(Circulation. 1998;98:1575-1582.)
© 1998 American Heart Association, Inc.
Low-Molecular-Weight Heparin
A Review of the Results of Recent Studies of the Treatment of Venous Thromboembolism and Unstable Angina
Jack Hirsh, MD
From Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.
Correspondence to Jack Hirsh, MD, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario, Canada L8V 1C3.
Key Words: heparin • angina • venous thrombosis
Low-molecular-weight heparins (LMWHs) are a new class of
anticoagulants derived from unfractionated heparin (UFH). They have a
number of advantages over UFH that have led to their increasing use for
a number of thromboembolic indications.1 This
article will review the limitations of UFH and the mechanisms by which
LMWHs overcome these limitations and discuss the results of recent
clinical trials evaluating LMWHs for the treatment of venous
thrombosis, pulmonary embolism, and unstable angina.
Limitations of UFH
Heparin has pharmacokinetic, biophysical, and biological
limitations.2 LMWHs overcome the pharmacokinetic
and some of the biological limitations of UFH, but they share the same
biophysical limitations.
Pharmacokinetic Limitations of UFH
The pharmacokinetic limitations of heparin are caused by its
nonspecific binding to proteins and cells.2 3
Because heparin is highly negatively charged, it binds in a
pentasaccharide-independent fashion to a variety of plasma
proteins (including histidine-rich glycoprotein,
vitronectin, lipoproteins, fibronectin, and fibrinogen) and
to proteins secreted by platelets (platelet factor 4 [PF4]
and high-molecular-weight von Willebrand factor) and
endothelial cells (high-molecular-weight von
Willebrand factor).2 Some heparin-binding
proteins are acute-phase reactants, the levels of which are elevated in
sick patients.4 In addition, during the clotting
process, PF4 and von Willebrand factor are released from
platelets and endothelial cells, respectively.
The variability in plasma levels of heparin-binding proteins in
patients with thromboembolic diseases4 is
responsible for both the unpredictable anticoagulant response to
UFH4 and the very high heparin requirements in
some of these patients (heparin resistance).5
Biophysical Limitations
The biophysical limitations of heparin reflect the inability of
the heparin-antithrombin complex to inactivate
thrombin-bound to fibrin6 and . . . [Full Text of this Article]
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