see also:

• pharmacology main index
• historical perspectives
• warfarin
• heparin
• enoxaparin (Clexane)
• General anticoagulation guidelines
• antithrombotic Rx for prevention of stroke
• Mx of lower limb DVT
• atrial fibrillation
• anticoagulation
• RCH guidelines - anticoagulation therapy in children

• orally active agents that block the reductive re-activation of vitamin K epoxide back to its active hydroquinone form which is needed for the gamma-carboxylation of several glutamate residues in the formation of the serine protease factors VII, IX, X & II which are involved in the clotting cascade, as well as the formation of Protein C & Protein S which are anti-thrombotic factors.
• this results in partially inhibited synthesis of these vit-K dependant factors whose half-lives are 6, 24, 40 & 60hrs for factors VII, IX, X & II respectively, hence there is a 8-12hr delay in onset of anticoagulation effect & a 1-3day delay from peak drug level to peak INR.
• prothrombin time (INR) is prolonged by reduction in functional levels of fibrinogen, factor V, or the vit-K dependant factors II, VII or X.
• it is NOT affected by reductions in levels of factor IX, or proteins C or S.

• see warfarin

• Once popular but no longer used as occasionally fatal HS reactions.

• A very long acting agent prolongs INR for 20 days - used as a rodenticide

• Similar to warfarin, used in US but no clear advantages.

• The original oral anticoagulant isolated, seldom used as erratic absorption & GIT effects.

• Used in Europe, it had longer half-life (5 days) than warfarin & longer duration of action (7-10D)

• see enoxaparin

• introduced in Australia in 2009 as Xarelto
• see rivaroxaban
• an orally active Factor Xa inhibitor marketed as Xarelto as an option in the prevention and Rx of DVT & PE
• onset of action ~3hrs after dose and lasts 8-12hrs but factor Xa activity does not return to normal within 24hrs allowing once daily dosing
• usual dose in adults 10mg once daily orally
• C/I in severe liver or renal disease as partly metabolised and partly excreted in urine unchanged
• appears to prevent more DVTs than enoxaparin but major bleeding post THR was 0.3% in the rivaroxaban group vs 0.1% in the enoxaparin group
• no anticoagulant effect monitoring required in short term use
• no antidote for overdosage
• current trials underway for use in Mx of AF - will these reveal hepatotoxicity in longer term use as was the case with ximelagatran (another oral anticoagulant) or will we at last be able to offer patients a useful substitute for warfarin?

• see apixaban
• oral reversible factor Xa inhibitor although there is no antidote to Mx bleeding complications
• introduced in Australia on PBS in 2011 as Eliquis 2.5mg film-coated tablets for prevention of post-op DVT, and in Sept 2013 for prevention of stroke in patients with non-valvular AF.

• see dabigatran
• Dabigatran is a potent, competitive and reversible direct thrombin inhibitor used in prevention of deep venous thrombosis (DVT) in orthopaedic surgery, and may be useful instead of warfarin for prevention of stroke in patients with atrial fibrillation

• see antiplatelet agents

• Heparin was discovered in 1915 by Jay McLean, searching for a pure procoagulant in dog liver & heart, but finding anticoagulants instead. McLean's insight & perserverence in pursuing this strange lead resulted in the discovery of heparin which became the standard Rx for a variety of thrombotic disorders in the 1940's.
• see heparin

• does not inhibit clot-bound thrombin, but safer than heparin.
• inhibit factors Xa & IIa
• given s/c
• therapeutic monitoring not required
• immediate onset
• protamine only partially reverses bleeding effect
• high cross reactivity with heparin
• can cause thrombocytopenia

• see enoxaparin

• as for LMW heparins BUT:
  • low cross-reactivity with heparin
  • minimal effect on platelets
  • bleeding effects not reversed by protamine

• A powerful & specific thrombin inhibitor derived from the leech & now prepared by recombinant DNA technology. Its action is independent of antithrombin III which means it can reach & inactivate fibrin-bound thrombin in thrombi.
• It has little effect o platelets or bleeding time.
• Like heparin it must be given parenterally & is monitored by APTT. Its half-life is 90mins.

• Is a 20 AA synthetic peptide inhibitor of thrombin designed using hirudin as a model.
• It inhibits free & clot-bound thrombin & thus prevents clot formation & extension.
• It may also facilitate clot lysis. It has a half life of 30min.
• It has comparable potency to hirudin, but being a synthetic molecule has less risk of antigenicity. It may be a better inhibitor of clot-bound thrombin due to its size.

• direct inhibitor of thrombin related to hirudin that reversibly binds to thrombin stopping the conversion of fibrinogen to fibrin.
• introduced in Australia in 2005 for use in cardiac angioplasties but still controversial cost:benefit over heparin.
• effects begins within a few minutes of IV dose, increasing clotting time, APTT, prothrombin time & thrombin time.
• half life 25min thus given as bolus followed by infusion
• 20% is renally excreted so renal impairment prolongs half-life.
• REPLACE-II trial showed it reduced major bleeding in coronary angioplasties from 4.1% when using heparin + glycoprotein inhibitor + aspirin, to 2.5% when using bivalirudin + glycoprotein inhibitor + aspirin