pharmacology of haemostasis and thrombosis Flashcards
What happens when the endothelium of a blood vessel is damaged?
The underlying collagen is exposed.
What happens when collagen is exposed in a damaged blood vessel?
von Willebrand factor (vWF) binds to the exposed collagen.
What is the function of vWF in this process?
vWF acts as a molecular bridge between platelets and exposed collagen.
How does vWF tether passing platelets to the exposed collagen?
vWF binds to a specific complex of glycoproteins on the platelet membrane called the glycoprotein 1b-IX-V complex.
What happens to the binding site on vWF before it is bound to collagen?
The binding site on vWF is masked until it is bound to collagen
What happens to the vWF molecule when it is exposed to the shear forces of blood flow past the immobilized vWF?
The vWF molecule unwinds and exposes the binding section.
What happens once a platelet is tethered to the exposed collagen via vWF?
More vWF-GP1b interactions occur as the platelet rolls with the force of blood flow over the endothelial surface, and lots of immobilized vWF is ready and waiting to bind to GP1b-IX-V complexes.
Are the interactions between vWF and the glycoprotein 1b-IX-V complex stable enough to keep platelets tethered on their own?
No, these interactions are not stable enough and rely on strengthening and stabilisation by various other interactions.
What do the further steps and interactions triggered by the vWF-GP1b-IX-V interactions do?
They help to “activate” the platelets.
What do activated platelets do that they wouldn’t normally do when they’re not activated?
They start to bind to fibrinogen via their GP2b3a, which is important in facilitating platelet aggregation (clustering).
How does GP2b3a crosslink with other platelets?
GP2b3a crosslinks with other platelets via the fibrinogen.
What do activated platelets generate from arachidonic acid under the influence of cyclooxygenase?
Activated platelets generate thromboxane A2.
What happens to the thromboxane A2 that is generated by activated platelets?
Thromboxane A2 is released from the platelet and binds to thromboxane receptors on other platelets.
Is thromboxane A2 an example of an agonist to platelet function?
Yes, thromboxane A2 is an example of an agonist to platelet function, meaning it enhances the effects of platelets.
What is the result of thromboxane A2 binding to its receptors on other platelets?
It promotes yet more activation, aggregation, and adhesion of platelets.
What are some potential side effects of aspirin?
Peptic ulceration, rash, and hearing loss/tinnitus (at high doses). Brain and liver damage have also been observed in children given aspirin for viral illness.
How does aspirin work to reduce inflammation and pain?
Aspirin blocks the production of prostaglandins and thromboxanes.
What is the mechanism of action of aspirin?
Aspirin irreversibly inhibits Cycloxygenase 1 (COX 1).
How does aspirin’s mechanism of action differ from that of other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like ibuprofen?
Aspirin is an irreversible inhibitor of COX 1, while NSAIDs like ibuprofen are reversible inhibitors.
What is the importance of prostaglandins in the gastric lining’s resistance to acid?
The gastric lining’s resistance to acid is prostaglandin dependent.
How does aspirin affect platelet function?
Aspirin works on cyclooxygenase, leading to decreased production of thromboxane. With less thromboxane, there can be less binding to the thromboxane receptor and so less agonistic effect on platelet adhesion, activation, and aggregation.
What is the role of prostacyclin in platelet function, and how does it compare to thromboxane A2?
Prostacyclin inhibits platelet aggregation and promotes vasodilation, whereas thromboxane A2 promotes platelet aggregation and vasoconstriction. Prostacyclin is released from normal endothelium under the influence of cyclooxygenase.
At high doses, how does aspirin affect the production of both thromboxane and prostacyclin?
At high doses, the effect of aspirin on COX1 inhibits production of both thromboxane and prostacyclin. This is slightly counterintuitive to what we are trying to achieve, which is inhibition of platelet aggregation.
How can lower doses of aspirin be used to selectively inhibit platelets
while keeping endothelial cell function intact?
Using a lower dose of aspirin can selectively inhibit platelets, while keeping endothelial cell function intact.
What is the overall effect of aspirin on platelet function?
The overall effect of aspirin is inhibition of activation, aggregation, and adhesion of platelets.
In which patients is aspirin used?
Aspirin is used in all patients with established vascular disease, including those with ischaemic heart disease (myocardial infarction, angina), cerebrovascular disease, and peripheral vascular disease.
How does aspirin improve prognosis?
Aspirin improves prognosis by reducing mortality and adverse events such as heart attack and stroke.
What is the cost of aspirin compared to other drugs?
Aspirin is a mainstay drug and is considered very cheap.
What is the role of ADP in platelet aggregation?
Activated platelets release ADP which binds to P2Y12 receptor on other platelets. This enhances the ability of platelets to aggregate, activate and adhere.
What is clopidogrel and why was it developed?
Clopidogrel is a platelet P2Y12 receptor inhibitor. It was developed to combat acute coronary stent thrombosis.
What is the CAPRI trial and what did it find?
The CAPRI trial (1996) compared clopidogrel to aspirin in patients with stable arterial disease. The trial found that clopidogrel was more effective with a similar safety profile.
When is clopidogrel used as part of dual anti-platelet therapy (DAPT)?
Clopidogrel is used as part of DAPT in patients post-MI and elective coronary stenting, and in patients with recurrent stroke despite aspirin. It is also first-line therapy for peripheral arterial disease.
