0402 - Anticoagulants Flashcards
List Common Indications for anticoagulation
Primary Prevention of DVT or systemic embolism in high risk patients.
Treatment/Secondary prevention of DVT/PE, MI, extracorporeal circulation (e.g. dialysis, cardiac bypass), angioplasty
Describe the coagulation cascade
Extrinsic (PT), Intrinsic (APTT), and Common Pathways.
Cascade in which one factor can activate many of the next.
Large amounts of positive and negative feedback.
Outline the extrinsic coagulation pathway
Triggered by exposure to Tissue Factor. Activates VII to VIIa, which activates X to Xa, starting common pathway.
Outline the intrinsic coagulation pathway
Triggered by exposure to foreign surfaces. All substances contained within the blood.
TENET, with the last being X to Xa, starting the common pathway.
Outline the common coagulation pathway
Starts with X to Xa. This cleaves Prothrombin (II) to Thrombin (IIa), and Fibrinogen (I) to Fibrin (Ia), which polymerises to form the clot.
Describe the mechanism of action of Heparin.
Essentially it potentiates ATIII. Pentasaccharide portion binds to AT, which then leads to a conformational change in AT.
This conformational change accelerates AT’s ability to inactivate thrombin, Xa and IXa (going up the pathway).
Highly charged anion, which binds non-specifically to many other plasma proteins, with a poor predictability of dose response.
Describe the pharmacokinetics of Heparin
Absorption - Not orally absorbed - needs parenteral/IV administration. Massive variation in dose requires monitoring.
Distribution - Binds to serum proteins - highly negatively charged.
Metabolism - Short half life. Saturable (endothelial cells/macrophages depolymerise it), and non-saturable (Liver).
Excretion - Liver (main) and some renal.
Describe the mechanism of action of Warfarin.
Blocks the regeneration of oxidised Vitamin K. In turn, this means that carboxyglutamic acid residues can’t be added to the TV Factors and Proteins C and S, meaning they cannot bind to the phospholipid surface and participate in the coag cascade. Actual effects of warfarin are dependent on the half-life of the clotting factors.
Outline the pharmacokinetics of Warfarin.
Absorption - Rapidly absorbed from GI tract in 1.5-2hrs
Distribution - 99% bound to albumin, bioavailability changes with different protein levels.
Metabolism - Long half-life (40 hours), metabolised in liver by CYP2C9 (so lots of interactions)
Excretion - Renal
Outline the mechanism of action of LMWH
Binds to and potentiates ATIII , allowing better inactivation of II and Xa.
Predictable dose response if patient is dosed according to eight.
Outline the pharmacokinetics of LMWH
A - Parenteral/IV administration. More predictable dose than Heparin.
D - Less binding to protein, so more predictable response to weight-adjusted dose than heparin. Also doesn’t bind well to endothelial cells (longer plasma ½ life).
M - Principally cleared by renal route - ½ life prolonged in renal failure.
E - Renal
What are some complications of heparin therapy?
Most common - bleeding and heparin-induced thrombocytopenia (Types I and II).
Less common, osteoporosis (long term use), transaminitis, hypersensitivity reaction.
Outline the two types of heparin-induced thrombocytopenia.
Type 1 - 10-20% of pts. Non-specific binding of heparin to platelets 1-4 days after commencement of therapy. Management is to observe.
Type 2 - 1-3% of pts. Immune response following long-term use, onset at 5-10 days. Ig’s against Heparin/Platelet Factor IV complex can lead to thromboembolism in 30-80%. Need to cease heparin, start alternative anticoagulants, and manage other complications.
What are some complications of Warfarin therapy?
Haemorrhage major complication (avoid by monitoring INR)
Warfarin-induced skin necrosis (microclots as anticoagulant Protein C is hit early on) - start heparin at same time.
What are some complications of LMWH therapy?
Bleeding (particularly in renal impairment)
Thrombocytopenia (though less than with heparin)
only 50% reversed with protamine.
