From the Cardiovascular Division (E.M.A.) and Department of Medicine
(R.H.), Brigham and Women's Hospital, Boston, Mass.
Correspondence to Elliott M. Antman, MD, Director, Samuel A. Levine Cardiac Unit, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}bustoff.bwh.harvard.edu
Modern
antithrombotic therapy for acute coronary syndromes rests on a
growing body of basic and clinical evidence that rupture or erosion of
the surface of a vulnerable plaque sets in motion a sequence of events
culminating in thrombus formation in the culprit
vessel.1 When the contents of a vulnerable plaque
are exposed to the bloodstream, platelets adhere to the
subendothelial matrix, release ADP and
thromboxane A2, and amplify the
generation of thrombin.2 As a result, a
platelet aggregate begins to develop. In addition, the coagulation
cascade is activated and fibrin strands are formed.
Importance of Thrombin
Thrombin (factor IIa) plays a pivotal role in the processes
described above because of its extensive procoagulant and prothrombotic
actions.3 In addition to catalyzing the
transformation of soluble fibrinogen into fibrin monomers and
activating factor XIII to produce cross-linked fibrin, thrombin
promotes clot formation by activating factors V and VIII. It is also
one of the most potent agents responsible for platelet adhesion,
activation, and aggregation. In vessels with a diseased
endothelium, thrombin promotes the release of the
vasoconstrictor endothelin 1. Importantly, thrombin also potentiates
the proliferative effects of multiple growth factors and is a key
mediator of early smooth muscle cell proliferation after
arterial injury.
There is now abundant evidence that thrombus formation can be
prevented by direct or indirect inactivation of thrombin or by
inhibition of thrombin production via the intrinsic or
extrinsic limbs of the coagulation pathway.3
Unfractionated heparin, the standard antithrombotic agent in clinical
practice, is a glycosaminoglycan, consisting of
chains of alternating residues of D-glucosamine and uronic
acid.4 Although familiar to the vast majority of
clinicians, unfractionated heparin has several disadvantages: (1) a
variable anticoagulant effect (necessitating frequent monitoring of
activated partial thromboplastin time), (2)
neutralization by platelet factor 4, (3) less effective
inhibition of clot-bound thrombin versus fluid-phase thrombin, and (4)
the potential to cause thrombocytopenia and HITS with paradoxical
thrombosis.4 5 6
Potential Advantages of LMWHs
There is increasing interest in LMWH preparations as an
alternative form of antithrombin therapy. They are formed by controlled
enzymatic or chemical depolymerization producing
saccharide chains of varying lengths but with a mean molecular
weight of
It has been argued that the enhanced anti-Xa:IIa ratio offered by
the LMWHs provides a therapeutic benefit. Because factor Xa generation
occurs several steps earlier in the coagulation cascade than thrombin
generation, inhibition of Xa has a profound effect on the later steps
in coagulation. Put another way, there is a distinct kinetic advantage
to inhibiting early reactions in coagulation: quenching a small amount
of Xa may prevent the formation of much larger quantities of thrombin.
Other features of LMWHs that are of particular clinical relevance are a
decreased sensitivity to platelet factor 4 and a more predictable
anticoagulant effect along with lower rates of thrombocytopenia and
HITS. In addition, the LMWHs are clinically attractive because of
better bioavailability, a more consistent pattern of clearance,
and ease of administration via the subcutaneous route. In theory, they
allow clinicians to prescribe relatively unsupervised long-term
self-administration of antithrombotic therapy by patients at home (ie,
"an insulin-like injection for coronary artery
disease").
Additional Antithrombotic Properties of LMWHs
In addition to the anti-Xa activity discussed above, another
antithrombotic property of these agents bears discussion. The
lipid-rich core of exposed atherosclerotic plaques has abundant
supplies of tissue factor, which results in activation of factor VII
and stimulation of the extrinsic limb of the coagulation cascade,
ultimately leading to formation of factor Xa.8
TFPI is a 276-amino-acid protease inhibitor that binds to
factor Xa and inactivates the tissue factor:VIIa:Xa
complex.9 TFPI circulates largely bound to
lipoproteins in plasma but can be released after administration of both
unfractionated heparin and LMWHs. Each LMWH has a unique TFPI release
profile that is also distinct from its anti-Xa
activity.10 Given the higher bioavailability and
more consistent blood concentration of the heparin-like
activity of LMWHs, one might speculate that they may also release TFPI
more efficiently than unfractionated heparin.
