This page contains a Flash digital edition of a book.
Introduction: Factor Xa


XIIa XI IX


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.


4


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


www.hospitalpharmacyeurope.com


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


Thrombin


Vlla TF


VKA X Prothrombin


VIIIa IXa


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36