Platelet Endothelial interaction: arterial thrombosis

Question 1

How is venous thrombosis different from arterial thrombosis?

Answer 1

Arterial:
-under high shear
-platelet and vWF dependent
-associated with abnormal vessel wall
Venous:
-under low shear
-thrombin and fibrinogen dependent
-less dependent on vessel wall abnormalities

Question 2

What are the steps in the formation of the fatty streak?

Answer 2

1. Perturbed endothelium
2. expression of adhesive receptors-and chemotactic factors produced by endothelial cells
3. migration of monocytes
4. lipid uptake, ingest oxidized lipids and become foam cells
5. fatty streak
   Foam cells express tissue factor on their surface, exposure of macrophages to blood limited by endothelial cels above fatty streak, but as fatty streak progresses, endothelium may bc denuded and micro thrombi of platelets and fibrin may form over fatty streak

Question 3

How are the events leading to the formation of the fibrous plaque (after fatty streak is formed)?

Answer 3

• activated platelets release PDGF and TGF-b. Thrombin is mitogenic–>proliferation of smooth muscle cells and synthesis of collagen
• platelets release PAI-1, inhibit fibrinolysis–>depressed metalloproteinases (degrade collagen)
• –inhibition of fibrinolysis leads to uncontrolled accumulation of excess collagen in lipid rich plaque

Question 4

Why does the rupture of the fibrous cap over an atheroma cause arterial thrombi?

Answer 4

• ruptured fibrous cap exposes blood to lipid and tissue factor rich macrophages and collagen fibers
• collagen fibrils can activate platelets–>generation of thrombin initiated by high TF concentration
• excess thrombin stimulates more platelet aggregation and deposition of fibrin to form platelet rich fibrin plug

Question 5

How is the treatment of an arterial thrombi different from an venous thrombi? and why?

Answer 5

Venous: slow flow
-fibrinogen mediates platelet aggregation via binding to GP IIb/IIIa –>platelet aggregation provides surface for thrombin generation
-treat with anticoagulants that will inhibit thrombin formation
Arterial: fast flow
-vWf mediates platelet aggregation via GPIIb/IIIa due to large size and multimeric structure of vWf
-exposure of sub endothelium rich in collagen and vWf allows for binding of platelets
-activated platelet expresses P-selectin, binds microvesicales, becomes site for thrombin generation
-treat with medications that inhibit platelet activation

Question 6

What are targets for anti-platelet therapy and some examples of drugs?

Answer 6

• inhibition of primary agonist signaling, i.e. thrombin. Hirudin and Bivalrudin
• inhibition of secondary, amplifying agonist signaling, e.g. ADP, TXA2. Aspirin, thienopyridines
• inhibition of GPIIb/IIIa receptor aggregation. Abciximab, Eptifibatide and tirofiban

Question 7

How do thienopyridines work as an anti platelet therapy?

Answer 7

• The thienopyridines, ticlopidine and clopidogrel, are irreversible inhibitors of the ADP receptor, P2Y12. Residual P2Y1 activity remain (20-30%).
• The active inhibitory agent is a hepatic metabolic product of both drugs that had yet to be isolated and structurally characterized.
• Repeated doses (>3)of ticlopidine are required before the development of effective platelet ADP receptor blockade. Effective blockade can occur within two hours of an oral loading dose (300 mg) of clopidogrel.
• Hematologic toxicities of ticlopidine (agranulocytosis, aplastic anemia, TTP) in addition to its slower onset of action has resulted in a pronounced shift to the use of clopidogel.

Question 8

How do the platelet glycoprotein IIB/IIIa receptor inhibitors function?

Answer 8

• There are two classes of GPIIb/IIIa inhibitors: the irreversible antagonist abciximab and the reversible (competitive) antagonists eptifibatide and tirofiban.
• Abciximab is a humanized monoclonal antibody that binds irreversibly to the GPIIb/IIIa receptor at the β-chain of the integrin.
• Eptifibatide and tirofiban are cyclic peptides which mimic the RGD sequence that binds the GPIIb/IIIa receptor.