Antiplatelet/Anticoagulant Flashcards
Describe the process of clotting
Clotting occurs after vessel damage, or in the presence of thrombogenic factors such as a ruptured atherosclerotic plaque. Platelets activate and aggregate, whilst clotting factors are activated via the clotting cascade which activates zymogen clotting factors to form a fibrin mesh. There are two parts to the clotting cascade, the intrinsic pathway (12, 11, 7, 9 converging on 10) and the extrinsic pathway (7 & 8, converging on 10). Factor 10 converts prothrombin to thrombin which converts fibrinogen to fibrin which aggregates. Warfarin acts mainly on the extrinsic pathway.
What are the factors that contribute to thrombosis?
Virchows triad consists of abnormalities of blood components (hypercoagulability), abnormalities of the endothelium and abnormalities of flow (stasis). Endothelial damage usually leads to arterial clots, cardiac abnormalities usually lead to arterial clots and venous stasis leads to venous clots
What is MOA of warfarin?
Vitmin K acts on clotting factors 2, 7, 9, 10, reducing the glu residues to negative gla residues allowing the clotting factors to localise to the site of endothelial damage where calcium ions attract them.
Vitamin K must be activated by vitamin K epoxide reductase.
Warfarin is a coumarin which competitively inhibits vitamin K epoxide reductase, preventing vitamin K action. This prevents complete synthesis of the new 1972 clotting factors.
Why is heparin cover required in warfarin use?
Warfarin prevents synthesis of new clotting factors however the ones remaining in the system will still work. It takes several days for warfarin to take effect
Warfarin also causes anticoagulation factors protein C and protein S drop faster than procoagulation factors initially so there is a transient hyper coagulable state in warfarin use.
What are the indications for warfarin?
DVT PE AF Mechanical prosthetic valves Inherited thrombophilia Cardiac thrombus CVA Cardiomyopathy
How is warfarin administered?
Good GI absorption so given orally
Slow onset so requires heparin cover initially
Slow offset so stop 5 days before surgery to synthesis more clotting factors
Heavily protein bound so interacts with drugs that displace it
Metabolised by CYP450
What is the INR?
The prothrombin time measures the extrinsic pathway (the test is carried out by measuring the clotting time of citrated plasma after adding calcium and thromboplastins). The INR is a ratio between the patients prothrombin time and normal prothrombin time, which accounts for differences between labs.
What are ADRs of warfarin?
• Haemorrhage (including intracranial haemorrhage) if INR is elevated
o Epistaxis
o GI bleeding - Anaemia, Melaena
• Teratogenic, can cause brain haemorrhage in newborn if given in third trimester
What DDIs can occur with warfarin?
Inhibition of CYP enzymes (hepatic metabolism) potentiates warfarin: Amiodarone Quinolone Metronidazole Cimetidine alchohol
Inhibition of platelet function, potentiates warfarin by acting synergistically:
Aspirin
Reduction of vitamin K production from gut bacteria (potentiates warfarin)
Cephalosporin antibiotics
Drugs that displace warfarin from albumin (NSAIDs)
Drugs that decrease absorption of vitamin K (fat soluble) from GI
Induction of CYP450 enzymes which increases metabolism of warfarin, reducing effect: anti epileptics (phenytoin), rifampicin, St John’s wort
**Interacts with cranberry and grapefruit juice, alcohol
How can the action of warfarin be reversed?
The two main options are administration of parenteral vitamin K, which acts slowly as the clotting factors have to be synthesised by the liver, and administration of fresh frozen plasma/cryoprecipitate which acts more quickly as it contains clotting factors.
How can warfarin action be reversed if INR is above target but below 6.0 and there is no bleeding?
If the INR is above target range but below 6.0, and there is no bleeding you just withhold/reduce the dose of warfarin, and recommence when INR is less than 5.0
How can warfarin action be reversed if INR is between 6-8 and there is no/minor bleeding?
