Antithrombotics

Question 1

Oral Anticoagulants - Warfarin MOA

Answer 1

Vitamin K antagonist

Vitamin K essential for production of prothrombin and factors 7,9,10 (“1972”).
Vitamin K important for post ribosomal carboxylation of glutamic acid residues of these proteins.

Warfarin blocks Vitamin K reductase, needed for Vit K to act as a cofactor in Vit K dependent carboxylation.

Question 2

Warfarin Use and Indications (4)

Answer 2

Used to prevent thrombosis. Takes several days to act because it inhibits the production of new clotting factors and so its action is delayed.

Used in......
Patients with mechanical artificial heart valves
Associated with AF (reduce risk of TIAs)
Prevent thrombosis due to PE
Prevent thrombosis due to DVT

Question 3

How to monitor warfarin activity

Answer 3

INR. International Normalised Ratio (Prothombin time)
With a specific target value and the dose is adjusted.

INRs are around 1
INR is increased by impaired clotting have due to warfarin and liver disease (as the liver produces coagulation factors).
Consult BNF for target INR values.

Question 4

Warfarin drug interactions - Effect potentiated by…

Answer 4

CP450 inhibitors such as 
Erythromycin, 
cimetidine,
Amiodarone (anti-arhythmic)
Fibrates (hypolipidaemic agents)

Plasma warfarin concentration and INR rise. These interactions are rapid in onset

Question 5

Warfarin drug interactions- effect reduced by……

Answer 5

Enzyme inducers for example,
Barbiturates
Carbamazepine

Reduced warfarin plasma concentrations and INR fall
Onset may be delayed as they require protein synthesis
Reversal may be delayed after stopping the interacting drug

Question 6

Increased Warfarin activity leads to increased bleeding leading to…. (6)

Answer 6

Gastric - risk of bleeding ulcers
Cerebral - risk of haemorrhagic stroke
Haemoptysis - coughing up blood 
Blood in faeces
Haematuria
Easy bruising

Question 7

Warfarin and pregnancy (3)

Answer 7

Teratogenic (esp 1st trimester)
Associated with fetal Vit K deficiency in late pregnancy and so generally avoided
Heparin is considered as a safer option

Question 8

Injectable anticoagulants. MOA.

Answer 8

Unfractionated heparin / LMWH e.g. Tinzaparin

They activate Antithrombin III (natural protein)

Antithrombin - inactivates some clotting factors and thrombin by complexing with serine protease of the factors
INHIBITS 9,10,11, thrombin

Question 9

Heparin. Use, monitoring, pregnancy

Answer 9

Immediate action
Prevents thrombosis (venous thrombosis, unstable angina)
Used while warfarin is initiated and takes effect

Longer term use (>5 days) is associated with thrombocytopenia and platelets should be monitored

Unfractionated - requires monitoring and screening via activated partial thromboplastin time (APTT)
LMWH - more predictable and does not require monitoring

Safe in pregnancy

Question 10

New antithrombotic

Answer 10

DABIGATRAN
Oral thrombin inhibitor
Prevents thromboembolism
Less bleeding than warfarin and fewer drug interactions

Question 11

Anti platelet drugs - Aspirin use

Answer 11

Low dose Aspirin (75mg)
Used to prevent MI in patient with MI Hx
Reduces stroke incidence
Inhibits COX irreversibly

Question 12

Aspirin. MOA and selectivity

Answer 12

Inhibits COX,
therefore inhibits PGI2 production (endothelium)
and Thomboxane production (platelets).

Favours PGI2 production over TXA2
Because
Platelets have no nuclei and cannot produce any more COX (therefore no more TXA2) until new platelets are synthesised (7 days).
Endothelial cells have nuclei, and can produce mRNA and therefore more COX (in 2 hours) and produce PGI2.

PGI2 = Prostacyclin. Inhibits platelet activation and vasodilates.
TXA2 = Thromboxane. Produced by activated platelets and stimulates activation of new platelets as well as increases platelet aggregation.

Question 13

Anti platelet drug - Dipyridamole. MOA and use

Answer 13

Phosphodiesterase inhibitor
Prevents breakdown of cAMP and cGMP (which are broken down by phosphodiesterases).

cAMP/cGMP -> inhibit aggregation

Used to prevent thrombosis
Used in conjunction with aspirin

Question 14

GP IIb/IIIa (2b/3a) Role

Answer 14

Binds fibrinogen which leads to cross linking of platelets.

ADP from aggregating platelets,
leads to expression of glycoprotein IIb/IIIa.

Question 15

Clopidogrel. MOA and use.

Answer 15

Inhibits ADP- induced expression of GP 2b/3a

New, for patients who can’t take aspirin - similarly effective/ safe.
Recent CURE trial - clopidogrel + aspirin greatly reduced MI in risky patients.
May be used with aspirin.

Question 16

Abciximab. MOA and use.

Answer 16

Monoclonal antibody against GP2b/3a.

Given to patients undergoing angioplasty. Only use once.

Question 17

Fibrinolysis. Process.

Answer 17

(E.g. Streptokinase - thrombolysis medication)

Endogenous system, dissolve clots.
Activated in parallel with clotting system.
Plasminogen to plasmin.

PLASMIN. Digests the fibrin of the clot (and also some clotting factors).

Fibrinolytic agents (CLOT BUSTERS). Activate plasminogen to plasmin conversion.

Question 18

Thrombolytics. Use

Answer 18

Given immediately after MI.
Dissolve thrombus that has caused blockage of coronary arteries and the MI.

Effective, best given with aspirin.

POTENTIAL use in thromboembolic stroke (require that haemorrhagic stroke is excluded prior to treatment).

Question 19

Thrombolysis. Take care….

Answer 19

Can cause bleeding 
CARE NEEDED
After recent surgery
Haemorrhagic stroke
Ulcers

Question 20

Anticoagulants types

Answer 20

Oral. Warfarin.

Injectable. Heparin.