Biomedical Engineering Reference
In-Depth Information
for each LMWH product,
130
especially since (unlike UFH) overdosage cannot be fully reversed with
protamine.
164
Development of a heparin derivative combining both high-AT-antithrombotic activities
and a longer intravenous half-life would be a boon.
18.4
OVERVIEW OF COVALENT ANTITHROMBIN-HEPARIN COMPLEXES
18.4.1 L
IMITATIONS
OF
C
URRENT
H
EPARINS
Many clinical issues have evolved that have added increasing challenges to heparin use. These
have given impetus for development of many new anticoagulant and antithrombotic drugs that are
presently undergoing clinical trials. Limitations in heparin use arise from either pharmacokinetic
problems or biophysical obstacles in pacifying prothrombotic activity on surfaces. Physical removal
of UFH from the circulation involves binding to cell surfaces (such as hepatocytes) or passage
through the kidneys.
155
These pharmacokinetic clearance mechanisms defi nitely involve free UFH
separated from its noncovalent AT-UFH complex since AT and UFH in coinjected mixtures dis-
appear from the circulation at different rates.
141
Due to variable protein interactions
in vivo
, UFH
has an intravenous half-life in humans ranging from 18 min to 1 h.
155
To compensate for the rapid
circulatory loss, UFH is administered by subcutaneous injection (which gives peak plasma levels
at 4 h)
165
or given by slow intravenous infusion.
166
Although LMWHs have increased intravenous
half-lives over UFH,
167
subcutaneous administration of LMWH gave peak plasma activity at 3 h
that returned to background by 12 h.
161
Other interactions confound UFH application since heparin
can bind to fl uid-phase plasma protein,
168,169
platelets,
170
and endothelial surfaces.
171
Complexation
of UFH and plasma proteins (other than AT and heparin cofactor II) occurs through nonselective
charge attractions
172
and results in reduced activity.
168
UFH function is simply masked by its binding
to basic plasma proteins since activity can be recovered by displacement with innocuous polyan-
ions.
173
It is, in part, the variable association-dissociation of UFH from basic plasma and cell sur-
face proteins that causes decreased regulation of heparin activity and reappearance of activity long
after protamine neutralization (referred to as the heparin rebound effect).
173
Nonspecifi c plasma
protein binding by UFH is somewhat molecular weight-dependent since LMWHs have reduced
binding.
174,175
Biophysical limitations of heparin are seen in the lack of ability to inhibit fi brin-
bound thrombin.
44,45
At prophylactic doses, UFH can even assist in accreting thrombin onto fi brin
clots,
176
where thrombin in the resultant thrombin-UFH-fi brin-ternary complex
177
is resistant to
reaction with AT·UFH.
178
This phenomenon results from an altered substrate reactivity by thrombin
in the ternary complex
179
so that reaction against exogenous AT·UFH is reduced.
178
Studies show
that LMWHs are also ineffective against clot-bound thrombin.
180
Further biophysical obstruction is
evident in the reduced rate of UFH inactivation of FXa when bound to phospholipid surfaces within
the prothrombinase complex.
181,182
Other UFH defi ciencies involving adverse side effects have long
been noted, the most signifi cant of which is bleeding risk.
183
Careful monitoring is required to maintain therapeutic levels of UFH activity without inducing
hemorrhage
184
and regimens are designed to optimize the effi cacy/bleeding ratio.
185
LMWH has a
more predictable anticoagulant profi le. Nevertheless, there is no clinical evidence that hemorrhagic
complications are decreased for LMWH treatment compared with that for UFH.
186,187
Several other
iatrogenic issues exist. Thrombocytopenia, arising from development of antibodies against epitopes
from platelet-bound heparin,
188
precludes further UFH treatment. Although data from acute coro-
nary syndrome patients has suggested that LMWH may have a lower risk of inducing thrombo-
cytopenia,
183
LMWH is not recommended for the treatment of thrombocytopenia patients since
LMWHs cross-react with about 80% of the antibodies from UFH-induced thrombocytopenia.
183
Finally, osteoporosis occurs in 17-36% of patients receiving chronic heparin treatment.
189,190
To avert the shortcomings of heparin, several nonheparinoid anticoagulants have been investi-
gated such as hirudin, hirulog, phe-pro-arg-chloromethyl ketone (PPACK), and ximelagatran.
191-195
Hirudin is a small-polypeptide (7000 MW) direct thrombin inhibitor that binds noncovalently with
