Antiplatelet/Anticoagulant

Question 1

Describe the process of clotting

Answer 1

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.

Question 2

What are the factors that contribute to thrombosis?

Answer 2

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

Question 3

What is MOA of warfarin?

Answer 3

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.

Question 4

Why is heparin cover required in warfarin use?

Answer 4

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.

Question 5

What are the indications for warfarin?

Answer 5

DVT
PE
AF
Mechanical prosthetic valves
Inherited thrombophilia
Cardiac thrombus
CVA
Cardiomyopathy

Question 6

How is warfarin administered?

Answer 6

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

Question 7

What is the INR?

Answer 7

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.

Question 8

What are ADRs of warfarin?

Answer 8

• 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

Question 9

What DDIs can occur with warfarin?

Answer 9

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

Question 10

How can the action of warfarin be reversed?

Answer 10

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.

Question 11

How can warfarin action be reversed if INR is above target but below 6.0 and there is no bleeding?

Answer 11

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

Question 12

How can warfarin action be reversed if INR is between 6-8 and there is no/minor bleeding?

Answer 12

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

Question 13

How can warfarin action be reversed if INR>8 and there is no/minor bleeding?

Answer 13

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

Question 14

How should warfarin be reversed if there is major bleeding?

Answer 14

If there is major bleeding: stop warfarin, give prothrombin complex concentrate or fresh frozen plasma, and give 5mg of vitamin K.

Question 15

What are heparins? What is there MOA?

Answer 15

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).

Question 16

What are the two heparins used? What is their method of administration? What clotting factors do they inactive?

Answer 16

• 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

Question 17

What are the advantages of LMWH?

Answer 17

• 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

Question 18

What is the difference in pharmacokinetics between UH and LMWH:
Dose-response
Bioavailability
Action
Administration
Initiation

Answer 18

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

Question 19

What are uses of heparin?

Answer 19

•	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

Question 20

How is heparin administered and monitored?

Answer 20

UFH - IV and monitored with aPTT

LMWH administered SC and doesn’t need monitoring

Question 21

What does APTT, and PT measure? What is INR? Target INR on warfarin?

Answer 21

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

Question 22

what are ADRs of heparin?

Answer 22

•	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

Question 23

How can you reverse the action of heparin?

Answer 23

Reversal of therapy is with protamine sulphate – it acts by dissociating heparin from anti-thrombin 3. It binds irreversibly. It risks allergy and anaphylaxis

Question 24

What is the MOA of aspirin? ADRs?

Answer 24

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

Question 25

What is the MOA of dipyridamole?

Answer 25

phosphodiesterase inhibitor (normally breaks down cAMP) which increases cAMP levels, leads to inhibition of platelet aggregation.
o Positive inotrope and vasodilator – leads to flushes and headaches
o Secondary prevention of stroke

Question 26

What is the MOA of colidogrel/prasugrel/ticagrelor?

Answer 26

ADP antagonist, increases cAMP via GPCR coupled to Gi, inhibition of platelet aggregation
o Used in acute coronary syndrome and PCI
o Used with aspirin – for example for a year after NSTEMI – but not for long term use

Question 27

What are the MOA of glycoprotein 2b and 3a inhibitors

Answer 27

decrease crosslinking of platelets by fibrinogen
o Monoclonal antibody (abciximab)
o Or peptides
o Used in high risk acute coronary syndromes and post PCI (increased bleeding complications, less acute thrombosis and re-stenosis)