A Textbook of Clinical Pharmacology and Therapeutics

Intrinsic pathway
XIIa
XIa
the activity of the coagulation pathway and there is an
increased risk of venous thrombosis associated with pregnancy,
oral contraception (especially preparations containing
higher doses of oestrogen), and with postmenopausal hormone
replacement therapy.
Two limbs of the coagulation pathway (intrinsic and extrinsic)
converge on factor X (Figure 30.2).
ANTICOAGULANTS
HEPARINS
IXa
VIII VIIIa
Fibrinogen
Prothrombin
Xa
Va
Thrombin
VIIa
Heparin is a sulphated acidic mucopolysaccharide that is
widely distributed in the body. The unfractionated preparation
is extracted from the lung or intestine of ox or pig,
and is a mixture of polymers of varying molecular weights.
Since the structure is variable, the dosage is expressed in terms
of units of biological activity. Low-molecular-weight heparins
(LMWH) are fragments or short synthetic sequences
of heparin with much more predictable pharmacological
effects, and monitoring of their anticoagulant effect is seldom
needed. They have largely replaced unfractionated heparin in
therapy.
The main indications for a heparin (LMWH or unfractionated)
are:
• to prevent formation of thrombus (e.g. thromboprophylaxis
during surgery);
• to prevent extension of thrombus (e.g. treatment of deepvein
thrombosis, following pulmonary embolism);
• prevention of thrombosis in extracorporeal circulations
(e.g. haemodialysis, haemoperfusion, membrane
oxygenators, artificial organs) and intravenous cannulae;
• treatment of unstable angina, non-ST elevation
myocardial infarction (NSTEMI) (Chapter 29);
V
Fibrin
Soft clot
Extrinsic pathway
TF
XIIIa Hard clot
Fibrin
ANTICOAGULANTS 205
Figure 30.2 Clotting factor cascade. An ‘a’
indicates activation of appropriate clotting
factor. TF, tissue factor. (Redrawn with
permission from Dahlback B. Blood coagulation.
Lancet 2000; 355: 1627–32.)
• following thrombolysis with some fibrinolytic drugs
used for ST-elevation myocardial infarction (STEMI)
(Chapter 29);
• arterial embolism;
• disseminated intravascular coagulation (DIC): as an
adjunct, by coagulation specialists.
LOW-MOLECULAR-WEIGHT HEPARINS
Low-molecular-weight heparins (LMWH) preferentially
inhibit factor Xa. They do not prolong the APTT, and monitoring
(which requires sophisticated factor Xa assays) is not
needed in routine clinical practice, because their pharmacokinetics
are more predictable than those of unfractionated
preparations. LMWH (e.g. enoxaparin and dalteparin) are at
least as safe and effective as unfractionated products, except
in patients with renal impairment. Thrombocytopenia and
related thrombotic events and antiheparin antibodies are less
common than with unfractionated preparations. Once-daily
dosage makes them convenient, and patients can administer
them at home, reducing hospitalization.
LMWH prevent deep-vein thrombosis (about one-third the
incidence of venographically confirmed disease compared with
unfractionated heparin in a meta-analysis of six trials) and pulmonary
embolism (about one-half the incidence) in patients
undergoing orthopaedic surgery, but with a similar incidence of
major bleeds. They are at least as effective as unfractionated
heparin in the treatment of established deep-vein thrombosis
and pulmonary embolism, and for myocardial infarction. In
view of their effectiveness, relative ease of use and the lack of
need for blood monitoring, they have largely supplanted
unfractionated heparin for the prophylaxis and treatment of
venous thromboembolism, in unstable angina and NSTEMI
and for use with some fibrinolytics in STEMI (Chapter 29).
LMWH are eliminated solely by renal excretion, unlike
unfractionated heparin; as a consequence, unfractionated