How does atherosclerosis lead to an ischaemic event (e.g. myocardial infarction or ischaemic stroke)?
Acute ischaemic events such as myocardial infarction (MI), stroke or acute limb ischaemia are caused by a sudden restriction in arterial blood flow to the heart, brain or limb. Historically, it was thought that these events were caused by narrowing of the vessel by large atherosclerotic plaques, allowing a small platelet thrombus to occlude the vessel completely.1 However, it is now understood that the majority of these events occur when a vulnerable plaque ruptures or is eroded, releasing procoagulant material into the bloodstream and leading to the formation of a large thrombus – a process known as atherothrombosis.2
Vulnerable plaques are atherosclerotic lesions that are at high short-term risk of thrombosis.3 The archetypal vulnerable plaque is characterized by a thin fibrous cap and an abundance of macrophage-derived foam cells beneath it.2 Eventually, the cap can no longer withstand the mechanical force of the blood pressure and the plaque may rupture.4 Alternatively, ischaemic events may be provoked by plaque erosion, a process that is poorly understood but results in the loss of the surface endothelium.3
Formation of platelet and fibrin-rich arterial thrombi
When a vulnerable plaque ruptures, the contents of the plaque become exposed to the blood with important clinical consequences:5
- Exposure of tissue factor in the lipid core leads to thrombin generation and activation of the coagulation cascade, culminating in the formation of fibrin which stabilizes the clot and facilitates its growth
- At the same time, collagen and von Willebrand factor in the subendothelial layer adhere to platelets, resulting in the rapid recruitment of additional platelets to the site to form a platelet plug. Thrombin further contributes to activating platelets
The activation of these two pathways concurrently allows for the rapid generation of a large thrombus, rich in both fibrin and platelets.6 If sufficiently large, this thrombus may substantially or even completely occlude the artery, restricting blood flow and causing an acute ischaemic event.