Prevention Of Arterial Thromboembolic Events Research Articles

Atherosclerosis and venous thromboembolism — similarities

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), and atherothrombosis have long been considered to be separate entities with distinct pathogenic mechanisms. The traditional rationale for this concept has been based on: (1) pathologic data showing platelet-rich thrombi in the arteries in contrast to ‘red clots’ observed in veins; (2) clinical data on a substantial efficacy of antiplatelet agents in the prevention of arterial thromboembolic events in contrast to negligible benefits from these drugs in patients with VTE; (3) experimental data demonstrating diffuse inflammatory infiltrates, extracellular cholesterol deposits, neovessel formation and calcification within advanced atherosclerotic lesions within the arterial wall in contrast to minor lesions largely within the endothelial layer of the thrombosed veins. A key component of this concept is the assumption that deranged local processes occurring inside the vessel wall account for arterial thrombosis with a minor contribution by blood-borne abnormalities, whereas a combination of extrinsic factors ranging from venous blood stasis to hypercoagulable blood that act on a normal wall of a vein determine the occurrence of venous thrombosis. Experimental data derived from biochemical laboratories, cell cultures and animal models has shown however many similarities in the pathophysiology of arterial and venous thrombosis [1]. Coagulation pathways and their regulation are in fact identical in arteries and veins. Blood circulating in the two types of vessels is the same in terms of coagulation proteins. All kinds of thrombosis are triggered with the same major physiological initiator of blood coagulation, i.e. tissue factor (TF) [2]. Finally, thrombus composition assessed following thrombectomy in patients with ST-segment elevation acute myocardial infarction (MI) is frequently hard to differentiate from that of thrombi obtained from thrombosed veins, as evidenced by the fact that fibrin represents the largest portion of the thrombotic mass in both types of vessels [3, 4]. Despite the key role of activated platelets as a driving factor of thrombus formation under high shear stress conditions, there is convincing evidence for a significant contribution of thrombin and blood coagulation proteins in arterial thrombosis, as well as for their expression in macrophages and other cells within atherosclerotic lesions [5]. Until the beginning of the current century, there was no clinical data to support basic science findings indicating that thrombus formation in most vessels follows the same pattern and once deranged haemostasis tilted toward thrombosis results in increased risk of thromboembolic events putting in danger both the arterial and venous beds. Within the last decade, accumulating evidence has indicated that patients following VTE are at risk of MI or ischaemic stroke and vice versa. However a lot of experimental and clinical questions are to be answered including those as to whether all affected patients are indeed prone to develop the other type of thrombosis and which diagnostic and therapeutic strategy should be adopted in such a clinical setting. This review summarises the most important clinical and experimental data on the association between arterial and venous thrombosis.

Rivaroxaban : mode d’action

Rivaroxaban is the first oral anticoagulant with a direct anti-Xa activity to be registered (approval). As for all first comers in a class, it should be assessed both for itself and for the class. The targeting of factor-Xa factor, key component in the coagulation cascade, has the theoretical benefit of being an effective antithrombotic and a potential risk for hemorrhage, both highly dose-dependent. Experience has shown us that the representativeness and predictiveness of in vitro tests and preclinical models are only partial and sometimes even misleading. This is why the responses can only come from clinical trials and rigorous research testing doses, which should be conducted specifically in all the indications foreseen, with no extrapolations. The oral anticoagulant drugs are developed in the prevention of arterial thromboembolic events caused by atrial fibrillation too, where the vitamin K antagonists (VKAs) are the current standard of care. The well-known problems of monitoring and adaptation doses with VKAs have led to developing new replacement classes without the need for control or biological adaptation. However, in certain conditions there is a need to monitor the patient. The advantage for the direct anti-Xa inhibitors such as rivaroxaban is that the prothrombin time, a routine test is sensitive and provides a prolonged response that is proportional to the plasma concentration within a wide range of concentrations. This test is potentially usable provided that the indispensable standardization is forthcoming.

Maladie thrombo-embolique veineuse : médicaments antithrombotiques d’aujourd’hui et de demain

Two new classes of anticoagulants are actually developed which would change in the near future our strategies for the prevention and the treatment of venous thromboembolic events. These two classes are the anti-factor Xa and anti-factor IIa (direct antithrombin) agents. Among the anti factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux is a synthetic form of the natural pentasaccharide, its pharmacokinetics allows one s.c. administration/24 hours. It is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade with a limited use due to several drawback. More recently synthetic direct antithrombins modified to allow oral route have been developed, the most advanced in development, melagatran, is active in the prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Melagatran is also active in the prevention of arterial thromboembolic events on atrial fibrillation. But other molecular forms of synthetic orally active direct antithrombin are also in development. Besides these important changes in our therapeutics which should appear in a near future, molecules aimed at other target are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis. These new drugs at our disposal to treat venous thromboembolism should modify completely our handling of the patients. But additionally the numerous clinical trials necessary to prove the efficacy of the drugs, modify our understanding in the implication of the coagulation and in the physiopathogeny of thrombotic events.