acetylsalicylic acid - prevents formation of thromboxane A2, important in platelet secretion and aggregation
heparin - catalyzes the activity of antithrombin III
clopidogrel - blocks platelet ADP receptor
warfarin - inactivates vitamin K regeneration and thereby clotting factor formation
Warfarin is a coumarin anticoagulant, first discovered in spoiled sweet clover silage after causing hemorrhagic disease in cattle.
Warfarin blocks the regeneration of vitamin K by blocking the liver enzyme epoxide reductase. Vitamin K is required for the carboxylation of several glutamate residues in prothrombin, factors VII, IX, and X, as well as anticoagulant proteins S and C. Accordingly, the presence of warfarin results in the incomplete, inactive clotting factors, reducing blood clotting capability.
Treatment should be initiated with small daily doses of 5mg x 3 days. Initial adjustment of prothrombin time is about 1 week, and PTT should be increased to a level representing 25% of normal activity. If activity is less than 20% dosage should be reduced or omitted until it again rises.
Therapeutic range is now defined by international normalized ratio (INR), which is the PTT ratio of test/control using an international reference.
For atrial fibriallation, aim for an INR between 2-2.5, and 2.5-3.5 for prosthetic valves.
Warfarin binds to plasma albumin, leading to small space of distribution, long plasma half-life (36 hours), and lack of urinary excretion.
There is an 8-12 hour delay in the action of warfarin, as anticoagulation is dependent on the degradation rate of active clotting factors. Half-lives for factors VII, IX, X, and II are 6, 24, 40, and 60 hours, respectively.
Heparin is a potent anticoagulant. There are a number of types of heparin, including unfractionated and low-molecular-weight.
It is a hetogeneous mixture of sulfated polysaccarides which bind to enfothelial cell surfaces.
Heparin's actions depends on antithrombin III, which inhibits pro-coagulant proteases such as thrombin and factors Xa, IXa, XIa, and XIIa by binding with them in 1:1 ratios. In the absence of heparin these reactions are slow. Heparin accelerates them by 1000x by inducing a conformational change in AT III, exposing its active site and facilitating its binding with clotting factors.
Heparin acts as a catalyst to increase AT III binding with proteases. Once this binding has occurred, heparin is released to bind further AT III molecules.
Regular, high molecular weight heparin (HMWH) is shorter acting, and cheaper.
Can be stopped as it's on a drip. Can be reversed with protamine, though be cautious, as too much protamine acts as an anticoagulant.
LMWH inhibits activated factor X, but has less activity on AT III. They are effective in preventing DVT postoperatively, in the treatment of acute coronary syndromes, and fir acute venous thromboembolic disease.
LMWH have increased bioavailability and less frequent dosing (1-2x daily).
INR/PTT does not change with LMWH.
The major adverse effect of heparin in bleeding, with a ~ 3% risk of hemorrhage.
Heparin-induced thrombocytopenia (HIT), occurring by inducing platelet activation and aggregation, occurs in ~25% of patients. It can be severe in 5% of people. It can occur with any form or route of administration, though is less common with LMWH.
Heparin is contraindicated in patients with:
Clopidogrel is an anti-thrombotic agent that reduces platelet aggregation.
Clopidogrel irreversibly blocks the ADP receptor in platelets, preventing aggregation.
In patients with MI, initiate early, with 300 mg loading dose and 75 mg once daily
omit 300 mg loading dose in STEMI patients over 75 years receiving thrombolyitc therapy
optimal duration of therapy is controversial, typically 1-12 months
There is a small but significant decrease in death and adverse events when given in addition to aspirin in ACS.
Integrilin is a platelet glycoprotein IIb/IIIa inhibitor