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Introduction: Factor Xa


Factor Xa inhibition in anticoagulation


An improved understanding of the complexity of the coagulation cascade and vascular haemostasis has led to the development of targeted inhibition of specific coagulation factors, resulting in a paradigm shift in anticoagulation


Erik Holy MD PhD Jan Steffel MD FESC FHRS University Heart Center Zurich, University Hospital Zurich, Switzerland


XI


During the process of coagulation, a regulated sequence of proteolytic zymogen activation is initiated in order to achieve appropriate and timely haemostasis. The exposure of circulating Factor VII/VIIa to tissue factor is the first in a series of steps that culminate in the conversion of fibrinogen to fibrin, resulting in clot formation. This synchronised cascade of events is counter-balanced by anticoagulant factors, which ensure that the haemostatic effect is limited to the site of the vascular injury. Conversely, under inherited or acquired pathological conditions, this haemostatic equilibrium may be unbalanced, leading to a prothrombotic state and enhanced propensity for clot formation. An improved understanding of the complexity of the coagulation cascade and vascular haemostasis has led to the development of targeted inhibition of specific coagulation factors, resulting in a paradigm shift in anticoagulant therapy. This article reviews the main events involved in the coagulation cascade, in particular the role of Factor Xa; and provides an overview of current Factor Xa inhibitors.


The coagulation cascade


The concept of the process of coagulation being based on a cascade of enzymatic activation of inactive precursors was first described in the 1960s.1


Two cascading pathways were identified: the so-called IX XIIa XIa IXa


Xa Va


TF VIIa X Prothrombin IXa VIIIa Thrombin VIIIa


Fibrinogen Figure 1: The coagulation cascade


“The concept of the process of coagulation being based on a cascade of enzymatic precursors was first described in the 1960s”


‘intrinsic pathway’, which depends on contact activation by negatively-charged surfaces and involves coagulation factors XII, XI, IX, VIII and V; and the ‘extrinsic pathway’, which requires the exposure of tissue factor to the blood flow and its binding to factor VII/VIIa. Ultimately both pathways converge in the activation of Factor X, followed by the generation of thrombin, and, finally, the conversion of fibrinogen to fibrin and clot formation. In this simplified concept of coagulation adopted by many clinicians, the initial recruitment of platelets was considered to be an independent mechanism. The current perception of the coagulation cascade has undergone a shift in understanding, from the


distinction between different pathways to a more integrative all-encompassing model (Figure 1). In addition to the stepwise activation and recruitment of zymogens, this new model also incorporates an interlinking of the pathways, a better understanding of regulatory mechanisms and the contribution of several vascular cell types and their surfaces upon which these reactions take place.2,3


Factor Xa: a key player in coagulation


The generation of thrombin from its precursor prothrombin is one of the most critical events in coagulation. Thrombin is generated via a complex


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Fibrin


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