The Central Role of Factor Xa
The importance of selectivity
Activated Factor X (Factor Xa) is a central component of the prothrombinase complex, which converts large amounts of prothrombin
(Factor II) to thrombin
, described as the “thrombin burst”. One molecule of Factor Xa
catalyses the formation of approximately 1,000 thrombin
molecules.25, 26, 27
Studies have demonstrated an increase in the anticoagulant efficacy
of heparin-based drugs as their selectivity for Factor Xa
- Low-molecular-weight heparins (LMWHs) have a higher ratio of Factor Xa-to-thrombin inhibition than unfractionated heparin (UFH)
- Numerous clinical trials have shown that the LMWHs provide more effective thromboprophylaxis after orthopaedic surgery than UFH. Along this line of argumentation, fondaparinux, which is a selective indirect inhibitor of Factor Xa, has been shown to be superior to LMWHs after orthopaedic surgery.26
Thus inhibition of Factor Xa
prevents clot formation more effectively than does inactivation of thrombin
. In addition, inhibition of Factor Xa
has an antithrombotic effect, without affecting existing thrombin
levels. This remaining thrombin
should be sufficient to ensure primary haemostasis, resulting in a favourable safety margin.26, 28
For these reasons, development of medications that directly inhibit Factor Xa
has been an active and promising area of pharmaceutical research.26
Xarelto® is a direct and highly selective inhibitor of Factor Xa
Xarelto is a synthetic small molecule that selectively targets Factor Xa
, the activated form of Factor X. It prevents the formation of a thrombin
burst by regulating the coagulation cascade
at the point of amplification. In the European Union, Xarelto is approved for the prevention of venous thromboembolism
in adult patients undergoing elective hip or knee replacement surgery.1, 8
Direct effect of Xarelto versus indirect inhibition by heparins and their derivatives
Xarelto inhibits both free and fibrin-bound Factor Xa
, as well as the prothrombinase complex. In contrast, the heparins (UFH, LMWH) and fondaparinux inhibit indirectly by binding to antithrombin. They can not directly inhibit Factor Xa
as part of the prothrombinase complex that catalyses the formation of approximately 1,000 thrombin
A higher efficacy
of direct Factor Xa
inhibitors can therefore be expected. Indeed, Xarelto was able to demonstrate significantly superior efficacy
versus the indirect inhibitor enoxaparin in the clinical RECORD programme (NOTE: RECORD2 compared Xarelto 35±4 days after surgery with enoxaparin 12±2 days after surgery) for the prevention of venous thromboembolism
(VTE) in patients undergoing elective hip or knee replacement surgery.2, 3, 4, 9, 26
- 25 - Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504-1514.
- 26 - 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.
- 27 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
- 28 - Leadley RJ Jr. Coagulation factor Xa inhibition: biological background and rationale. Curr Top Med Chem. 2001;1(2):151-159.
- 1 - Xarelto® (rivaroxaban) Summary of Product Characteristics as approved by the European Commission.
- 8 - Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs. 2006;15(8):843-855.
- 2 - Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
- 3 - Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39.
- 4 - Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
- 9 - International Congress on Thrombosis: Rivaroxaban is first novel oral anticoagulant to significantly reduce the composite outcome of symptomatic VTE and death [press release]. Leverkusen, Germany: Bayer HealthCare AG; June 30, 2008.
- Factor Xa
- Pivotal component of blood clotting cascade. Stimulates the production of thrombin, the enzyme in the coagulation cascade that promotes the formation of blood clots.
- Inactive version of thrombin, the enzyme in the coagulation cascade that promotes the formation of blood clots. Factor Xa stimulates the conversion of prothrombin to thrombin.
- Enzyme in the blood clotting cascade that promotes the formation of blood clots.
- The ability of a drug to produce the desired effect.
- Preventative treatment for blood clotting.
- Coagulation cascade
- A chain of biochemical reactions that result in clot formation. Anticoagulants work by blocking or regulating a stage, or stages, of the coagulation cascade.
- Venous thromboembolism
- A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.