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Specialty Section: Vascular Surgery
Low Molecular Weight Heparins: Current Use and Indications
Mohammed A Quader, MD, Lisa S Stump, MS, RPh, and Bauer E Sumpio,
MD, PhD, FACS
Heparin is a naturally occurring anticoagulant synthesized
and secreted primarily by the mast cells in the body. Unfractionated
heparin has been commonly used for prevention and treatment of
arterial and venous thrombosis. However, because of complications,
such as bleeding, thrombocytopenia, and osteoporosis, clinicians
continue to search for additional antithrombotic options. Over
the past 2 decades, low molecular weight heparins (LMWH) have
been intensely investigated, and researchers have reported several
advantages of these compounds over unfractionated heparin. LMWH
was previously approved for use in the prophylaxis of deep venous
thrombosis (DVT) and in the inpatient treatment of DVT and pulmonary
embolism (PE). In May 1998, LMWH (Enoxaparin, Rhone-Poulenc Rorer,
Collegeville, PA) was deemed approvable by the Food and Drug
Administration for in- and outpatient treatment of DVT and PE
and extended use of LMWH for outpatient treatment of DVT and
PE.
BIOCHEMICAL PROPERTIES
Heparin is a mucopolysaccharide composed of alternating units
of sulfated d-glucosamine and d-glucuronic acid (Fig. 1). The
esterified sulfuric acid component gives unfractionated heparin
its acidic property and electronegative charge. The strong electronegative
charges on the unfractionated heparin molecule attract and bind
to electropositive charges on clotting factors and are an important
step in their inactivation.
Figure 1. Chemical structure of a single unit of unfractionated
heparin molecule.
The molecular weight of unfractionated heparin ranges from
3000 to 30,000 daltons. The LMWHs are synthesized from larger
unfractionated heparin molecules by enzymatic or chemical depolymerization,
resulting in unfractionated heparin molecules with an average
molecular weight of about 5000 daltons (range 3000-7000 daltons).
Because of the different methods of defractionation, LMWHs are
a heterogeneous class of compounds, with differences in molecular
weight, pharmacokinetics, and antithrombotic and anticoagulant
activity. Though we discuss these compounds as a group, each
one must be considered individually when selecting a product
and dose for a specific use (Table 1).
MECHANISM OF ACTION
Heparin produces its anticoagulant effects by binding to antithrombin
III and inhibiting thrombogenesis primarily through inactivation
of factors, IIa and Xa (Fig. 2, A, B). The interaction with antithrombin
III is mediated through a unique pentasaccharide molecule distributed
randomly in the unfractionated heparin molecule. The antithrombotic
effects of unfractionated heparin require interaction with antithrombin
III and factor Xa. Binding of the unfractionated heparin antithrombin
III complex to factor Xa causes a conformational change leading
to inactivation of factor Xa. Unfractionated heparin can also
bind to and inactivate factor II (thrombin). However, this process
requires simultaneous binding of the unfractionated heparin antithrombin
III complex with thrombin, which necessitates that the unfractionated
heparin be at least 18 saccharide units. The longer saccharide
units ([lt] 18 units) comprise less than 50% of the total fraction
of low molecular weight heparins, so LMWHs have a relatively
higher antifactor Xa, and lower antifactor II activity compared
to unfractionated heparin. Potency of LMWH is reflected by the
ratio of antifactor Xa to antifactor IIa activity (Xa:IIa ratio)
(Table 1). |
Table 1. Properties of Low Molecular Weight Heparins
|
|
Name |
Trade name |
Manufacturer |
Synonyms |
Defractionation method |
Halflife (h) |
Factor Xa:IIa ratio (daltons) |
Average molecular weight (U) |
|
|
Marketed in U.S. |
|
Enoxaparin |
Lovenox6 |
Rhone-Poulenc Rorer |
PK 10169 Enoxaparine Pharmuka 10169 |
Benzylation and alkaline depolymerization |
4.5 |
2.7:1 |
4,500 |
|
Dalteparin |
Fragmin6 |
Pharmacia and Upjohn |
FR 860
Kabi 2165
Tedelparin |
Nitrous acid depolymerization |
2-4 |
2.0:1 |
4,000-6,000 |
|
Ardeparin |
Normiflo6 |
Wyeth-Ayerst |
RD 11885 |
Peroxidative depolymerization |
1.2-3.3 |
2.0:1 |
5,600-6,500 |
|
Used worldwide |
|
Nadroparin |
|
Sanofi |
CY 216D Fraxiparin Seleparina |
Nitrous acid depolymerization |
3.5 |
2-4.1 |
4,500 |
|
Parnaparin |
|
Opocrin |
OP 2123
Alpha LMWH
Fluxum Minidalton |
Cupric acid and hydrogen peroxide degradation |
4 |
3:1 |
4,500-5,000 |
|
Reviparin |
|
Knoll |
LU 473111
Clivarin |
Nitrous acid depolymerization |
NA |
3-5:1 |
4,300 |
|
Tinzaparin |
|
Novo |
Logiparin
Novo LHN 1
Innohep |
Enzymatic degradation |
1.3 |
2:1 |
4,900 |
|
Bioparin |
|
Bioberica |
-- |
NA |
NA |
NA |
NA |
|
Miniparin |
|
Syntex |
-- |
NA |
NA |
NA |
NA |
|
Sandoparin |
|
Sandoz |
Monoembolex |
NA |
NA |
NA |
NA |
|
Figure 2A. Schematic representation of the mechanism of action
of unfractionated heparin. Because of its molecular structure,
ie a mean of 45 saccharide units per chain of unfractionated
heparin, it successfully binds to both factor Xa and factor II,
inactivating them. AT-III, anti-thrombin III; Factor-II, prothrombin;
UH, unfractionated heparin.
Figure 2B. Schematic representation of the mechanism of action
of LMWHs. Any unfractionated heparin molecule with at least 5
saccharide units can attach to AT-III and as a complex combines
with factor Xa and inactivates it. However, attachment of unfractionated
heparin AT-III complex to thrombin (Factor-II) requires unfractionated
heparin molecule to have at least 18 saccharide units. Less than
50% of LMWHs have molecules with 18 saccharide units compared
to 90% molecules in unfractionated heparin. Thus, the ratio of
antifactor Xa to antifactor II is more than 1 for LMWHs. Because
of its molecular structure, ie, a mean of 15 saccharide units
per chain of LMWH, not all the chains of LMWH bind to Factor
II; however, it has no problem binding to factor Xa as it requires
only 5 units per chain. LMWHs have a higher antifactor Xa activity
than antifactor II activity. AT-III, antithrombin III; Factor-II,
prothrombin; LMWH, low molecular weight heparin.
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