Biomedical Engineering Reference
In-Depth Information
TABLE 18.2
Plasma Clearance of Heparins and Covalent
Antithrombin-Heparin Complexes
Intravenous Half-Life (h)
Method
Heparin Precursor
ATH (
α
-Phase)
ATH (
β
-Phase)
1
0.23
±
0.03
<
0.5
0.65
±
0.06
2
0.23
±
0.03
0.89
±
0.26
—
3
2.35
±
0.17
1
7.85
±
0.18
4
2.50
±
0.18
1
7.63
±
0.75
5
—
>
UFH
—
6
—
<
3
—
7
0.32
2.6
13
Methods
: (1) ATH prepared by tolylene-2,4-diisothiocyanate linkage of N-
desulfated high-affi nity heparin to antithrombin;
231
(2) ATH prepared by
tolylene-2,4-diisothiocyanate linkage of hexyl-amino substituted high-affi nity
heparin to antithrombin;
231,246,272
(3) ATH prepared by tolylene-2,4-diisothio-
cyanate linkage of hexyl-amino substituted high-affi nity low-molecular
weight heparin (MW
=
3200) to antithrombin;
271,314
(4) ATH prepared by
tolylene-2,4-diisothiocyanate linkage of hexyl-amino substituted high-affi nity
low-molecular weight heparin (MW
=
4300) to antithrombin;
271,314
(5) ATH
prepared by reduction by NaBH
3
CN of Schiff base between aldehyde on
anhydromannose-terminating heparin and amino on antithrombin;
247,249
(6)
ATH prepared by reaction of CNBr-activated heparin and antithrombin;
250,251
and (7) ATH prepared by Amadori rearrangement of Schiff base between
aldehyde on aldose-terminating unfractionated heparin and amino on
antithrombin.
141,261,264
0.18 h, respec-
tively).
270
To test antithrombotic activity for hexyl-amino UFH- or LMWH-containing ATH, a
Wessler rabbit thrombus prevention model was used, whereby, after systemic injection of differ-
ent doses of test compounds, glass-activated plasma was incubated in a jugular vein segment for
10 min to semiquantitatively assess diminution of thrombus growth within the vessel.
272
When
activated plasma was placed in the vessel segment up to 45-60 min after administration of anti-
coagulant, similar clot sizes were observed for all conjugates relative to equal mass doses of the
corresponding noncovalent AT
free GAGs (half-lives of 3200 and 4300 LMWHs were 2.35
±
0.17 h and 2.50
±
heparinoid mixtures. When activated plasma was introduced
from 60 to 120 min after anticoagulant injection, a reduction in size and number of thrombi was
observed for the ATH products relative to noncovalent mixtures because of increased half-lives
of the conjugates.
272
No data on bleeding side effects of Ceustermans et al. ATH is available.
Regarding Björk et al. ATH, intravenous bolus injection of small amounts into 12-week-old mice
gave successful antibody production against the human AT-containing complex,
249
although no
pharmacokinetics was reported. Observations of low nonspecifi c binding to surface molecules of
hybridoma cells
249
may indicate that the Björk et al. conjugate might have an increased intravenous
half-life from reduced affi nity for
in vivo
protein binding. However, a low 5.2 unit mg
-
1
anti-FXa
activity measured for the conjugate in these studies makes for a dubious antithrombotic potential.
More extensive study of
in vivo
effi cacy of the Mitra and Jordan ATH has been done.
250,251
Blood
samples were taken from rabbits after completion of intravenous infusion with 84 or 200 anti-FXa
units kg
−
1
of ATH or UFH at 2 mL kg
-
1
. APTT tests of the samples showed functional activity for
+
