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Chapter 149 Antithrombotic Drugs 2177

Elevated Levels of Transaminases. Therapeutic doses of heparin heparin-binding proteins in plasma, LMWH produces a more pre-
frequently cause modest elevation in the serum levels of hepatic dictable dose response, and resistance to LMWH is rare. With a
transaminases, without a concomitant increase in the level of biliru- longer half-life and more predictable anticoagulant response, LMWH
bin. The levels of transaminases rapidly return to normal when the can be given subcutaneously once or twice daily without coagulation
drug is stopped. The mechanism responsible for this phenomenon is monitoring, even when the drug is given in treatment doses. These
unknown. properties render LMWH more convenient than unfractionated
heparin. Capitalizing on this feature, studies in patients with venous
thromboembolism have shown that home treatment with LMWH is
Low-Molecular-Weight Heparin as effective and safe as in-hospital treatment with continuous intra-
venous infusions of heparin. Outpatient treatment with LMWH
Consisting of smaller fragments of heparin, LMWH is prepared from streamlines care, reduces health care costs, and increases patient
unfractionated heparin by controlled enzymatic or chemical depoly- satisfaction.
merization. The mean molecular weight of LMWH is about 5000,
one-third the mean molecular weight of unfractionated heparin.
LMWH has several advantages over heparin (Table 149.5) and is used Monitoring
instead of heparin for most indications.
In the majority of patients, LMWH does not require coagulation
monitoring. If monitoring is necessary, anti–factor Xa levels must be
Mechanism of Action measured because most LMWH preparations have little effect on the
aPTT. Therapeutic anti–factor Xa levels with LMWH range from 0.5
Like heparin, LMWH exerts its anticoagulant activity by activating to 1.2 U/mL when measured 3 to 4 hours after drug administration.
antithrombin. With a mean molecular weight of 5000, which When LMWH is given in prophylactic doses, peak anti–factor Xa
corresponds to about 17 saccharide units, at least half of the levels of 0.2 to 0.5 U/mL are desirable.
pentasaccharide-containing chains of LMWH are too short to bridge Indications for LMWH monitoring include renal insufficiency
thrombin to antithrombin (see Fig. 149.4). However, these chains and morbid obesity. LMWH monitoring in patients with a creatinine
retain the capacity to accelerate factor Xa inhibition by antithrombin clearance of 50 mL/min or less is advisable to ensure that there is no
because this activity is largely the result of the conformational changes drug accumulation. Although weight-adjusted LMWH dosing
in antithrombin evoked by pentasaccharide binding. Consequently, appears to produce therapeutic anti–factor Xa levels in patients who
LMWH catalyzes factor Xa inhibition by antithrombin more than are overweight, this approach has not been evaluated extensively in
thrombin inhibition. Depending on their unique molecular weight those with morbid obesity. It may also be advisable to monitor the
distributions, LMWH preparations have anti–factor Xa to anti–factor anticoagulant activity of LMWH during pregnancy because dose
IIa ratios ranging from 2 : 1 to 4 : 1. requirements can change, particularly in the third trimester. Monitor-
ing also is important in high-risk settings, such as in patients with
mechanical mitral valves who are given LMWH for prevention of
Pharmacology valve thrombosis.
Although usually given subcutaneously, LMWH also can be admin-
istered intravenously if a rapid anticoagulant response is needed. Dosing
LMWH has pharmacokinetic advantages over heparin. These advan-
tages reflect the fact that shorter heparin chains bind less avidly to The doses of LMWH recommended for prophylaxis or treatment
endothelial cells, macrophages, and heparin-binding plasma proteins. vary depending on the LMWH preparation. For prophylaxis, once-
Reduced binding to endothelial cells and macrophages eliminates the daily subcutaneous doses of 4000 to 5000 U are often used, whereas
rapid, dose-dependent, and saturable mechanism of clearance that is doses of 2500 to 3000 U are given when the drug is administered
a characteristic of unfractionated heparin. Instead, the clearance of twice daily. For treatment of venous thromboembolism, a dose of 150
LMWH is dose independent, and its plasma half-life is longer. Based to 200 U/kg is given if the drug is administered once daily. If a
on measurement of anti–factor Xa levels, LMWH has a plasma twice-daily regimen is employed, a dose of 100 U/kg is given. In
half-life of about 4 hours. LMWH is cleared almost exclusively by patients with unstable angina, LMWH is given subcutaneously on a
the kidneys, and the drug can accumulate in patients with renal twice-daily basis at a dose of 100 to 120 U/kg.
insufficiency.
LMWH exhibits about 90% bioavailability after subcutaneous
injection. Because LMWH binds less avidly than heparin to Side Effects
The major complication of LMWH is bleeding. Recent metaanalyses
suggest that the risk of major bleeding may be lower with LMWH
TABLE Advantages of Low-Molecular-Weight Heparin Over than with unfractionated heparin. HIT and osteoporosis are less
149.5 Heparin common with LMWH than with unfractionated heparin.
Advantage Consequence
Bleeding
Better bioavailability and longer Can be given subcutaneously The risk of bleeding with LMWH is increased with concomitant use
half-life after subcutaneous once or twice daily for both of antiplatelet or fibrinolytic drugs. Recent surgery, trauma, or
injection prophylaxis and treatment underlying hemostatic defects also increase the risk of bleeding with
Dose-independent clearance Simplified dosing LMWH.
Although protamine sulfate can be used as an antidote for LMWH,
Predictable anticoagulant response Coagulation monitoring is protamine sulfate incompletely neutralizes the anticoagulant activity
unnecessary in most patients
of LMWH because it binds only the longer chains of LMWH. Because
Lower risk of heparin-induced Safer than heparin for short- or longer chains are responsible for catalysis of thrombin inhibition by
thrombocytopenia long-term administration antithrombin, protamine sulfate completely reverses the anti–factor
Lower risk of osteoporosis Safer than heparin for extended IIa activity of LMWH. In contrast, protamine sulfate only partially
administration reverses the anti–factor Xa activity of LMWH because the shorter
pentasaccharide-containing chains of LMWH do not bind to