Anticoagulants & Antiplatelets Flashcards
Outline the components of Virchow’s triad.
Hypercoaguability
- genetic e.g. protein C & S deficiency, factor V deficiency
- acquired e.g. antiphospholipid synthesis, OCP, smoking, malignancy, prosthetic heart valves
Endothelial damage (arterial)
- atheroma (MI, stroke)
- hypertension
- toxins (cigarettes, homocysteine)
Stasis
- ARTERIAL (cardiac abnormality) = AF, mitral valve disease, post-MI, carotid-cavernous fistula (CCF)
- VENOUS (immobility) = ill health, post-op, economy class
Outline the clotting cascade.
Intrinsic pathway (exposed collagen, kallikrein): XII ---> XIIa XIIa catalyses XI ---> XIa XIa catalyses IX ---> IXa IXa catalyses X ---> Xa
Extrinsic pathway (tissue damage releasing tissue factor, thromboplastin, calcium): VII catalyses X ---> Xa
Xa catalyses prothrombin (II) —> thrombin (IIa)
Thrombin (IIa) cleaves fibrinogen to fibrin
XIII helps fibrin form clot
Fibrinogen & thrombin stimulate further aggregation of platelets
What inhibits the different part of the clotting cascade?
Heparin-antithrombin complex inhibits XIIa, XIa, IXa, Xa, thrombin (IIa)
Hirudin inhibits thrombin (IIa)
Warfarin inhibits production of vitamin K dependent clotting factors = IX, VII, X, prothrombin (II)
What are the functions of warfarin?
Coumarins
Inhibits production of vitamin K dependent clotting factors in liver (competitive; synthesis of non-functional clotting factors)
- stops conversion of vitamin K to active reduced form
- affects prothrombin (II), IX, X, and VII (EXTRINSIC PATHWAY)
- initially increases coagulability due to inhibition of synthesis of proteins C & S (therefore initially give heparin)
Describe the pharmacokinetics of of warfarin.
Slow onset - days (need to deplete activated clotting factors; therefore give heparin to cover)
Slow offset: t1/2 = ~48hrs (time needed to synthesise new clotting factors; need to stop 3 days before surgery)
Good GI absorption - give PO (indicated for long-term anticoagulation)
Heavily bound to albumin (caution needed with NSAIDs - displace drugs from albumin)
Metabolised by CYP450 (take caution in liver disease and with CYP450 inducers and inhibitors)
Crosses placenta - contraindicated in first trimester (teratogenic) and third trimester (risk of baby’s head bleeding as its head is distorted during vaginal delivery)
How is warfarin monitored? Why is this important?
- concentration of extrinsic pathway factors
- prothrombin time
- International Normalised Ratio (INR) = standard value; the higher the INR, the thinner the blood
Extreme variation in individual dose requirements; avoid complications of hypercoaguable blood and excessive bleeding
Give some examples of drugs potentiating the action of warfarin.
CYP450 inhibitors e.g.
- amiodarone
- quinodone
- metronidazole
- cimetidine
- alcohol (acute)
- aspirin (anti-platelet)
- reduced vitamin K secretion from gut bacteria e.g. cephalosporins
- NSAIDs displace warfarin from albumin —> increased conc. of free warfarin (temporary)
- drugs reducing GI absorption of vitamin K (temporary)
Give some examples of drugs inhibiting the action of warfarin.
CYP450 inducers e.g.
- anti-epileptics
- rifampicin
- St. John’s Wort
- chronic alcohol
What are the indications for warfarin? What are the different INR ranges for each indication?
DVT: 3-6 months (provoked for 3 months, unprovoked for 6 months), INR 2.0-3.0
PE: 3-6 months (provoked for 3 months, unprovoked for 6 months), INR 2.0-3.0
AF: until risk of bleeding exceeds benefit of reduced risk of CVS events
Mechanical prosthetic valves: INR 2.5-4.5
Recurrent thromboses on warfarin: INR 2.5-4.5
Thrombosis associated with inherited thrombophilic conditions: INR 2.5-4.5
Cardiomyopathy
MI
Stroke
What are some ADRs associated with warfarin?
Bleeding/bruising
- GI bleeding
- intracranial haemorrhage
- epistaxis
- injection site
Teratogenesis (advise in young, female patients)
Inform when to consult a doctor
Give anticoagulant card
How can warfarin be reversed?
Parenteral vitamin K (slow)
Fresh frozen blood (fast)
Prothrombin complex concentrate (fast)
Replace with heparin cover for 6 weeks
note: severe bleeding = stop warfarin and restart when INR is less than 5.0
What is heparin? What is its function? Outline its pharmacokinetics.
Pentasaccharide glycosaminoglycan with sulfate groups (-ve charge)
Produced by mast cells
Activates anti-thrombin III —> inhibits thrombin and Xa (+ IXa, XIa, XIIa)
Rapid onset and offset
Poor GI absorption (therefore give parenterally)
What is unfractionated hepatin?
~20kDa (mix of variable length chains)
Bolus then IV infusion (occasionally SC as prophylaxis - monitoring required via activated partial thromboplastin time)
Large enough to bind simultaneously to thrombin (IIa) and anti-thrombin III (catalyses inhibition of Xa)
Binds to cells and proteins (low bio-availability and unpredictable dose response)
What is low molecular weight heparin?
4-5kDa
Activates anti-thrombin III —> inhibits Xa
Too small to bind to thrombin (IIa) and anti-thrombin III (cannot catalyse inhibition of thrombin)
Given SC once or twice daily (NOT IM - causes muscular bleeding)
Higher bioavailability (90%+) than unfractionated heparin
Longer biological half life than unfractionated heparin
More predictable dose response than unfractionated heparin (does not bind to macrophages, endothelial cells, or plasma proteins)
Renal clearance
Less likely to cause thrombocytopenia
Usually no monitoring required
Give some examples of newer anti-coagulants apart from heparin and warfarin.
Selective factor Xa inhibitors e.g. fondaparinux
Direct thrombin inhibitors e.g. dabigatran