Anticoagulants Flashcards
What are the antiplatelet drugs we need to know
Low dose aspirin
Clopidogrel
What are the anticoagulants we need to know?
- Low mol wt heparins (enoxaprin)
- VKAs (Coumarins): Warfarin
- NOACs: dabigatran
What are the fibrinolytic drugs we need to know?
rt-PAs (alteplase, tenecteplase)
What processes does haemostasis involve?
- Platelet activation & adhesion
* Forms clot - Blood coagulation
- Fibrin formation
- Reinforces clot
What things stop us from forming thrombi under normal conditions?
- Prostacyclin (PGI2)
- It’s a prostaglandin synthesised and secreted by endothelial cells
- Inhibits platelet aggregation and secretion
- It does this by increasing platelet cAMP release, and this decreases platelet COX activity. This decreases pro-thrombotic TXA2 production
- Antithrombin - it’s a circulating plasma protein, it inhibits coagulation.
- Thrombomodulin and Protein C
* Antithrombotic proteins expressed on endothelial cells bind and inactivate coagulation factors.
What are the mechanisms of thrombus formation following initial damage?
- Platelet Adhesion
- PGI2 synthesis and secretion by endothelial cells is decreased
- Platelets adhere to extracellular matrix proteins
- vWF & collagen
- The aggregated platelets initially generate thrombin
- Platelet Shape Change
- Thrombin: potently activates platelets
- Causes platelet shape change (Causes Ca2+ to enter platelet, resulting in the shape change which allows for more aggregation)
- Platelet Granule Release leading to aggregation and consolidation
- Thrombin: Also causes platelets to release more active compounds from platelet granules activate other platelets (G protein mediated):
- Including TXA2 & ADP.
- TXA2: also causes vasoconstriction at the site of vascular injury (Decreases cAMP)
- Fibrin stabilises platelets
- thrombin also facilitates the conversion of fibrinogen to fibrin
- Fibrin: Polymerises to form fibrous matrix and stabilizes aggregated platelets - the platelet rich thrombus (look at slide for pics)
- fibrin activates thrombin, which provides the scaffolding for coagulation to occur
How does ADP release lead to more platelet activation?
ADP works in two pathways, the PKA inhibition and PLC-mediated platelet activation.
PKA inhibition: ADP binds to P2Y receptors and inhibits cAMP formation resulting in decreased PKA (protein kinase formation), and this decreased PKA activity leads to the expression of fibrinogen receptors.
PLC-mediated platelet activation: Thrombin binds to the thrombin receptor, and ADP binds to a P2Y1 receptor. Both of these receptors once activated increase PLC activity, and this increases fibrinogen receptor expression.
So a decrease in PKA activity, and an increased PLC activity results in fibrinogen receptor activation.
What factors does antithrombin inhibit?
Impacts upon Factors IIa (thrombin) and X
What are the three ways that drugs can prevent haemostasis?
- By reducing platelet aggregation
- By reducing blood coagulation (fibrin formation)
- By increasing fibrin breakdown (fibrinolysis)
What are the antiplatelet drugs?
Low dose aspirin and clopidogrel
What is the MOA for oral low dose aspirin (75-150 mg/ day)
Aspirin is acetylsalicylate.
It inhibits platelet aggregation, and reduces the risk of thrombin formation.
- Acetylsalicylate is a non-selective COX inhibitor
- It irreversibly binds platelet COX-1, reducing TXA2 production for the lifetime of the platelet (since it has no nucleus) (7-9days)
- It has little effect on COX-2 by endothelial cells (therefore no affecting PGI2 production much) due to the esterase action in liver
- acetylsalicylate is metabolised and deactivated from acetylsalicylate to salicylate in the liver. And also because if it binds to COX-2, the cell can replace the enzyme since it has a nucleus.
Where does lose dose aspirin act on platelets in the circulation?
Acts on platelet COX in the portal circulation before being metabolised in liver to salicylate (COX effects)
If its high dose, un metabolised aspirin gets past the liver and has more effects of endothelial COX2
Should low dose aspirin be used for cardiovascular disease prevention?
No, it the negatives outweigh the benefits
- Decreases mucous production
- ulceration
- Gastric bleeding
- Reye’s syndrome
What is the MOA for clopidogrel? And why might it be used over aspirin
Clopidogrel is used if the patient cannot tolerate aspirin.
MOA: It non-competitively blocks ADP (purinergic P2Y) receptors
- This prevents activation of GPIIb-GPIIIa receptor (fibrinogen receptors)
- This reduces platelet aggregation since the fibrinogen cross bridges can’t form
- It’s synergistic with aspirin
What are the two main ways ADP aids platelet aggregation and activation?
- Causes a conformational change in the platelet and induces GPIIb/IIIa complex (fibrinogen receptor) presentation.
How is Warfarin taken, and what is it’s MOA?
Warfarin is given orally (So it can access the liver)
- MOA: Competiviely blocks Vitamin K recycling in liver by inhibiting vitamin K epoxide reductase (prevents oxidised form returning to reduced form, this is its active form)
- As a result, this prevents Vitamin K from activating factors 2, 7, 9, 10 and proteins C & S
Overall, VKAs reduce formation of fibrin
Pic showing how VKAs inhibit fibrin formation
Pic of drug reducing and potentiating factors for warfarin
How do fibrinolytic drugs work, and when are they used?
We use fibrinoyltics when the thrombus has already formed, as it breaks down the thrombus.
Tissue plasinogen activators are serine proteases normally synthesised by endothelial cells. They promote thrombolysis by converting plasminogen to plasmin to degrade fibrin.
