New Anticoagulation Targets

Direct Factor Xa inhibitors: a promising approach

Based on preclinical and clinical trial data published to date, direct Factor Xa inhibitors have the potential to advance the field of anticoagulant therapy. Many features of direct Factor Xa inhibition make this a promising approach to the problem of thrombosis.

Factor Xa occupies a critical juncture in the coagulation process

Factor Xa also is an attractive target for the design of new anticoagulants as Factor Xa is positioned at the start of the common pathway of coagulation. As the amount of serine protease is amplified at each step of the cascade, it has been hypothesized that the selective inhibition of coagulation factors above thrombin might be a highly effective antithrombotic strategy.

Sylvia Haas, MD

Professor of Medicine and former Director of the Haemostasis and Thrombosis Research Group at the Institute for Experimental Oncology and Therapy Research, Technical University of Munich, Germany

Factor Xa occupies a critical juncture in the coagulation process. It converts prothrombin (Factor II) to thrombin (Factor IIa). Consistent with the observation that coagulation progresses in an amplified manner, one molecule of Factor Xa catalyses the formation of approximately 1000 molecules of thrombin^{15, 16}
Inhibition of Factor Xa can effectively prevent both platelet-rich arterial thrombi and fibrin-rich venous thrombi⁸⁸

Factor Xa has well-recognised, specific physiologic activity

The only known functions of Factor Xa are to promote coagulation and inflammation. Therefore, in contrast to thrombin inhibition, blocking Factor Xa is less likely to have pleiotropic effects¹⁷
Selective inhibition of Factor Xa can inhibit thrombin generation while allowing existing thrombin to continue its vital functions in normal haemostasis¹⁷

Direct Factor Xa inhibitors: comparison with indirect Factor Xa inhibitors

Indirect Factor Xa inhibitors, such as fondaparinux, require antithrombin as a cofactor and do not inhibit Factor Xa bound to the prothrombinase complex. In contrast, direct Factor Xa inhibitors directly engage the active centre of the Factor Xa molecule and inhibit both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex¹⁷
Factor Xa activates clotting over a wider concentration range than thrombin, in both in vitro and in vivo systems. Consequently, direct Factor Xa inhibitors may have a wider therapeutic window than thrombin inhibitors. A wider therapeutic window may reduce the need for coagulation monitoring, which would be a major advantage over warfarin¹⁷

Factor Xa inhibitors in development

Direct Factor Xa inhibitors in development have many properties of an ideal anticoagulant, including oral administration, rapid onset of action, and predictable pharmacokinetics and pharmacodynamics.^{17, 89}

A number of small-molecule, orally administered direct Factor Xa inhibitors are currently in development. These include rivaroxaban, apixaban, betrixaban and a group of as yet unnamed clinical entities (LY517717, YM150 and DU-176b). At present, the clinical trial program for rivaroxaban is the most advanced.^{17, 89} Rivaroxaban has been approved in September 2008 in the European Union for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.¹⁵³

EU marketing approval for rivaroxaban was received on Sept 30th 2008 following a review of data from the extensive RECORD clinical programme that included three Phase III trials of rivaroxaban involving nearly 10,000 patients undergoing elective hip or knee replacement surgery (RECORD1, 2 and 3 trials).
Results from these three studies demonstrated the superior efficacy of rivaroxaban, both in head-to-head comparisons with enoxaparin (RECORD1 and 3) as well as when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin (RECORD2). In all three trials, rivaroxaban and enoxaparin had comparable safety profiles including low rates of major bleeding.¹⁵³

An early evaluation of results from the ADVANCE-1 study of apixaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement indicates that the primary endpoint of this study was not met.¹⁵⁴

Direct thrombin inhibitors

Thrombin has a central role in the coagulation cascade. Produced in small amounts in the initiation phase and large amounts in the propagation phase, thrombin is essential for the amplification of coagulation and fibrin formation.^{15, 88}

Parenteral direct thrombin inhibitors currently available for clinical use ― lepirudin, bivalirudin, and argatroban ― are generally reserved for the treatment of patients with heparin-induced thrombocytopenia. These medications are administered parenterally and require individual dosing based on lab monitoring.⁸⁸

