Single Coagulation Factor Inhibitors
Indirect Factor Xa inhibitors
Fondaparinux is a synthetic indirect inhibitor of Factor Xa. Its structure is based on the natural pentasaccharide contained within heparin and low-molecular-weight heparins (LMWHs). It potentiates the rate of neutralisation of Factor Xa by antithrombin. Unlike heparin, fondaparinux does not inactivate thrombin. In addition, fondaparinux does not inhibit Factor Xa bound in the prothrombinase complex and therefore does not completely inhibit Factor Xa. Long-term use is limited by the requirement of subcutaneous injection.17, 105
Bleeding is the most common adverse event with fondaparinux, with major bleeding occurring at about the same rate as seen with patients treated with LMWHs. Unlike the heparins, however, protamine cannot be used to reverse the effect of fondaparinux when bleeding is excessive.105
Direct thrombin inhibitors
In the final steps of the coagulation cascade, thrombin converts fibrinogen to fibrin. Fibrin-bound thrombin remains active and continues to promote thrombus expansion. The heparin-antithrombin complex does not inactivate fibrin-bound thrombin. In contrast, direct thrombin inhibitors do not require antithrombin and can inactivate the clot-bound thrombin.106
Parenteral direct thrombin inhibitors are used during percutaneous coronary interventions (PCIs) and to treat or prevent thrombosis in patients with heparin-induced thrombocytopenia (HIT). Three such medications are currently in clinical use — lepirudin, bivalirudin, and argatroban. These drugs differ with respect to thrombin binding sites, reversibility, pharmacology, and specific indications.106
The first oral direct thrombin inhibitor available for clinical use was ximelagatran. This medication represented a major advance over existing oral anticoagulants (eg, vitamin K antagonists) because it did not require anticoagulant monitoring or dose adjustments. In clinical trials for venous thromboembolism (VTE) prevention and treatment, ximelagatran was either more effective than or comparable to warfarin. However, safety monitoring revealed liver toxicity in 6% of patients. For this reason, use of the drug was discontinued in 2006.88
A second direct oral thrombin inhibitor, dabigatran etexilate, was approved for marketing in the European Union in March 2008 for primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to its active principal dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Further studies in stroke prevention in atrial fibrillation (AF) and other thromboembolic conditions are under way.89
reddit
Facebook
del.icio.us
blinklist
newsvine
Yahoo! My Web
digg
StumbleUpon
Propellor
Mixx
Google Bookmarks
Windows Live- 17 - Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27(6):1238-1247.
- 105 - Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost. 2005;3(8):1843-1853.
- 106 - Frenkel EP, Shen YM, Haley BB. The direct thrombin inhibitors: their role and use for rational anticoagulation. Hematol Oncol Clin North Am. 2005;19(1):119-145, v-vii.
- 88 - Spyropoulos AC. Investigational treatments of venous thromboembolism. Expert Opin Investig Drugs. 2007;16(4):431-440.
- 89 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
- Antithrombin
- Antithrombin, also known as antithrombin III, is the most important member of a larger family of antithrombins. It is a small protein molecule (a glycoprotein) produced in the liver that binds to a specific pentasaccharide sequence on heparin. This binding to heparin leads to an anticoagulant effect through two different mechanisms: It causes a conformational change in antithrombin that allows antithrombin to bind to and thereby inhibit Factor Xa, which leads to a subsequent decrease in thrombin levels It causes a direct increase of thrombin inhibition as a result of antithrombin binding to the heparin pentasaccharide sequence and thrombin binding to an adjacent segment of heparin at the same time.
- Factor Xa
- The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
- Fondaparinux
- An indirect Factor Xa inhibitor comprising a synthetic pentasaccharide sequence matching the part of the heparin molecule that binds to antithrombin. It is administered by subcutaneous injection.
- Heparin
- An anticoagulant that exerts its activity by binding to antithrombin and greatly increasing its activity. The principal coagulation factors inhibited by heparin are Factors IIa and Xa. It is administered by intravenous or subcutaneous injection.
- Prothrombinase complex
- The prothrombinase complex consisting of the coagulation factors Xa and Va, phospholipid and calcium catalyzes the conversion of prothrombin (Factor II) to thrombin (Factor IIa).
- Subcutaneous
- Below the skin.
- Thrombin
- Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.
- Coagulation cascade
- Series of reactions by which a small stimulus is amplified to produce rapid coagulation.
- Fibrin
- The primary end product of the coagulation cascade. Fibrin links itself into strands to form a net. This net traps blood cells and tightens itself through cross-linkages, resulting in a dense blood clot.
- Parenteral
- Not through the alimentary canal but rather by injection through another route.
- Vitamin K
- An essential cofactor in the carboxylation of glutamic residues on the procoagulant forms of Factors II, VII, IX, and X. This ultimately leads to increased formation of thrombin and fibrin.
- Warfarin
- A vitamin K antagonist. Most commonly used oral anticoagulant in chronic prevention or treatment of VTE.
- Venous thromboembolism
- A condition in which a blood clot (thrombus) forms in a vein, which in some cases then breaks free and enters the circulation as an embolus, finally lodging in and completely obstructing a blood vessel, e.g., in lungs causing a PE. The term encompasses both DVT and PE.
- Ximelagatran
- Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acted by directly inhibiting the actions of thrombin. Ximelagatran was withdrawn in February 2006 following safety data suggesting hepatotoxicity of the drug and that severe liver damage could develop after withdrawal.
- Dabigatran
- The active form of the prodrug dabigatran etexilate, an oral direct thrombin inhibitor.
Search