If the INR is between 6 and 8, and there is either no bleeding or minor bleeding you should just stop warfarin and restart when its less than 5.0
How can warfarin action be reversed if INR>8 and there is no/minor bleeding?
If the INR is greater than 8 and there is either no bleeding or minor bleeding you should stop warfarin and restart when INR is less than 5. If other risk factors for bleeding are present you should give o.5-2.5mg of vitamin K
How should warfarin be reversed if there is major bleeding?
If there is major bleeding: stop warfarin, give prothrombin complex concentrate or fresh frozen plasma, and give 5mg of vitamin K.
What are heparins? What is there MOA?
Heparins are glycosaminoglycans with different groups on each glucose. They are naturally produced by mast cells.
They activate antithrombin 3 which deactivates 10a, 2a, 9a (and potentially 7a, 11a and 12a).
What are the two heparins used? What is their method of administration? What clotting factors do they inactive?
• Unfractionated heparin – which can be given intravenously or subcutaneously.
They inactivate 2, 9 & 10, but:
o They can only inactivate 2 by simultaneously binding 2 and antithrombin 3
• Low molecular weight heparins (LMWHs) which are given subcutaneously.
o LMWHs are not big enough to inactivate 2 as it cant bind 2 and antithrombin 3 at the same time
o But they can still inactivate 10
What are the advantages of LMWH?
- Absorbed more uniformly
- High bioavailability – 90%
- Long half-life
- More predictable dose response (unlike heparin doesn’t bind to macrophages, endothelial cells or plasma proteins)
- No monitoring required
- Cleared by the kidneys (hence care is needed in renal failure)
- Less likely to cause thrombocytopenia
What is the difference in pharmacokinetics between UH and LMWH: Dose-response Bioavailability Action Administration Initiation
UFH: Non linear dose response Variable bioavailability due to unpredictable binding to calls and proteins Variable action - monitor with APTT Administration IV Bolus then IV infusion
LMWH:
Predictable dose response
Predictable bioavailability as less binding to macrophages and the endothelium
No monitoring needed, little affect on APTT
SC administration
Once or twice daily
What are uses of heparin?
• Prevention of thromboembolism o Perioperatively (since easy to reverse) o Immobility (in congestive cardiac failure or the frail, unwell patients)
• Treating thromboembolism
o DVT, PE and AF (to cover the onset of warfarin)
o Acute coronary syndromes – reduces recurrence and extension of coronary artery thrombosis
o Pregnancy – used cautiously, better than warfarin
How is heparin administered and monitored?
UFH - IV and monitored with aPTT
LMWH administered SC and doesn’t need monitoring
What does APTT, and PT measure? What is INR? Target INR on warfarin?
Activated partial thromboplastin time measures speed of clotting by intrinsic pathway
Prothrombin time measures speed of clotting of extrinsic pathway
Patient Prothrombin time/normal prothrombin time
2-3 target INR
2.5-3.5 if mechanical prosthetic valve
what are ADRs of heparin?
• Bruising and bleeding o Intracranial o Injection site o GI loss o Epistaxis
• Thrombocytopenia
o Heparin induced thrombocytopenia – autoimmuner phenomenon – may bleed or get serious thromboses
o This is because heparin binds to platelet factor 4 (PF4). The body forms antibodies against this complex, and these complexes including the antigen then activate platelets, which depletes platelet levels as well as causing thromboses.
o It is diagnosed by having platelets less than 100 (or 50% reduction)
o You should stop heparin and add hirudin, an alternative anticoagulant
• Osteoporosis can result from long term use
How can you reverse the action of heparin?
Reversal of therapy is with protamine sulphate – it acts by dissociating heparin from anti-thrombin 3. It binds irreversibly. It risks allergy and anaphylaxis
What is the MOA of aspirin? ADRs?
COX-1 inhibition which inhibits production of thromboxane A2 which is released by platelets to signal aggregation, and hence inhibits platelet aggregation
Peptic ulcers with NSAIDs
