A Textbook of Clinical Pharmacology and Therapeutics

ANTICOAGULANTS 205

the activity of the coagulation pathway and there is an
increased risk of venous thrombosis associated with preg-
nancy, oral contraception (especially preparations containing
higher doses of oestrogen), and with postmenopausal hor-
mone replacement therapy.
Two limbs of the coagulation pathway (intrinsic and extrin-
sic) converge on factor X (Figure 30.2).

ANTICOAGULANTS

HEPARINS

Heparinis a sulphated acidic mucopolysaccharide that is
widely distributed in the body. The unfractionated prepara-
tion 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 hep-
arins (LMWH) are fragments or short synthetic sequences
of heparinwith much more predictable pharmacological
effects, and monitoring of their anticoagulant effect is seldom
needed. They have largely replaced unfractionated heparinin
therapy.
The main indications for a heparin(LMWH or unfraction-
ated) are:

• to prevent formation of thrombus (e.g. thromboprophy-
  laxis during surgery);


• to prevent extension of thrombus (e.g. treatment of deep-
  vein 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);
  
  
  • 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 monitor-

ing (which requires sophisticated factor Xa assays) is not

needed in routine clinical practice, because their pharmaco-

kinetics are more predictable than those of unfractionated

preparations. LMWH (e.g. enoxaparinanddalteparin) 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

unfractionatedheparinin a meta-analysis of six trials) and pul-

monary 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

heparinin 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

unfractionatedheparinfor 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

unfractionatedheparin; as a consequence, unfractionated

Intrinsic pathway

XIIa

Prothrombin

XIa

IXa

VIII VIIIa

Thrombin

Fibrinogen

Fibrin

Fibrin

V

VIIa

TF

Extrinsic pathway

Soft clot

XIIIa Hard clot

Xa

Va

Figure 30.2Clotting factor cascade. An ‘a’

indicates activation of appropriate clotting

factor. TF, tissue factor. (Redrawn with

permission from Dahlback B. Blood coagulation.

Lancet2000;355:1627–32.)