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Venous thromboembolism


Intrinsic pathway


Extrinsic pathway


Intrinsic pathway


Extrinsic pathway


Vitamin K antagonist XI TF XI IX X VIII II V VIII VII


AT IX


AT X AT II V


Heparins TF


VII


Fibrin clot A


Vitamin K antagonists interfere with the hepatic maturation of clotting factors VII, IX, X and II. Treatment with these drugs reduces the levels of functional factor in the blood.


Figure 2A–D: Mechanism of action of anticoagulant drugs


inhabitants, but with a much higher frequency in risk groups.1


PE is a major


cause of morbidity, and has an associated mortality of up to 10%. A study in six European countries estimated an incidence of over one million annual VTE episodes, and attributed 12% of all deaths in these countries to VTE.2


What causes VTE? The variety of clinical syndromes caused by VTE share a single common pathophysiology: an abnormal activation of the coagulation system. This leads to the sequential activation of a series of clotting factors (Figure 3), culminating in the generation of a burst of activated factor II or thrombin. Thrombin then converts circulating fibrinogen into a network of fibrin fibres, entrapping red and white blood cells to form a clot.3


12


In contrast to arterial thrombosis, where platelet activation at sites of a diseased vessel wall is the main trigger for thrombus formation, the trigger for VTE may vary. Three general conditions that contribute to venous thrombosis were described well over 150 years ago by the German physician, Rudolf Virchow. These conditions are


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reduced blood flow, increased tendency for blood clotting, and abnormalities in the vessel wall.3


Pathophysiology The pathophysiology of VTE has two important implications. First, it offers a clear common target for treatment and prevention of VTE: reduction of the activation of key clotting factors by anticoagulant drugs. Second, understanding factors involved in thrombus formation allows to identify individuals who are at an elevated risk for VTE. When the risk of a first or a recurrent thrombosis is sufficiently high, preventive therapy may be useful.4


This is the case in


patients undergoing major orthopaedic surgery, where a short-term course of preventive anticoagulation strongly reduces the risk of symptomatic VTE. On the other hand, selection of patients who have had VTE and who are at a high risk of recurrence can be more challenging.


Treating VTE Prevention of VTE is a crucial part of thrombosis care. VTE constitutes the most preventable cause of death in hospitalised


patients, and thus the prevention of VTE is among the top priorities for improving the quality of health care.4,5 Once the diagnosis of VTE is made, the treatment consists of three continuous phases.1,6


B


Fibrin clot


In the presence of heparin, the anticoagulant effect of antithrombin is strongly potentiated, reducing thrombus formation. Unfractionated heparin inhibits factors IX, X and II, whereas LMWHs, with a shorter chain length, mainly inhibit factor X, and, to a lesser extent, factor II.


For the acute treatment, prompt initiation of anticoagulant therapy is crucial. In this first phase, timely adequate anticoagulation can minimise clot extension, reducing the risk of embolisation and of chronic sequellae of VTE. In the weeks and months following a


DVT or PE, patients are at a high risk of new events. In this second phase, anticoagulation is maintained to prevent early recurrence. Finally, the third phase consists of secondary prevention of late recurrent events. This phase requires an invidualised risk assessment. Patients at low risk of recurrence, such as those who suffered VTE due to a transient risk factor that is no longer present, may require only counselling on prophylactic measures in future risk situations. On the other end of the spectrum, patients with multiple previous recurrences, or with strong non-reversible risk factors such as active cancer or thrombophilia, may require permanent life-long anticoagulation.


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