Clinical Trials of LMWHs in UA/NQMI
Beginning with the initial encouraging open-label trial with
nadroparin (anti-Xa:anti-IIa ratio of 3:1) conducted by Gurfinkel and
colleagues,11 a series of trials of LMWHs in the
management of UA and NQMI have been undertaken in the past several
years.15 The FRISC trial demonstrated that
dalteparin (anti-Xa:anti-IIa ratio of 2:1) was superior to placebo for
the acute-phase management of UA/NQMI.12 However,
with longer-term follow-up and continued treatment with a once-daily
injection of dalteparin, event rates for the dalteparin and placebo
groups began to converge, and there was no significant difference in
event rates in the 2 groups by 150 days. The FRIC trial demonstrated
equivalence between dalteparin and intravenous
unfractionated heparin during the acute-phase management of patients
with UA/NQMI.13 The ESSENCE study showed, after a
median duration of treatment of 2.6 days, a 16.2% reduction in the
relative risk of death, MI, or recurrent ischemia in the group
treated with enoxaparin (anti-Xa:anti-IIa ratio of 3:1) compared with
unfractionated heparin.14 It has been argued that
the superiority of nadroparin and enoxaparin compared with
unfractionated heparin is derived in part from their anti-Xa:anti-IIa
ratios of 3:1. LMWHs with a lower anti-Xa:anti-IIa ratio, such as
dalteparin (2:1), appear to be equivalent to unfractionated heparin in
the acute phase of UA/NQMI management.
Intriguing New Data on LMWH Preparations
In this issue, Montalescot and colleagues report the results
of a French substudy from the ESSENCE trial.15
This substudy sheds new light on another potential difference between
unfractionated heparin and enoxaparin that may translate into a
clinical advantage. The purpose of the substudy was to evaluate the
prognostic value of a variety of markers of inflammation, hemostasis,
myocardial necrosis, and the vasoconstrictor peptide endothelin 1. The
essential observations of Montalescot and coworkers are that the
baseline levels of such acute-phase markers as C-reactive protein,
fibrinogen, and von Willebrand factor were all elevated when
patients were admitted and that these markers increased further over
the next 48 hours, consistent with the concept of an ongoing
inflammatory process. However, only the increment in von
Willebrand factor during this 48-hour period was an independent
predictor of adverse clinical outcome at both 14 and 30 days of
follow-up. Although elevations of von Willebrand factor have
been reported previously in patients with acute coronary
syndromes,16 17 the unique contribution of the
French substudy is the finding that enoxaparin blunted the increase in
von Willebrand factor compared with unfractionated heparin. Why
is this observation potentially so important, and what are its
implications?
von Willebrand factor is a heterogeneous,
multimeric plasma glycoprotein with 2 major
functions18: (1) It promotes platelet
interaction with the damaged vessel wall under conditions of high shear
stress by binding to the platelet glycoprotein Ib and
IIb/IIIa receptors, and (2) it is the carrier of factor VIII, an
essential cofactor in the generation of factor Xa. Binding of factor
VIII to von Willebrand factor protects factor VIII from
inactivation by activated protein C.
von Willebrand factor can also promote platelet
aggregation by cross-linking multiple activated platelets.
Although fibrinogen is the predominant plasma molecule that binds to
the activated glycoprotein IIb/IIIa receptor, this
is related in part to the higher concentration of fibrinogen compared
with von Willebrand factor. Given its combined effects on
platelet adhesion/aggregation and its procoagulant effect, von
Willebrand factor plays an important role in thrombus formation
and propagation. The multiplier effects and feedback loops involved in
the dynamic interplay between the coagulation cascade and platelet
aggregation promote the release of additional stores of von
Willebrand factor from the
Previous epidemiological observations suggest that an elevated
level of von Willebrand factor is a risk factor for the
development of coronary heart disease. In addition, elevated
levels of von Willebrand factor have been reported in patients
with acute MI, with UA, and after coronary
angioplasty.16 17 18 19 An elevated von
Willebrand factor level may arise from a combination of
increased biosynthesis, perhaps mediated by inflammatory
cytokines, or enhanced release of preformed von
Willebrand factor stored in endothelial cell
Weibel-Palade bodies. Successful coronary reperfusion with
thrombolytics blunts the rise in von Willebrand
factor levels after acute MI.16
What does all this information about von Willebrand
factor have to do with heparin fragments, and where does enoxaparin fit
in? Structure-function studies of von Willebrand factor have
begun to identify key domains of the molecule.18
In addition to domains responsible for binding to factor VIII and the
glycoprotein Ib and IIb/IIIa receptors, there are also
heparin-binding domains on the von Willebrand factor molecule.
Sobel et al20 21 showed that unfractionated
heparin as well as specific novel fractions of standard heparin are
capable of binding to von Willebrand factor via its
heparin-binding domain and inhibiting platelet interactions with
von Willebrand factor.
