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Introduction: Factor Xa

(approximately 30%).

LMWHs LMWHs are derived from UFH by enzymatic depolymerisation, which generates polysaccharide chains with a molecular weight ranging from 2000 to 9000.8

Similar to UFH, LMWHs exert their antithrombotic effect through binding to antithrombin. However, the majority of LMWH molecules are too short to catalyse thrombin inhibition, but retain factor Xa inhibition, and as a result, exert a higher specificity towards factor Xa inhibition than UFH.7,8


shorter polysaccharide chains exhibit less non-specific plasma- and endothelial binding, and therefore display far more predictable pharmacokinetics. However, under certain circumstances, such as in patients with moderate renal failure, obesity or in pregnancy, monitoring of anticoagulation may be recommended. In these cases anti-FXa levels can be used to monitor anticoagulation.


These plasma proteins participate in calcium-dependent phospholipid membrane interactions, which are mediated through the presence of gamma-carboxyglutamyl residues in

Oral anticoagulation with coumarins has been a mainstay of cardiovascular therapy for over six decades. Vitamin K (2-methyl-3-phytyl-1,4-naphthoquinone) is required for the hepatic synthesis of prothrombin, factor VII, factor IX factor X, and the anticoagulant proteins C and S.7,8

their amino-terminal region. Vitamin K is required for the post-ribosomal conversion of glutamyl residues in liver precursors of these proteins to gamma- carboxyglutamyl residues in the completed plasma proteins. This carboxylation reaction leads to oxidation of vitamin K and results in the production of vitamin K 2,3-epoxide. Reduction of vitamin K epoxide via the vitamin K epoxide reductase (VKOR) reactivates vitamin K. VKAs in turn inhibit the regeneration of vitamin K by interfering with VKOR.9,10


mechanism of action of VKA is therefore based on the inhibition of γ-carboxylation of glutamate residues of coagulation factors II, VII, IX and X, as well as in the anticoagulant proteins C and S, resulting in their inactivation. In contrast to heparins or the target-specific inhibitors, inhibition of the coagulation cascade by VKA is therefore not a result of direct factor inhibition but of a reduced production of coagulation factors, including Factor X.

Warfarin is completely absorbed after oral administration, and peak plasma concentrations are reached within four hours. A single, oral dose of warfarin is eliminated with first-order kinetics and the metabolites are largely recovered in the urine (approximately 80%) and faeces (approximately 20%). The half-life of warfarin ranges from 20 to 60 hours, with a mean of approximately 40 hours and a duration of anticoagulatory effect lasting two to five days.9,10

Phenprocoumon is eliminated as a

parent compound (approximately 40%) and hydroxylated metabolites (approximately 60%).11

As for warfarin,

The longer elimination half-life of phenprocoumon (110–156 hours) is the result of both enterohepatic recycling of conjugated phenprocoumon and a lower clearance of cytochrome enzymes regulating the hydrolysation of phenprocoumon.

elimination follows first-order kinetics and occurs via urine (65%) and faeces (35%).9

Specific factor Xa inhibitors Parenteral factor Xa inhibitors Fondaparinux is a synthetic parenteral factor Xa inhibitor with high affinity to antithrombin and which shares the pentasaccharide sequence that mediates the interaction of heparin with antithrombin.12

Fondaparinux has a

molecular weight of 1728 Da and its binding to antithrombin induces a conformational change of the active site of antithrombin that catalyses its reactivity with factor Xa. Fondaparinux is too short to bridge antithrombin to thrombin, which explains why in contrast to UFH and LMWH, fondaparinux only inhibits Factor Xa. Following subcutaneous injection, its bioavailability reaches almost 100%; it is rapidly absorbed and has a half-life ranging from 17 to 22 hours. Fondaparinux is excreted unchanged in the urine. It does not bind to plasma proteins other than antithrombin and therefore exhibits linear pharmacokinetics with a more predictable anticoagulant response than UFH and LMWH.

Direct oral Factor Xa inhibitors: apixaban, edoxaban, rivaroxaban In contrast to indirect inhibitors, direct oral Factor Xa inhibitors selectively inhibit Factor Xa and do not require the presence of cofactors such as antithrombin.

Apixaban demonstrates potent and highly selective reversible inhibition of free- and clot-bound factor Xa with additional minimal affinity for thrombin.16,17

Apixaban has a high oral

bioavailability and achieves a peak plasma concentration within three hours. The effective half-life is 8–11 hours when administered twice daily. Hepatic metabolism occurs via O-demethylation through the CYP3A4 system. Of the administered apixaban dose, approximately 25% is recovered as


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