Anticoagulants

Overview

 

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

Warfarin is a coumarin anticoagulant, first discovered in spoiled sweet clover silage after causing hemorrhagic disease in cattle.

 

Indications

• stroke prevention in atrial fibrillation
• DVT/PE
• prosthetic valves

 

Mechanism

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.

 

 

Dose and Half Life

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.

 

 

Adverse Effects

short term

• can have transient hypercoagulant effects by blocking protein S and C (the shortest half-life)
• risk of major hemorrhage
• cutaneous necrosis can occur with reduced activity of protein C, leading to hypercoagulability. An erythematous macule leads to purpura and necrosis, predominantly on limbs, trunk, and penis. Immediately stop warfarin, give vitamin K and heparin IV, and consider FFP or protein C concentrate.

long term

• teratogen

 

Heparin

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.

 

 

Indications

• prevention of deep vein thrombosis
• treatment of acute venous thromboelmolism
• treatment of acute coronary syndrome

 

Mechanism

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.

 

Unfractionated

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.

Uses:

• acute DVT/PE
• arterial embolism
• prosthetic vaolves
• ACS
• DVT prophylaxsis

 

Low molecular weight heparin (enoxaparin, dalteparin, tinzaparin)

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.

 

Adverse Effects

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:

• active bleeding
• advanced renal/hepatic disease: creatinine clearance less than 30
• hemophilia
• thrombocytopenia
• purpura
• severe hypertension
• intracranial hemorrhage
• infective endocarditis
• active tuberculosis
• inflammatiry bowel disease
• visceral carcinoma

 

Clopidogrel

Clopidogrel is an anti-thrombotic agent that reduces platelet aggregation.

 

Indications

 

 

Mechanism

Clopidogrel irreversibly blocks the ADP receptor in platelets, preventing aggregation.

 

Dose and Half Life

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

 

Adverse Effects

• ttp: thrombotic thrombocytopenic purpura
• bleeding

There is a small but significant decrease in death and adverse events when given in addition to aspirin in ACS.

• in NSTEMI, NNT 48 (CURE trial, NEJM 2001)

 

Other Medications

 

Eptifibatide (Integrilin)

Integrilin is a platelet glycoprotein IIb/IIIa inhibitor

 

• GP2b3a inhibitors
• not being used widely in thrombolytic therapy due to increased risk
• tend to be reserved during PCI, especially in aptients with STEMI
• studies being done to see if they nave use upstream