The data from Montalescot et al raise several
hypotheses.15 It is possible that enoxaparin is
more efficient than unfractionated heparin in binding to the
heparin-binding domain of von Willebrand factor, ultimately
leading to less von Willebrand factor–dependent platelet
adhesion and aggregation and the release of less von Willebrand
factor from platelet
Given the small sample size of the Montalescot study (n=68), it
is appropriate to interpret the data cautiously and consider them to be
hypothesis-generating rather than conclusive and definitive. If
additional data emerge supporting the notion that enoxaparin more
efficiently inhibits the interaction of von Willebrand factor
with platelets and the ultimate release of additional von
Willebrand factor in acute coronary syndromes, one may
then add an antiplatelet action to enoxaparin's portfolio as an
antithrombotic agent.
Test of a New Antithrombotic Strategy for UA/NQMI
As emphasized by Merlini and
colleagues,22 increased activity of the
coagulation cascade is seen in patients with UA and MI not only during
the acute phase of their illness but also persisting for several
months. It seems logical, therefore, to provide effective
antithrombotic therapy during both the acute phase and the chronic
phase of management of patients with UA/NQMI. The constellation of
properties discussed so far for LMWHs (enriched anti-Xa activity, more
effective release of TFPI, potential suppression of and inhibition of
von Willebrand factor, and high bioavailability by the
subcutaneous route) makes them attractive candidates for testing new
strategies of antithrombotic therapy.
The TIMI 11B trial, which recently concluded enrollment,
randomized patients with UA/NQMI to the standard strategy of
unfractionated heparin in the acute phase (for 3 days) followed by no
additional antithrombotic therapy other than aspirin in the chronic
phase versus the novel strategy of subcutaneous enoxaparin twice daily
during the acute phase and continued twice daily in a slightly reduced
dose for an additional month after hospital discharge.
Investigators have sought to improve on unfractionated heparin
since purified extracts of it were introduced into clinical trials 50
years ago in Canada and Sweden. Previous interest in direct
antithrombins has been tempered by a combination of lackluster results
in clinical trials to date, failure to achieve a durable treatment
effect, and a narrow therapeutic:toxic ratio. In contrast, the
available data suggest that LMWHs are clearly easier to administer than
unfractionated heparin, are of at least equivalent efficacy in treating
patients with UA/NQMI, and may be superior, depending on the agent
studied. Additional data on the role of enoxaparin in the acute and
chronic phases of management of UA/NQMI will be forthcoming from TIMI
11B; valuable information on its role in angioplasty will come from the
ENTICES and ATLAST trials, and its use as adjunctive therapy to tissue
plasminogen activator for ST-segment elevation
MI will come from HART-II. Exciting times are
ahead—clinicians may have a replacement for unfractionated heparin as
the new millennium arrives.
Selected Abbreviations and Acronyms
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Dr Antman receives grant support for clinical trials on enoxaparin from Rhône-Poulenc-Rorer via his affiliation with the TIMI group.
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© 1998 American Heart Association, Inc.
Editorial
Low-Molecular-Weight Heparins
An Intriguing New Twist With Profound Implications
Key Words: Editorials • heparin • thrombin
5000.4 Much of the discussion
regarding potential advantages of the LMWHs centers around their
enhanced ratio of anti-Xa:anti-IIa activity. The explanation for this
is that a chain length of 
18 saccharides is required to form
a ternary complex between heparin, antithrombin, and
thrombin.7 A critical pentasaccharide
sequence is required for attachment of a heparin fragment to
antithrombin, and an additional 13 saccharide residues are
necessary to allow the heparin fragment to simultaneously
attach itself to the heparin-binding domain of thrombin, thus creating
the ternary complex.4 LMWH fragments of <18
saccharides retain the critical pentasaccharide
sequence, which is all that is required for formation of a
Xa:antithrombin:heparin complex. 
-granules of platelets and
the Weibel-Palade bodies of endothelial
cells.18 -granules. Alternatively, or in addition,
the greater anti-Xa activity of enoxaparin compared with unfractionated
heparin may result in less thrombin generation, which could also lead
to less platelet activation and smaller amounts of von
Willebrand factor released from storage depots. It is also
possible that LMWHs may decrease the rate of von Willebrand
factor synthesis by endothelial cells.
HITS
=
heparin-induced thrombocytopenia syndrome
LMWH
=
low-molecular-weight heparin
MI
=
myocardial infarction
NQMI
=
non–Q-wave myocardial infarction
TFPI
=
tissue factor pathway inhibitor
UA
=
unstable angina
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