Session 8 - Warfarin and other anti-clotting things

Question 1

What is haemostasis?

Answer 1

the body’s response to stop bleeding and loss of blood.

Question 2

What does successful haemostasis depend on?

Answer 2

o Vessel wall
o Platelets
o Coagulation System
o Fibrinolytic System

Question 3

Outline virchow’s triad

Answer 3

o	Changes in blood flow
	Stagnation, turbulence
o	Changes in vessel wall
	Atheroma, injury, inflammation
o	Changes in blood components
	Smokers, pregnancy

Question 4

What is a thrombosis?

Answer 4

The formation of a solid mass of blood within the circulatory system during life

Question 5

What do arterial thrombi look like?

Answer 5

Pale
Granular
Lines of Zahn
Lower cellular content

Question 6

What do venous thrombi look like?

Answer 6

Deep red
Soft
Gelatinous
High cell content

Question 7

What do arterial thrombi cause

Answer 7

o Ischaemia
o Infarction
o Depends on site and collateral circulation

Question 8

What do venous thrombi cause?

Answer 8

o Congestion
o Oedema
o Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure)
o Infarction

Question 9

What is the mechanism of action for vitamin K antagonists?

Answer 9

Vitamin K antagonists (e.g. Warfarin) block the reduction of vitamin K epoxide, to its active form.

Question 10

What is vitamin K good for?

Answer 10

The reduced, active form of Vitamin K is necessary for its action as a cofactor in the synthesis of:
o	Factor II (Prothrombin)
o	Factor VII
o	Factor IX
o	Factor X

Question 11

Give two indications for warfarin

Answer 11

o Prophylaxis and treatment of deep vein thrombosis and pulmonary embolism
o Prophylaxis of embolization in atrial fibrillation/patients with prosthetic heart valves, Thrombosis associated with inherited thrombophilia conditions

Question 12

What is the target INR in DVT and PE?

Answer 12

 Deep Vein Thrombosis – Target INR of 2.0 – 3.0 for 3-6 months
 Pulmonary Embolism – Target INR of 2.0 – 3.0 or 6 months

Question 13

What is the target INR in atrial fib and prosthetic heart valves with warfarin?

Answer 13

 Atrial Fibrillation – Target INR of 2.0 – 3.0 until Risk > Benefit
 Prosthetic heart valves – Target INR of 2.5 – 4.5

Question 14

How fast is warfarins onset of action

Answer 14

o Slow onset of action
 Heparin cover
 Increases clotting initially as a result of increased protein C factors

Question 15

How fast is warfarin in stopping its effects once withdrawn?

Answer 15

 Need time to synthesise new clotting factors

 Need to stop 3 days before surgery

Question 16

How do warfarin interact with other drugs?

Answer 16

o Heavily Protein Bound
 Caution with drugs that can displace it (see below)
o Hepatic Metabolism (CYP450 system)
 Caution with Liver Disease
 Caution with CYP450 inducers/inhibitors

Question 17

Why should you not give warfarin in pregnancy?

Answer 17

 Crosses Placenta
 Do not give in 1st Trimester – Teratogenic
 Do not give in 3rd Trimester – Brain Haemorrhage

Question 18

What is an INR?

Answer 18

The effect of Warfarin is monitored via Prothrombin Time, which is expressed as the International Normalised Ratio (INR). This is calculated from the ratio of Prothrombin times of test and control samples. It is a measure of the Extrinsic Pathway of coagulation

Question 19

What clotting factors do INR measure and what is their function/.

Answer 19

o Factor I – Fibrinogen
o Factor II – Prothrombin
 (Requires Vit. K for synthesis – Warfarin site of action)
o Factor V
o Factor VII
 (Requires Vit. K for synthesis – Warfarin site of action)
o Factor X
 (Requires Vit. K for synthesis – Warfarin site of action)

Question 20

What will warfarin treatment do to INR?

Answer 20

RAISE IT

Question 21

What is the therapeutic range from Warfarin?

Answer 21

is an INR of 2.0 – 3.0

Question 22

What is the therapeutic range for warfarin in high risk patients (prosthetic valves)

Answer 22

target INR of 2.4 – 4.5

Question 23

Give two adverse effects of warfarin

Answer 23

o	Bleeding / Bruising
	Intracranial
	Epistaxis
	Injection site
	GI loss
o	Teratogenic

Question 24

Name drugs which potenitate Warfarin due to CYP450 inhibition

Answer 24

o CYP450 inhibitors
 GO-DEVICES
 Grapefruit Juice, Omeprazole, Disulfiram, Erythromycin, Volporate, Isoniazid, Cimetidine & Ciprofloxcain, Ethanol (acutely), Sulphonamides

Question 25

Name some other causes of warfarin potentiation (3)

Answer 25

o Inhibition of Platelet function
 Aspirin – different site of action (see below)
o Reduce Vitamin K from gut bacteria
 Cephalosporin Antibiotics
o Displacement from plasma proteins (e.g. via NSAIDs

Question 26

Name some drugs whicbh inhibit warfarin

Answer 26

o CYP450 inducers
 PCBRAS
 Phenytoin, Carbamazepine, Barbiturates Rifampicin, Alcohol (chronic), Sulphonylureas and St. John’s Wort

Question 27

How can warfarin be reversed?

