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Introduction: Factor Xa


Fondaparinux Idraparinux Apixaban Edoxaban Rivaroxaban

Antithrombin LMWH UFH TF: tissue factor; VKA: vitamin K antagonist; UFH: unfractioned heparin; LMWH: low-molecular weight heparin Figure 2: Mechanisms of action of Factor X/Xa inhibitors.

series of proteolytic reactions that are initiated when cell-bound tissue factor becomes exposed at sites of vascular injury to circulating factor VIIa (Figure 1). Tissue factor binds circulating factor VIIa to form an enzyme complex that activates factor X and factor IX (generating factor Xa and factor IXa). The FVIIIa/FIXa complex, also called ‘intrinsic tenase’, and the Factor Va/Xa complex (prothrombinase) assemble on the surface of activated platelets, accelerating the generation of Factor Xa and thrombin. The resulting burst of thrombin generation cleaves fibrinogen to form fibrin in sufficient quantities to allow for clot formation. Thus, factor X activation is essential for the propagation of coagulation.


The unique position of Factor Xa at the junction of different pathways of the coagulation cascade makes it an attractive target for anticoagulation. Indeed, first results from preclinical experiments performed with the naturally occurring Factor Xa inhibitors antistatin and tick anticoagulant peptide (isolated from leeches and ticks, respectively) confirmed the suitability of Factor Xa inhibition as a mode of

anticoagulation and further fuelled the development of factor-specific inhibitors.

Factor Xa inhibition as a therapeutic target Until a decade ago, the available anticoagulants (essentially heparin, vitamin K antagonists (VKAs) and low-molecular weight heparins (LMWHs)) were multi-target drugs acting on multiple coagulation factors. Newer drugs designed for antithrombotic therapy are available, which are more selective in their action by specific inhibition of coagulation factors such as Factor Xa.4

The mechanisms of Factor

Xa inhibitors in current use are shown in Figure 2. According to the clinical context, the ideal anticoagulant would be administered orally, with predictable dose response and pharmacokinetics, a wide therapeutic window, without the need for monitoring of anticoagulant effect, and without haemorrhagic side effects.5

Heparin derivatives Unfractionated heparin (UFH) Probably the oldest anticoagulant drug to be identified and manufactured is

heparin, which was already commercially available in the 1920s.6

Heparin consists

of highly sulfated polysaccharide chains with a molecular weight ranging from 3000–30,000 Dalton (Da), with a mean of approximately 15,000 Da. Heparin requires the presence of antithrombin to exert its anticoagulatory effect. Only one-third of the polysaccharide chains (comprising in total more than 18 saccharide units) possess the corresponding sequence that exhibits high affinity for antithrombin, which catalyses the inhibition of the serine proteases, Factor II, VII, IX, and X. The non-linear kinetics of heparin clearance are mainly due to initial non-specific binding to different cell types, such as endothelial cells or platelets, as well as its renal elimination.7

Protamine sulfate

quickly reverses the anticoagulatory effect of heparin. Initially derived from hepatic tissue, it is now mainly manufactured from porcine intestinal tissue or synthesised. Heparin is administered either subcutaneously or intravenously; however, when administered subcutaneously, higher doses of UFH are needed to overcome the much lower bioavailability

Fibrinogen Fibrin XIa IXa

Xa Va


Vlla TF

VKA X Prothrombin


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