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 [VKAs]) 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 oral direct 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. Administration of both 150 and 220 mg dabigatran was demonstrated to be as effective and safe as enoxaparin (40 mg) in preventing VTE and all cause mortality in the RE-NOVATE™ and RE-MODEL™ trials, respectively. Another agent in this class, TGN167, is currently in clinical development.^{88, 132}

In contrast to Factor Xa, thrombin has pleiotropic effects. Activation of protein C that is mediated by thrombin-thrombomodulin inhibits both coagulation and inflammation.¹⁷

Tissue Factor (TF) VIIa complex

The TF-VIIa complex initiates the coagulation process. Exposure of TF during orthopaedic surgery and in certain patients with cancer may contribute to the high rates of VTE in these groups. TF-VIIa therefore presents a possible target for pharmacologic therapy.⁸⁸

Nematode anticoagulant proteins, which inhibit the TF-VIIa/FXa complex, are currently being explored for VTE prophylaxis in orthopaedic surgery.⁸⁸

Factor IXa

Theoretically, the advantages of Factor IXa inhibition should be similar to those anticipated for Factor Xa inhibition (ie, blocking an early stage of coagulation amplification, effectiveness in both arterial and venous thromboembolic disease).⁸⁸ Since most of Factor Xa is produced by the intrinsic “tenase,” which includes Factor IXa, targeting Factor IXa may be an effective approach to anticoagulation.^{13, 135} Research in this area, however, is not as advanced as research into Factor Xa inhibition. An oral direct Factor IXa inhibitor, TTP889, is currently in clinical trials for VTE prevention in orthopaedic surgery.⁸⁸

Factors V and VIII

Activated Factors V and VIII serve as cofactors in the prothrombinase and extrinsic “tenase” complexes, respectively. These factors are the targets of the natural anticoagulant activated protein C, a key element of the physiologic thrombomodulatory system. Inhibition by pharmacologic means of one of these factors could potentially block coagulation propagation.^{6, 135}

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Article references

15 - Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21(1):1-11.
16 - Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504-1514.
88 - Spyropoulos AC. Investigational treatments of venous thromboembolism. Expert Opin Investig Drugs. 2007;16(4):431-440.
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.
89 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
153 - Bayer’s Novel Anticoagulant Xarelto® now also Approved in the EU [press release]. Leverkusen, Germany: Bayer HealthCare AG; October 1, 2008; Available at http://www.press.bayer.com/baynews/baynews.nsf/id/4107FE412DC2C1A3C12574D5002C8130?Open&ccm=001
154 - Bristol-Myers Squibb and Pfizer Provide Update on Apixaban Clinical Development Program [press release]. PRINCETON, N.J. & NEW YORK: Bristol-Myers Squibb Company & Pfizer Inc.; August 26, 2008; Available at http://newsroom.bms.com/article_display.cfm?article_id=5371
132 - Novel oral anticoagulant Pradaxa (dabigatran etexilate) approved by the European Commission [press release]. Available at http://www.fiercebiotech.com/press-releases/novel-oral-anticoagulant-pradaxa-dabigatran-etexilate-approved-european-commission. Accessed April 10, 2008.
13 - Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003;23(1):17-25.
135 - Bates SM, Weitz JI. New antithrombotic drugs. In: Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1763-1783.
6 - Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ. Overview of hemostasis. In: Colman RW, Clowes AW, George JN, Goldhaber SZ, Marder VJ, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2006:1-16.

Factor Xa: The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
Prothrombin: Factor II, also called prothrombin, is converted into thrombin as part of the coagulation cascade.
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.
Pleiotropic: Producing many effects in addition to primary one
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.
Coagulation monitoring: Coagulation monitoring is practice of checking a specific coagulation parameter in order to adjust the dose. A precise adjustment of the drug intake allows the patient to stay within a defined therapeutic range, which is measured by prothrombin time or International Normalized Ratio (INR).
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.
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).
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.
Enoxaparin: A low-molecular-weight heparin currently regarded as the standard of care for VTE prevention in orthopaedic surgery. Enoxaparin is administered by subcutaneous injection and is associated with a low risk of heparin-induced thrombocytopaenia.
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.
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.
Prophylaxis: The prevention of a disease or pathological condition.