Answer 27

o Stop Warfarin treatment
o Consider bleeding, INR, indication (e.g. if mechanical valve call cardiologist)
o IV Vitamin K
 Slow acting, fresh clotting factors need to be synthesised
 Pro-coagulant
 Will affect re-warfarinisation for 6 weeks
o Prothrombin Complex Concentrate (Fast acting)
o Fresh Frozen Plasma (Fast acting)
o Need to stop Warfarin 3 days before elective surgery

Question 28

Give five contraindications for warfarin

Answer 28

 Cerebral thrombosis, peripheral arterial occlusion, peptic ulcers, hypertension, pregnancy

Question 29

What are the two types of heparin

Answer 29

Unfractionated heparin

Low molecular weight heparin

Question 30

What is unfractionated heparin?

Answer 30

o Mix of variable long length heparin chains (12-15 kDaltons)
o Binds to and Increases the activity of Anti-Thrombin III
o Anti-Thrombin III
 Inactivates Thrombin (Factor IIa)
 Inactivates Factor Xa
 Also inactivates factors V, VII, IX, XI

Question 31

What is fractionated heparin?

Answer 31

o Smaller heparin chains (4-5 kDaltons)
o High bioavailability (> 90%)
o Long t½
o More predictable dose response
 No macrophage/endothelial cell/plasma protein binding)
o Binds to Anti-Thrombin III
 Inactivates Factor Xa ONLY
 DOES NOT INACTIVATE Thrombin (Factor IIa)
o Cleared by Kidneys – careful with dose in Renal Failure

Question 32

How do the mechanisms of fractionated and unfractionated heparin differ

Answer 32

To catalyse the inhibition of Thrombin (Factor IIa) by Anti-thrombin III, Heparin needs to bind simultaneously to both molecules. Unfractionated Heparin is large enough to do this, but LMWH is not.

Factor Xa inhibition by Anti-thrombin only requires Heparin to bind to Anti-thrombin III, so both Unfractionated and LMW Heparin can act there.

Question 33

When is heparin used prophylactically?

Answer 33

o Prevention of Thrombo-Embolism
 Peri-Operative (LMWH low dose)
 Immobility (Heart failure, frail or unwell patient)
o Used to cover thrombosis risk around operation in patients normally on warfarin, but who have had it stopped for surgery, as Heparin quick offset time allows cessation if bleeding occurs

Question 34

What is heparin used to treat?

Answer 34

o Deep Vein Thrombosis, Pulmonary Embolism and Atrial Fibrillation
 Administered prior to Warfarin, as quick onset will cover patient whilst Warfarin loading is achieved
 LMWH often used unless fine control is required
o Acute Coronary Syndromes
 Reduces recurrence/extension of coronary artery thrombosis
 MI, unstable angina
o Pregnancy
 Can be used cautiously in pregnancy in place of Warfarin

Question 35

How is unfractionated heparin adminstered?

Answer 35

 Loading dose, then IV infusion

 Monitor APTT (Activated Partial Thromboplastin Time, intrinsic factor measurement)

Question 36

How is low molecular weight heparin>

Answer 36

 Prophylaxis SC once a day (until Warfarin loading is achieved)
 Treatment SC once/twice a day

Question 37

What must you EVER NEVER DO with heparin?

Answer 37

Never give Heparin Intramuscularly – Risk of Intramuscular Haemorrhage

Question 38

What is activated partial thromboplastin time?

Answer 38

o Used to monitor the Intrinsic Coagulation Pathway
o Plasma sample taken, mixed with an Intrinsic Pathway Activator (e.g. Silica) and time to form Thrombus measured
o Normal range 30 – 50 seconds

Question 39

Give two of the main adverse effects of heparin?

Answer 39

o	Bleeding/Bruising
	Intracranial
	Injection sites
	GI loss
	Epistaxis
o	Heparin Induced Thrombocytopenia (HIT)
	Autoimmune response to Heparin on platelet surface, causing immune complex aggregation
	Thrombosis and depletion of platelets due to aggregation
	Lab assay for antibodies
	Stop Heparin, add Hirudin

Question 40

How is heparin reversal achieved?

Answer 40

o Stop Heparin
o Protamine Sulphate
 Dissociates Heparin from Anti-Thrombin III
 Irreversibly binds to Heparin
 Given in allergy, anaphylaxis and if patient is actively bleeding
o Monitor APTT if using Unfractionated Heparin