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Venous thromboembolism

Intrinsic pathway

Extrinsic pathway

Intrinsic pathway

Extrinsic pathway


Xa inhibitors IX X VIII II V VIII X VII


XI Direct thrombin inhibitors IX X V VII


Fibrin clot C

Direct factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, bind to the active site of factor X molecules, and inhibit their function.


The search for safe and convenient treatment

All anticoagulants act by interfering with the function of one or more clotting factors, reducing the normal coagulation response (Table 1 and Figure 2). Although this prevents and limits the abnormal clotting responsible for thrombosis, anticoagulants also interfere with haemostasis, and thus increase the risk of bleeding. The first use of anticoagulants to treat

VTE was over 75 years ago, when Murray and Best demonstrated that unfractionated heparin (UFH), isolated from porcine intestines, reduced mortality in patients with venous thrombosis.7

Heparin is a

potentiator of the natural anticoagulant molecule antithrombin, and indirectly reduces the activity of factors II and X, and, to a lesser extent, IX and XI (Figure 4A). However, UFH has several drawbacks that make it challenging to use. Rather than a single molecule, UFH is a mixture of molecules with a molecular mass ranging from 5000 to over 30,000. It has to be administered parenterally, and due to this variable composition and the high non- specific protein binding, its effect is highly inconsistent and requires continuous

Fibrin clot

Direct thrombin inhibitors, such as dabigatran, directly block the active site on thrombin molecules, directly preventing the final step in the formation of fibrin clots.

monitoring and dose adjustment. Vitamin K antagonists (VKAs) were introduced in the 1950s. These drugs block the recycling of vitamin K in the liver, leading to a defect maturation of coagulation factors II, VII, IX and X (Figure 4B). VKAs can be administered orally, but also have a highly unpredictable and unstable anticoagulant effect due to inter-individual variability in metabolisation and a multitude of drug and food interactions.8

As with UFH, continuous

measurement of the anticoagulant effect and appropriate adjustment of the dose is required to avoid under- or over- anticoagulation. Furthermore, due to the slow onset of action, VKAs are not effective for the acute treatment of VTE.9 For many decades, the combination of an initial treatment with short-acting heparins, followed by a continued treatment with VKA was the standard treatment for VTE.10 The use of heparin molecules with a shorter chain length, the low molecular weight heparins (LMWHs) largely replaced UFH because of their more predictable pharmacokinetics. More recently, a synthetic analogue of the active antithrombin-activating site was developed

(fondaparinux; Table 1 and Figure 2A).11 These drugs allowed a more convenient dosing, obviating the need for continuous monitoring, thus improving convenience and promoting outpatient treatment. Nevertheless, the need for parenteral administration renders them impractical for long-term use, and the paradigm of short-term course of subcutaneous heparin analogues followed by long-term oral VKA remained unchanged.

In an effort to further optimise the

convenience of anticoagulant effect, orally active target-specific anticoagulants were developed. To date, four of these non-VKA oral anticoagulants (NOACs) have been approved to prevent and treat VTE. These NOACs specifically inhibit either thrombin (direct thrombin inhibitors, dabigatran) or factor Xa (Xa inhibitors, rivaroxaban, apixaban, and edoxaban).12

(Figure 2C, D).

The NOACs aim to combine rapid onset of action, a predictable anticoagulant effect, and the convenience of oral administration (Table 1).

Overview of clinical data Prevention of VTE

Patients undergoing major orthopaedic 13

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