Biomedical Engineering Reference
In-Depth Information
patient but leads to serious risk of thrombotic complications such as stroke.
11
Thus, obviation of clot
induction by catheter surfaces would solve the major cause of thrombotic disease in children.
Evolution of a thrombus by biomaterial surfaces involves the activation of plasma coagulation
proteins in a cascade pathway that leads to the production of thrombin. Systemic thrombin genera-
tion
in vivo
depends on a number of parameters. Parameters such as plasma levels of procoagu-
lant or anticoagulant molecules and cell or extracellular matrix surfaces that initiate or inhibit the
coagulation cascade control the hemostatic state within the individual.
12
Ultimately, activation of
factors within the coagulation cascade determines the generation of thrombin from its precursor
prothrombin.
13
Once generated, thrombin converts fi brinogen to fi brin monomer that polymerizes
to form the fi brin clot.
14
Within the thrombotic process, thrombin is a key enzyme in the regulation
of coagulation.
15
After the initial thrombin is formed, it can provide feedback to activate cascade
factors such as FV,
16
FVIII,
17
and FXI
18
that are involved in its generation. Also, thrombin activates
FXIII to FXIIIa, which can in turn cross-link fi brin to form a more stable clot.
19,20
Furthermore,
thrombin activates platelets to bind with other cells or the fi brin within the clot
21
and converts
thrombin-activatable fi brinolysis inhibitor into an active form that inhibits fi brinolysis.
22-24
In addi-
tion to these procoagulant features, thrombin can also act as an anticoagulant that limits its own for-
mation. When bound to endothelial thrombomodulin, thrombin can activate protein C.
25
Activated
protein C, along with cofactor protein S, converts FVa and FVIIIa into inactive forms incapable of
accelerating thrombin generation.
26
Thus, thrombin has a multifunctional capability to affect the
progress of coagulation. As a corollary, inhibition of thrombin would be a key step in the control
of coagulation.
Antithrombin (AT) is a member of the family of serine protease inhibitors (serpins). AT acts
mainly to irreversibly neutralize enzymes generated from activation of the coagulation cascade.
27
Thus, AT forms irreversible serpin-protease inhibitor complexes with FXIIa, FXIa, FIXa, FXa,
and thrombin.
13,28,29
However, AT is most effective at thrombin inhibition, as evidenced by rate con-
stant comparisons.
30
Further acceleration of thrombin reaction with AT can be affected by heparin
and heparan sulfate glycosaminoglycans (GAGs). In the case of commercial unfractionated heparin
(UFH), the rate of thrombin inhibition by AT is elevated at least 1000-fold.
31
This rate enhancement
is due to two major factors. First, UFH molecules bind to AT through a unique oligosaccharide
sequence
32
that induces a conformational chain in the serpin that makes it more reactive toward
thrombin.
33
Second, UFH can act as a template that binds both thrombin and AT so that a tertiary
complex is formed in which the UFH is a bridge that localizes the enzyme and inhibitor.
34
After
thrombin and AT have reacted to produce an irreversible thrombin-AT (TAT) complex, massive
structural changes in the AT moiety cause a decrease in affi nity for the UFH so that the GAG can
dissociate and catalyze another thrombin
AT reaction.
35
UFH's acceleration of thrombin inhibi-
tion allows for more effective neutralization by AT of the fi rst thrombin formed after initiation of
coagulation, so that propagation of thrombin generation from feedback activation is ablated.
17
Although UFH, along with its low-molecular-weight derivatives, is the most common clinically
used anticoagulant,
36,37
there are several major limitations associated with its application. One phar-
macokinetic problem is that UFH has a short, dose-dependant intravenous half-life.
38
Rapid loss
from the circulation results from nonspecifi c binding to positively charged plasma and cell surface
proteins,
39
as well as passage through tissue layers because of its small size.
40
It is due to the variation
in the UFH-binding proteins between individuals that UFH has such an unpredictable anticoagulant
effect.
41
Other factors limiting UFH anticoagulation treatment and prophylaxis are biophysical in
origin. The major issue relates to the resistance of UFH toward inhibition of coagulation factors
adhering to surfaces. For example, noncovalent AT-UFH complexes are unable to neutralize FXa
bound to phospholipid
42,43
and fi brin-bound thrombin.
44,45
Clinically, this is signifi cant since evi-
dence indicates major impacts from the lack of pacifi cation of fi brin clot-associated procoagulant
activity. Thus, the fact that there is an early recurrence of unstable coronary artery syndromes
when UFH treatment is discontinued
46
gives credence to the concept that lack of neutralization of
clot-bound thrombin by UFH infl uences clot propagation.
42-44
Although high doses of UFH might
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