A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

CHAPTER 30
ANTICOAGULANTS AND
ANTIPLATELET DRUGS
● Introduction 204
● Pathophysiology of thrombosis 204
● Anticoagulants 205
● Antiplatelet drugs 208
● Anticoagulants in pregnancy and puerperium 209
INTRODUCTION
The treatment and prevention of thrombosis involves three
classes of drugs, namely anticoagulants, antiplatelet drugs and
fibrinolytics. Fibrinolytics are discussed in Chapter 29. The clinical
pharmacology of the anticoagulants and antiplatelet drugs is
described in the present chapter. Anticoagulants inhibit the
coagulation cascade. Their main use is to treat and prevent
venous thrombosis (‘red thrombus’) and its major complication,
pulmonary embolism, whereas antiplatelet drugs are mainly
used in the treatment of platelet-rich coronary and other arterial
thrombi (‘white thrombus’). Nevertheless, there are many links
between platelet activation and the coagulation cascade, so it is
not surprising that anticoagulants can also have beneficial effects
in the prevention of coronary artery disease, or that antiplatelet
drugs have some (albeit a minor) effect on venous thrombosis.
PATHOPHYSIOLOGY OF THROMBOSIS
Haemostasis is achieved by an exquisitely balanced series
of interlocking control systems involving both positive
feedbacks – permitting very rapid responses to the threat of
haemorrhage following sharp injury – and negative feedbacks –
to prevent the clotting mechanism from running out of control
and causing thrombus to propagate throughout the circulation
following haemostasis at a site of injury. In addition there
is an endogenous fibrinolytic system that dissolves thrombus
that has done its job. Not surprisingly, these systems sometimes
go wrong, resulting in bleeding disorders, such as
haemophilia or thrombocytopenic purpura, or in thrombosis.
Thrombosis is caused by injury to the vessel wall, stasis
and activation of coagulation processes (platelets and the
coagulation cascade), these three processes being referred to
as Virchow’s triad (Figure 30.1). Coagulation involves the
sequential activation of a cascade of clotting factors which
amplifies a small initial event to produce a macroscopic plug
of fibrin. Each factor is present in blood as an inactive zymogen.
Several of these factors (II, VII, IX and X) are glycoproteins
which contain γ carboxyglutamic acid residues introduced
by post-translational modification. This process requires vitamin
K. After activation (indicated by the letter ‘a’ after the
Roman numeral that designates the zymogen), several of the
factors acquire proteolytic activity. Thrombin and factors IXa,
Xa, XIa and XIIa are all serine proteases. Oestrogens increase
Thrombin Fibrin Endothelium Subendothelium
IXa
Xa
Platelet
Factor VIII molecule
Von Willebrand
factor
Figure 30.1: Interactions between the clotting system,
platelets and the blood vessel wall.