How does healthy endothelium prevent platelet aggregation?
- Prostacyclin is released from healthy endothelium.
- This increased cAMP production.
- cAMP prevents Ca+ release, preventing platelet aggregation.
- GP11B/GP11A receptors are also stabilised.
How does unhealthy endothelium promote platelet aggregation?
- Collagen fibres from exposed subendothelial surface activate platelets
- Activated platelets release chemical mediators - Thomboxane A2, ADP, serotonin, PAF
- More platelets are recruited to the platelet plug
- Chemical mediators cause Ca2+ release and less cAMP production.
- Elevated Ca2+ causes - release of platelet granules, activated thromboxane A2, activated GPIIB/GPIIA receptors.
- Cascade amplification and recruitment of other platelets.
How does aspirin work?
- Inhibits COX-1 mediated production of thomboxane A2
- Reduced platelet aggregation irreversibly
- Used at low non analgesic doses (75mg)
- Higher doses inhibit endothelial prostacyclin
What are some contraindications for aspirin?
- Bleeding time prolonged - haemorrhagic stroke, GI bleeding
- Reye’s syndrome - avoid <16yo
- Hypersensitivity
- 3rd trimester - premature closing ductus arteriosus
What should you give to a patient if giving aspirin long term?
A ppi
Name 3 ADP receptor antagonists
Clopidogrel
Prasugrel
Ticagrelor
How do ADP receptor antagonists work?
Inhibit binding of ADP to P2Y12 receptor, inhibiting activation of GP11B/GP11A receptors.
- Independent of COX pathway
Are clopidogrel/prasugrel irreversible?
Yes
Which ADP receptor antagonists have a faster onset?
Ticagrelor and prasugrel
What are some contraindications and side effects for ADP receptor antagonists?
- Bleeding
- GI upset - Dyspepsia and diarrhea
- Thrombocytopenia
- Caution in renal and hepatic impairment
What is important about clopidogrel and CYP enzymes?
- Clopidogrel requires CYP’s for activation
- Caution with CYP inhibitors (esp omeprazole use other gastric protection)
What is abciximab?
A glycoprotein 11B/111A inhibitor.
How do glycoprotein IIB/IIIA inhibits work?
- An antibody which blocks the GPIIIB/GPIIA receptors.
- This blocks binding of fibrinogen and von Willebrand factor, targeting the final common pathway.
What are some side effects of abciximab?
- Bleeding, adjust dose for body weight
- Thrombocytopenia
- Hypotension
- Bradycardia
Name a phosphodiesterase inhibitor?
Dipyridamole
How do phosphodiesterase inhibitors work?
- Inhibits cellular reuptake of adenosine, increasing plasma adenosine
- This inhibits platelet aggregation via A2 receptors
- Also inhibits phosphodiesterase which prevents cAMP degradation and inhibits expression of GPIIA/GPIIIB
What are some side effects of dipyridamole?
Flushing, headaches, hypersensitivity
Name three thombolytic agents
Streptokinase - can only be used once
Alteplase
Tranexamic acid
What needs ruling out before you give a thombolytic agent?
Intracranial haemmorhage
Name an antifibrinolytic - how does it work?
Tranexamic acid
Inhibits activation of plasminogen from plasmin
What drug activates plasminogen to plasmin?
Streptokinase/Alteplase
