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January, 1998



Franklin A. Bontempo, M.D.
Medical Director
Coagulation Laboratory


Traditionally, the anticoagulants available for clinical use have consisted of standard unfractionated heparin (UFH), warfarin (Coumadin), and aspirin (ASA). Recently, several new anticoagulants have been released for use in the U.S. or are about to be. Characteristics, indications, and where possible, doses of these new anticoagulants are reviewed.


Low Molecular Weight Heparins

Three low molecular weight (LMW) heparins have been released in the U.S., enoxaparine (Lovenox), dalteparin (Fragmin) and ardeparin (Normoflo). LMW heparins are fractionated pieces of the regular heparin molecule which differ depending on the part of the molecule isolated. Compared to UFH, they are longer acting, more homogeneous molecules, with a more reliable dose-response curve requiring little or no monitoring, and a lower incidence of heparin-induced thrombocytopenia, but are much more expensive. They do not appear to cross the placenta and can probably be used safely in pregnancy. At present, all the LMW heparins should be viewed as separate drugs since their doses, actions, and indications may differ.

Enoxaparine (Lovenox) - approved for use as deep venous thrombosis (DVT) prophylaxis in hip and knee surgery where they are probably better than many anticoagulant regimens. The dose is 30 mg SQ q12h usually starting 12 hours post-operatively. Small studies have also shown benefit in patients with cancer and unstable angina. Though not approved for treatment of established clots, excellent randomized trials have shown equivalent results for outpatient enoxaparine vs. inpatient IV UFH when both are used with oral anticoagulants in patients with deep venous thromboses and pulmonary emboli. The treatment dose for established clots is 1 mg/kg SQ q12h. Protamine may be used for overdosage at a dose of 1 mg per mg of enoxaparine.

Dalteparin (Fragmin) - another LMW heparin, approved for post-operative DVT prophylaxis in abdominal surgery with once daily dosing of 2500 U SQ. Protamine may be used for overdosage at a dose of 1 mg per 100 units of dalteparin.

Ardeparin (Normiflo) - recently released in the U.S. for DVT prophylaxis in patients undergoing hip and knee surgery. The dose is 50 U/kg SQ q12h. Protamine may be used for overdosage at a dose of 1 mg per 100 units of ardeparin.

Danaparoid (Orgaran) - recently approved for use in the U.S., represents a breakthough for use in patients with heparin-induced thrombocytopenia since the cross-reactivity with UFH is reported to be only 6-10%. Danaparoid is a heparin-like substance with anticoagulant activity. The half-life is 24 hours after SQ administration with peak effect at 2-5 hours but dosing is q12h to maintain maximum anithrombotic activity. The prophylactic dose is 750 mg SQ q12h and the dose for treatment of established clots is 1250 SQ q12h. Monitoring is usually not required although the anti-factor Xa assay can be used. There is no known antidote for reversal of its effect.

Ticlopidine (Ticlid) - is an oral platelet antagonist which has been found to be useful in patients with unstable angina and for prevention of stroke in patients with transient ischemic attacks. It is also of benefit in patients with coronary artery stents when used in conjunction with ASA for 40 days.

Ticlopidine exerts its antiplatelet action for the life of the platelet, i.e. 10 days and may cause prolongation of the bleeding time. It should be stopped 10-14 days prior to surgery. Side effects of ticlopidine include nausea, diarrhea, and neutropenia. The latter may require its discontinuation and monitoring white blood counts every 2 weeks during the first three months therapy is necessary. Recent reports have clearly indicated that ticlopidine is also associated with thrombotic thrombocytopenic purpura (TTP). The standard dose is 250 mg PO q12h. Overdosage has not been a clinical problem but prolonged bleeding times with ticlopidine may be normalized with methylprednisolone at a dose of 20 mg IV.

Hirudin is a direct thrombin inhibitor derived from leech venom available in both natural and recombinant forms. Recent studies indicate that a hirudin derivative may be superior to enoxaparine for DVT prophylaxis after total hip replacement. Use of hirudin for other indications has been limited by an increased rate of hemorrhagic stroke in some studies and it has not yet been approved for use in the U.S. Hirudin is administered intravenously and prolongs the APTT. It has no known antidote.

Argatroban (Novastan) - is a synthetic arginine derivative that competitively inhibits thrombin, both soluble and thrombus-bound, has a half-life of only a few minutes, and is administered intravenously. It was developed for use in patients with heparin-induced thrombocytopenia, is not currently released for general use, but is available for compassionate use on clinical protocol. The APTT is used for monitoring argatroban and currently there is no known cross-reactivity with heparin in patients with heparin-induced thrombocytopenia.

Abciximab (ReoPro) is a human-mouse monoclonal antibody for intravenous infusion which binds to the glycoprotein IIb/IIIa receptor on human platelets and inhibits platelet aggregation. It may markedly prolong the bleeding time and while it has a half-life of only 10 minutes, low levels of glycoprotein IIb/IIIa receptor blockade may be present for up to 10 days after infusion. The major indication for abciximab is as adjunctive therapy with heparin and aspirin for prevention of abrupt coronary vessel closure after angioplasty. The major side effects are bleeding and thrombocytopenia ( 5%) and caution must be taken in patients with any predisposing bleeding risks. The dose is 0.25 mg/kg IV given as a bolus 10-60 minutes prior to the start of angioplasty followed by an infusion of 10 microgm (.01 mg)/min IV for 12 hours.

Tirofiban (Aggrastat, MK-383) - is a synthetic glycoprotein IIb/IIIa inhibitor for intravenous use that should soon be approved for use in the U.S. for unstable angina and as an adjunct to heparin and aspirin therapy in coronary angioplasty. It is also currently being studied in an oral form.

Copyright 1998, Institute For Transfusion Medicine


For questions regarding the New Anticoagulants, please contact
Franklin A. Bontempo, M.D. at: (412) 209-7322

Copies of the Transfusion Medicine Update can be obtained by contacting
Deborah Small at (412) 209-7320