Chemistry Reference
In-Depth Information
with global deaths estimated over 7 million.
3
The underlying etiology for CAD
is atherosclerosis, a chronic, progressive, inflammatory, and proliferative
response to cholesterol infiltration into arterial wall, leading to arterial plaques.
Arterial plaques grow in size with time, thereby causing luminal narrowing that
results in restricted blood flow to the myocardium, which often gives rise to
symptoms of stable angina, such as exercise-induced chest pain.
4,5
The abrupt
clinical manifestations of CAD, however, are triggered by the rupture of an
atherosclerotic plaque, which marks the sudden transition from a stable,
clinically-silent disease to a symptomatic, life-threatening condition.
6
When a
plaque ruptures in a coronary artery, blood comes into contact with the
vasoactive components of the endothelial matrix, initiating two principal
mechanisms of thrombosis—activation of platelets and activation of blood
coagulation—thereby leading to an occlusive thrombus formation.
7,8
The
obstruction of blood flow and the myocardial underperfusion that results leads
to ischemic disorders, presenting a spectrum of clinical conditions known as
acute coronary syndrome (ACS) that includes Q-wave myocardial infarction,
non-Q-wave myocardial infarction, and unstable angina.
9-11
Thrombin plays a very important dual role in thrombosis (Figure 2.1). In its
role as a procoagulant, thrombin cleaves fibrinogen to fibrin, which poly-
merizes to form a meshwork. Thrombin, being the most potent activator of
platelets, also causes platelets to aggregate. The fibrin meshwork traps aggre-
gated platelets and other plasma particles such as red blood cells to give rise to a
fast growing thrombus, which gains further rigidity and mechanical strength by
factor XIIIa-mediated cross-linking reactions.
12
Antithrombotic agents are the mainstay of pharmacological therapy for
thrombotic disorders.
13-15
Thrombosis, a localized clotting of blood, can occur
either in the arterial or venous segment of the circulation system, and, depending
on the local milieu, thrombus composition and pathophysiology may vary and
need to be treated with different antithrombotic agents.
16,17
Mechanistically, the
function of an antithrombotic agent is to prevent the formation of new thrombi
in the blood vessels or to disrupt the existing thrombi and restore blood flow.
18
In general, arterial thrombi are abundant in aggregated platelets and venous
thrombi have polymerized fibrin as the major component. Depending on their
functional mechanism, the antithrombotic agents can be divided into anti-
coagulants, antiplatelet agents, and fibrinolytic agents (Table 2.1). The anti-
coagulants either modulate the endogenous levels of thrombin or inactivate the
enzymatic function of thrombin.
19,20
Antiplatelet agents inhibit platelet activa-
tion and aggregation, integral processes of hemostasis and thrombosis.
21
Fibrinolytic agents, which are enzyme or protein preparations, are intravenously
administered under clinical emergency to cause lysis of an existing thrombus.
22
2.2 Mechanism of Platelet Activation
Normally, platelets circulate freely in blood vessels without interacting with
each other or the vascular endothelium. In the context of endothelial damage, a
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