Session 8 - Warfarin and other anti-clotting things Flashcards
What is haemostasis?
the body’s response to stop bleeding and loss of blood.
What does successful haemostasis depend on?
o Vessel wall
o Platelets
o Coagulation System
o Fibrinolytic System
Outline virchow’s triad
o Changes in blood flow Stagnation, turbulence o Changes in vessel wall Atheroma, injury, inflammation o Changes in blood components Smokers, pregnancy
What is a thrombosis?
The formation of a solid mass of blood within the circulatory system during life
What do arterial thrombi look like?
Pale
Granular
Lines of Zahn
Lower cellular content
What do venous thrombi look like?
Deep red
Soft
Gelatinous
High cell content
What do arterial thrombi cause
o Ischaemia
o Infarction
o Depends on site and collateral circulation
What do venous thrombi cause?
o Congestion
o Oedema
o Ischaemia (If Tissue Pressure due to Oedema > Arterial Pressure)
o Infarction
What is the mechanism of action for vitamin K antagonists?
Vitamin K antagonists (e.g. Warfarin) block the reduction of vitamin K epoxide, to its active form.
What is vitamin K good for?
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
Give two indications for warfarin
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
What is the target INR in DVT and PE?
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
What is the target INR in atrial fib and prosthetic heart valves with warfarin?
Atrial Fibrillation – Target INR of 2.0 – 3.0 until Risk > Benefit
Prosthetic heart valves – Target INR of 2.5 – 4.5
How fast is warfarins onset of action
o Slow onset of action
Heparin cover
Increases clotting initially as a result of increased protein C factors
How fast is warfarin in stopping its effects once withdrawn?
Need time to synthesise new clotting factors
Need to stop 3 days before surgery
How do warfarin interact with other drugs?
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
Why should you not give warfarin in pregnancy?
Crosses Placenta
Do not give in 1st Trimester – Teratogenic
Do not give in 3rd Trimester – Brain Haemorrhage
What is an INR?
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
What clotting factors do INR measure and what is their function/.
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)
What will warfarin treatment do to INR?
RAISE IT
What is the therapeutic range from Warfarin?
is an INR of 2.0 – 3.0
What is the therapeutic range for warfarin in high risk patients (prosthetic valves)
target INR of 2.4 – 4.5
Give two adverse effects of warfarin
o Bleeding / Bruising Intracranial Epistaxis Injection site GI loss o Teratogenic
Name drugs which potenitate Warfarin due to CYP450 inhibition
o CYP450 inhibitors
GO-DEVICES
Grapefruit Juice, Omeprazole, Disulfiram, Erythromycin, Volporate, Isoniazid, Cimetidine & Ciprofloxcain, Ethanol (acutely), Sulphonamides
Name some other causes of warfarin potentiation (3)
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
Name some drugs whicbh inhibit warfarin
o CYP450 inducers
PCBRAS
Phenytoin, Carbamazepine, Barbiturates Rifampicin, Alcohol (chronic), Sulphonylureas and St. John’s Wort
How can warfarin be reversed?
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
Give five contraindications for warfarin
Cerebral thrombosis, peripheral arterial occlusion, peptic ulcers, hypertension, pregnancy
What are the two types of heparin
Unfractionated heparin
Low molecular weight heparin
What is unfractionated heparin?
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
What is fractionated heparin?
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
How do the mechanisms of fractionated and unfractionated heparin differ
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.
When is heparin used prophylactically?
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
What is heparin used to treat?
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
How is unfractionated heparin adminstered?
Loading dose, then IV infusion
Monitor APTT (Activated Partial Thromboplastin Time, intrinsic factor measurement)
How is low molecular weight heparin>
Prophylaxis SC once a day (until Warfarin loading is achieved)
Treatment SC once/twice a day
What must you EVER NEVER DO with heparin?
Never give Heparin Intramuscularly – Risk of Intramuscular Haemorrhage
What is activated partial thromboplastin time?
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
Give two of the main adverse effects of heparin?
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
How is heparin reversal achieved?
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
