with specific sequence of fibrinogen to bind to receptor BUT doesn't illicit response |
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Term
| What are GP antagonists used for? |
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Definition
Prevent ischemic events in PCI
Used in combo with clopidogrel
|
|
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Term
| Main ADR of GP antagonists |
|
Definition
|
|
Term
| Explanations of why GP antagonists failed at PO administration |
|
Definition
1. Inappropriate dose or dosing regimen
2. lack of sufficient therapeutic window
3. may increase platelet activation |
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