Essence of this article
A link between atherothrombosis and ischaemia is now well recognized. A better understanding of the underlying pathophysiological mechanisms will give new insights into the development of more-effective and safer anticoagulants for secondary prevention of acute atherothrombosis, with a therapeutic benefit for patients with coronary and/or peripheral artery disease.
Coronary and peripheral artery disease as risk factors for arterial thrombosis
Peripheral artery disease (PAD) is a marker of systemic atherosclerosis that stems from vascular endothelial dysfunction. Most patients with PAD also have concomitant coronary artery disease (CAD), and a large burden of morbidity and mortality in patients with PAD is related to myocardial infarction, ischaemic stroke and cardiovascular death.423 The formation of arterial thrombi induced by ruptured atherosclerotic plaques occupies a central role in the context of CAD/PAD.437 The major thrombogenic plaque components – collagen and tissue factor (TF) – induce platelet activation and coagulation, respectively. Blood coagulation is a two-step process. First, glycoprotein VI-mediated platelet adhesion and aggregation occurs rapidly on collagenous plaque components within 1 minute of atherosclerotic plaque rupture. After a few minutes, TF triggers thrombin and fibrin production, causing the formation of arterial thrombi.438
Blood coagulation and platelet activation in arterial thrombus formation
Thrombosis plays a critical role in the underlying pathological mechanism of ischaemia, where disruption of an atherosclerotic plaque exposes blood to subendothelial collagen, TF and other procoagulant molecules, such as thrombin, which trigger activation of platelets and formation of fibrin within the vessel lumen. The process of thrombus formation in patients with CAD and/or PAD involves the dual pathways of platelet activation and initiation of the coagulation cascade (Figure 1).439
Figure 1. Schematic representation demonstrating the activation of the blood coagulation cascade in the context of arterial thrombus formation.
F, Factor; TF, tissue factor.
Therapeutic targets in the coagulation cascade
Great advances have been made in recent years in understanding the haemostatic system and the molecular and cellular basis of thrombus formation. This is helping to provide new options for the management of thromboembolic disorders.440 With the simultaneous activation of platelet aggregation and the formation of fibrin via the coagulation cascade, it is clear that treatment based on antiplatelets and anticoagulants may yield improved outcomes in patients with CAD and/or PAD. The coagulation pathway provides many targets for the clinical development of potential anticoagulants and antiplatelets.
Factor Xa and thrombin are indispensable components of the coagulation cascade and targeted inhibition of Factor Xa or thrombin has proven to be an effective means of anticoagulation therapy.441 Targeting the TF−Factor VIIa complex inhibits the initiation phase of coagulation, inhibitors of Factor IXa or Factor Xa prevent the proliferation of coagulation, and thrombin inhibitors reduce thrombin activities.442 Direct, oral inhibitors of Factor Xa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran) have been developed. These agents have successfully completed phase III studies demonstrating non-inferiority, or more effective anticoagulation, compared with traditional anticoagulants such as vitamin K antagonists.443-448 These agents may help overcome the healthcare burden associated with vitamin K antagonist treatment (i.e. the need for regular international normalized ratio monitoring and dose adjustments, patient compliance issues and the risk of major bleeding). Antiplatelet agents are also recommended for the prevention and acute treatment of arterial thrombosis.449
A better understanding of the underlying pathophysiological mechanisms associated with thrombosis will not only pave the way for the development of safer and more effective agents, but also for better clinical management of patients with CAD and/or PAD who require combined antiplatelet/anticoagulation therapy.