Monograph: |
Low-molecular-weight Heparins
Low-molecular-weight heparins are salts of sulphated glu-
cosaminoglycans and have a mass-average molecular mass of
less than 8000. They are obtained by fractionation or de-
polymerisation of heparin of natural origin and, depending on
the method of production, display different chemical struc-
tures at the reducing and non-reducing end of the polysaccha-
ride chains.
The Ph.Eur specifies that potency is not less than 70 units of
anti-factor Xa activity per mg with reference to the dried sub-
stance and that the ratio of anti-factor Xa activity to anti-fac
tor lla (antithrombin) activity is not less than 1.5.
A white or almost white hygroscopic powder. Freely soluble
inwater. A 1% solution in water has a pH of 5.5 to 8.0. Store
in airtight containers.
Units
The first International Standard for low-molecular-
weight heparin was established in 1986 and is used
to calibrate products for both anti-factor Xa and
anti-factor lla activities. Potency is expressed in
terms of units of anti-factor Xa activity per mg and
the ratio of anti-factor Xa to anti-factor lla activity.
This ratio differs for individual low-molecular-
weight heparins and neither they nor unfractionated
heparin can be used interchangeably unit for unit.
Adverse Effects
As for Heparin: a possible decreased risk of
bleeding complications compared with heparin has
not been established (see below).
Effects on the adrenal glands. Hyperkalaemia related to
hypoaldosteronism has been reported in a patient treated with
a low-molecular-weight heparin. In a study of 12 patients giv-
en enoxaparin and 15 given nadroparin the mean plasma-al-
dosterone concentration decreased after 4 days of treatment.
This was accompanied by an increase in the mean serum-po-
tassium concentration. Both values returned towards normal
after withdrawal of therapy.
Effects on the blood. It was hoped that. because of their
higher ratio of anti-factor Xa to anti-thrombin activity com-
pared with heparin. low-molecular-weight heparins might
cause less bleeding while maintaining their antithrombotic
activity. Although animal studies found a lower incidence of
bleeding for an equivalent antithrombotic effect this is yet to
be established in clinical studies in humans. Some large
studies have suggested less bleeding with low-molecular-
weight heparins than with unfractionated heparin Despite
this it is thought that the risk may well be similar.
Thrombocytopenia has also been reported with low-molecu-
lar-weight heparin, although in one study the incidence
was less than with unfractionated heparin.
There has also been a report of thrombocytosis in one patient
receiving enoxaparin.
Effects on the skin. Skin necrosis at the site of enoxaparin
injection has been reported in 2 patients. A third patient de-
veloped necrosis at enoxaparin injection sites when enoxa-
parin was substituted for heparin an association with
heparin-induced thrombocytopenia was suggested.
A delayed eczematous reaction developed at the site of previ-
ous injections in a woman who had been receiving certoparin
for 5 months There was no reaction when therapy was
changed to an alternative low-molecular-weight heparin.
Hypersensitivity. Reports of hypersensitivity reactions as-
sociated with low-molecular-weight heparins are rare. How-
ever. a patient being treated with enoxaparin 20 mg
subcutaneously daily developed a widespread pruritic urticar-
ia and swelling of lips and tongue after three days of treat-
ment. Antihistamines and prednisone given with enoxaparin
failed to control the reaction and enoxaparin treatment was
stopped after a further three days. Urticaria and angioedema
rapidly resolved on withdrawal of enoxaparin.
Treatment of Adverse Effects
Severe bleeding with low-molecular-weight
heparins usually caused by accidental overdosage.
may be reduced by the slow intravenous administra-
tion of protamine sulphate. The recom-
mended doses of protamine sulphate are given in the
individual monographs and should completely neu-
tralise the anti-thrombin effect of the low-molecu-
lar-weight heparin but will only partially neutralise
the anti-factor-Xa effect. Not more than 50 mg of
protamine sulphate should be injected for any one
dose.
Precautions
As for Heparin.
Low-molecular-weight heparins should not be ad-
ministered to patients who have developed thrombo-
cytopenia with heparin and who have a positive in-
vim platelet aggregation test (that is, cross-reactiv-
ity) with the particular low-molecular-weight
heparin to be used.
Local anaesthesia. Spinal and epidural haematomas, some-
times leading to paralysis, have occurred in patients receiving
low-molecular-weight heparin in association with spinal or
epidural anaesthesia or analgesia. The risk of haematoma ap-
peared to be higher in patients who had indwelling catheters
or who were receiving concomitant therapy with other drugs
that affect haemostasis.
Interactions
As for Heparin.
Pharmacokinetics
Although the precise pharmacokinetic parameters of
different low-molecular-weight heparins vary (see
individual monographs), they generally have a
greater bioavailability after subcutaneous injection
and a longer half life than heparin.
Uses and Administration
Low-molecular-weight heparins are salts of frag-
ments of heparin produced by chemical or enzymat-
ic depolymerization of the heparin molecule.
Commercially available low-molecular-weight
heparins differ in their method of production, mo-
lecular-weight range, and degree of sulphation. Like
heparin, these compounds enhance the ac-
tion of antithrombin HI but they are characterised by
a higher ratio of anti-factor Xa to anti-factor Ua (an-
tithrombin) activity than heparin. The possibility
that such selective factor-Xa inhibition would result
in antithrombotic activity without anticoagulant and
hence haemorrhagic effects has not been fully con-
firmed by clinical experience in humans. Low-mo-
lecular-weight heparins also have less effect on
platelet aggregation than heparin. They have no sig-
nificant effect on blood coagulation tests such as ac-
tivated partial thromboplastin time (APTT).
Therapy may be monitored by measurement of plas-
ma-anti-factor-Xa activity.
Low-molecular-weight heparins are used in the
management of venous thrombo-embolism (deep-
vein thrombosis and pulmonary embolism).
They are used for prophylaxis, particularly during
surgery, and for treatment of established thrombo-
embolism. They are administered by subcutaneous
injection once or twice daily: laboratory monitoring
is not generally necessary. They are also given intra-
venously to prevent coagulation during haemodialy-
sis and other extracorporeal circulatory procedures,
and subcutaneously in the management of unstable
angina.
Doses are expressed either in terms of the weight of
low-molecular-weight heparin or in terms of units of
anti-factor Xa activity. Since low-molecular-weight
heparins differ in their relative inhibition of factor
Xa and thrombin. doses, even when expressed in
terms of anti-factor-Xa activity, cannot be equated.
Different preparations of the same low-molecular-
weight heparin may also have different doses de-
pending on the reference preparation used.
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