Anti-platelets/Fibrinolytic agents Flashcards
What is the platelet aggregation pathway?
- rupture of atherosclerotic plaque in artery
- adhesion of platelets to thrombotic surface
- activation of platelets
- arachidonic acid generation
- production of cyclic endoperoxidases
- synthesis of thromboxane (TXA2)
- expression of glycoprotein IIb/IIa receptors
- linkage of adjacent platelets by fibrinogen binding to GP IIb/IIa receptors
- aggregation of platelets
ADP released can cause the expression of GP IIb/IIa receptors
platelet exposure to acidic phospholipids can actiavte coagulation process and thereby activate factor II
- factor IIa can further activate platelets and cause linkage of adjacent platelets by fibrinogen binding to GP IIb/IIa receptors
What is the mechanism of action of aspirin?
inactivates cyclooxygenase-1 (COX-1) by irreversibly acetylating serine amino acid in its active site
- reduces TXA2 synthesis in platelets
- reduces PGI2 synthesis in platelets
= alters the balance between TXA2 and PGI2
after cessation of treatment, COX-1 activity in platelets is dependent on new platelets
- because platelets do not contain nuclei, they cannot synthesis new COX-1 but must instead wait for new platelets to be synthesised
What are the different anti-platelet drugs? What is their mechanism of action?
ticlopidine and clopidogrel
- block platelet P2Y12 receptors (purinergic)
= inhibits ADP dependent platelet aggregation
abciximab
- monoclonal antibody
= binds to GP IIb/IIa receptors (prevents fibrinogen binding)
tirofiban
- decoy peptide that contains the ‘RGD’ motif common to GP IIb/IIa receptors (competitive binding)
epoprostenol
- synthetic PGI2
= is vasodilatory
What is fibrinolysis/thrombolysis?
refers to the breakdown of blood clots
How is the fibrinolytic system activated?
system is activated via the activation of plasminogen
tissue plasminogen activator (tPA)
- production and secretion is mainly from endothelial cells
- triggers include: shear stress, histamine, bradykinin and thrombin
- converts plasminogen to plasmin
urokinase type plasminogen activator (uPA)
- synthesised by endothelial, renal and malignant cells
kallikrein
neutrophil elastase
What is the purpose of plasminogen activators?
plasminogen activators are serine proteases
mechanism of action
- diffuse into clots
- cleaves plasminogen to release plasmin
- plasmin has trypsin-like proteolytic activity
= digests fibrin, fibrinogen and factors II, V and VII
What are the fibrinolytic agents? What is their mechanism of action?
streptokinase - activates plasminogen
urokinase
alteplase/duteplase
reteplase - similar to alteplase/duteplase but has a longer half life
What is the mechanism of action of alteplase/duteplase?
is a recombinant tissue plasminogen activator (tPA)
- more active on fibrin bound plasminogen than plasma plasminogen
= is active on the surface of a fibrin clot
diffuses into the clot
acts on fibrin bound plasminogen and cleaves it to release plasmin
plasmin which has typist like proteolytic behaviour digests the clot
= is clot selective
- is not antigenic = does not trigger an immunogenic response
What are the side effects of fibrinolytics?
bleeding
- can be treated with tranexamic acid
= anti-fibrinolytic agent which inhibits plasminogen activation
What is the function of thrombin?
factor IIa
- is a protease = has proteolytic activity
cleaves fibrinogen to form fibrin by activating factor XIII (fibrinoligase)
How does aspirin prevent coagulation of blood?
it prevents the production of cyclic endoperoxidases and thereby synthesis of thromboxane A2 synthesis from arachidonic acid via the inhibition of COX1
inhibition of TXA2 means that platelet aggregation is reduced/inhibited as TXA2 which increased the expression of glycoprotein IIb/IIa receptors and linkage of platelets is not present
