Session 8 - Warfarin and other anti-clotting things Flashcards Preview

Semester 5 - Farmocology > Session 8 - Warfarin and other anti-clotting things > Flashcards

Flashcards in Session 8 - Warfarin and other anti-clotting things Deck (40)

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?

Lines of Zahn
Lower cellular content


What do venous thrombi look like?

Deep red
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How fast is warfarin in stopping its effects once withdrawn?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?



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
 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
 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