Anti-Platelet Agents

Question 1

What are the 4 broad categories of anti-platelet agents?

Answer 1

Aspirin/NSAIDs, Thienopyridines, Dipyridamole, IIb/IIIa inhibitors

Question 2

Mechanism of Aspirin

Answer 2

Irreversibly inhibits COX-1, preventing the synthesis of Thromboxane A2 (TxA2). TxA2 normally binds a GPCR surface receptor on platelets and activates the PLC pathway, leading to increased Ca secretion and upregulation of gp-IIb/IIIa

Question 3

Mechanism of NSAIDs

Answer 3

Reversibly inhibits COX-1, preventing the synthesis of Thromboxane A2 (TxA2). TxA2 normally binds a GPCR surface receptor on platelets and activates the PLC pathway, leading to increased Ca secretion and upregulation of gp-IIb/IIIa

Question 4

Clinical uses of Aspirin

Answer 4

Reduce risk of MI and stroke

CAD/IHD: acute and chronic treatment

Question 5

Clinical uses of NSAIDs

Answer 5

Reduce risk of MI and stroke

Question 6

How long does it take for normal platelet activity to recover after stopping aspirin? After stopping NSAIDs? What is the reasoning behind this difference?

Answer 6

Aspirin: 7-10 days. The irreversible inhibition of COX-1 prevents platelets from functioning permanently. New platelets must be synthesized for activity to recover.

NSAIDs: as soon as treatment is stopped. The reversible inhibition of COX-1 allows for platelet activity to recover upon cessation of treatment.

Question 7

Mechanism of Thienopyridines

Answer 7

Bind the P2Y12-ADP receptor on the surface of platelets to prevent the action of ADP. ADP normally binds this GPCR receptor and causes downregulation of cAMP levels and PKA activity, resulting in upregulation of gp-IIb/IIIa

Question 8

Naming of Thienopyridines

Answer 8

“grel” in the name (clopidogrel, prasugrel, ticagrelor)

Question 9

Mechanisms of Dipyridamole

Answer 9

1) Inhibit adenosine uptake, resulting in more extracellular adenosine that can bind to platelet receptors. Adenosine normally acts to inhibit platelet activity.
2) Inhibit the activity of phosphodiesterase and phospholipase A2 in platelets, resulting in increased cAMP and PKA activity, causing downregulation of gp-IIb/IIIa.

Question 10

Mechanism of gp-IIb/IIIa inhibitors

Answer 10

Abciximab is a monoclonal antibody that directly targets gp-IIb/IIIa on platelet surfaces. Eptifibitide and tirofiban are competitive inhibitors of the gp-IIb/IIIa receptor that prevent binding of fibrinogen.

Gp-IIb/IIIa on platelets normally binds fibrinogen (factor I). Multiple platelet receptors can bind the same fibrinogen molecule, resulting in platelet aggregation.

Question 11

Clinical uses of Thienopyridines

Answer 11

Reduce risk of MI and stroke

CAD/IHD: acute treatment (can use in conjunction w/aspirin, or replace it altogether)

Question 12

Clinical uses of gp-IIb/IIIa inhibitors

Answer 12

Prevent clotting during cardiac catheter interventions

CAD/IHD: prevent re-thrombosis in patients that have undergone angioplasty

Question 13

Clinical uses of Dipyridamole

Answer 13

CAD/IHD: chronic treatment, used alongside aspirin to prevent repeat strokes