Anticoagulant Agents

1. Heparin: enhances activity of antithrombin III; parenteral agent of choice. LMWH is the preparation of choice (enoxaparin or dalteparin). It can be administered SC, monitoring of the PTT is unnecessary, and it is less likely to induce antibodies and thrombocytopenia. The usual dose is 100 U/kg SC bid. Unfractionated heparin should be given only if LMWH is unavailable. In adults, the dose of unfractionated heparin is 25,000-40,000 U continuous IV infusion over 24 h following initial IV bolus of 5000 U; monitor by following PTT; should be maintained between 1.5 and 2 times upper normal limit. Prophylactic anticoagulation to lower risk of venous thrombosis recommended in some pts (e.g., postoperative, immobilized). Prophylactic doses of unfractionated heparin are 5000 U SC bid or tid. Major complication of unfractionated heparin therapy is hemorrhage—manage by discontinuing heparin; for severe bleeding, administer protamine (1 mg/100 U heparin); results in rapid neutralization.
2. Warfarin (Coumadin): vitamin K antagonist, decreases levels of factors II, VII, IX, X, and anticoagulant proteins C and S. Administered over 2-3 days; initial load of 5-10 mg PO qd followed by titration of daily dose to keep PT 1.5-2 times control PT or 2-3 times if the International Normalized Ratio (INR) method is used. Complications include hemorrhage, warfarin-induced skin necrosis (rare, occurs in persons deficient in protein C), teratogenic effects. Warfarin effect reversed by administration of vitamin K; FFP infused if urgent reversal necessary. Numerous drugs potentiate or antagonize warfarin effect. Potentiating agents include chlorpromazine, chloral hydrate, sulfonamides, chloramphenicol, other broad-spectrum antibiotics, allopurinol, cimetidine, tricyclic antidepressants, disulfiram, laxatives, high-dose salicylates, thyroxine, clofibrate. Some pts who are sensitive to warfarin effects have genetic defects metabolizing the drug. Antagonizing agents include vitamin K, barbiturates, rifampin, cholestyramine, oral contraceptives, thiazides.
3. Fondaparinux: a pentapeptide that directly inhibits factor Xa. It is given at a dose of 2.5 mg SC daily for prophylaxis and 7.5 mg SC daily for treatment of thrombosis and does not require monitoring. Unlike the heparins, it does not bind to platelet factor 4 and does not elicit the antibodies that produce HIT. Apixaban and rivaroxaban are oral factor Xa inhibitors. Apixaban (5 mg PO bid) as effective as warfarin in DVT and more effective in stroke prevention in atrial fibrillation (AF).
4. Argatroban and lepirudin: direct thrombin inhibitors. These agents are being compared to LMWH and are commonly used in pts with HIT. Both are monitored with the activated PTT. Dabigatran (150 mg PO bid) is an oral thrombin inhibitor and is non-inferior to warfarin in both DVT and stroke prevention in AF.

In-hospital anticoagulation is usually initiated with heparin for 4-10 days, with subsequent maintenance on warfarin after an overlap of 3 days. Duration of therapy depends on underlying condition; calf DVT with clear precipitating cause, 3 months; proximal or idiopathic DVT or PE, 6-12 months; recurrent idiopathic DVT, 12 months minimum; embolic disease with ongoing risk factor, long term, indefinite. The new oral Xa and thrombin inhibitors are easier to use than warfarin but much more expensive. They are at least comparably effective, have lower bleeding rates, and do not require laboratory monitoring. Reversal agents are in development.