Biomedical Engineering Reference
In-Depth Information
Table 12.5
Thrombolytic agents approved for general medical use
Product
a
Company
Activase (rh-tPA)
Genentech
Ecokinase (rtPA; differs from human tPA in that three of its fi ve domains
have been deleted)
Galenus Mannheim
Retavase (rtPA; see Ecokinase)
Boehringer Manheim/Centocor
Rapilysin (rtPA; see Ecokinase)
Boehringer Manheim
Tenecteplase (also marketed as Metalyse) (TNK-tPA, modifi ed rtPA)
Boehringer Ingelheim
TNKase (tenecteplase; modifi ed rtPA; see Tenecteplase)
Genentech
Streptokinase (produced by
Streptokinase haemolyticus
)
Va r ious
Urokinase (extracted from human urine)
Various
Staphylokinase (extracted from
Staphylococcus aureus
and produced in
various recombinant systems
Va r ious
a
r: recombinant; rh: recombinant human.
12.4.1 Tissue plasminogen activator
The natural thrombolytic process is illustrated in Figure 12.11. Plasmin is a protease that catalyses
the proteolytic degradation of fi brin present in clots, thus effectively dissolving the clot. Plasmin is
derived from plasminogen, its circulating zymogen. Plasminogen is synthesized in, and released
from, the kidneys. It is a single-chain 90 kDa glycoprotein that is stabilized by several disulfi de
linkages.
tPA (also known as fi brinokinase) represents the most important physiological activator of plas-
minogen. tPA is a 527 amino acid serine protease. It is synthesized predominantly in vascular
endothelial cells (cells lining the inside of blood vessels) and displays fi ve structural domains,
each of which has a specifi c function (Table 12.6). tPA displays four potential glycosylation sites,
three of which are normally glycosylated (residues 117, 184 and 448). The carbohydrate moieties
play an important role in mediating hepatic uptake of tPA and, hence, its clearance from plasma.
It is normally found in the blood in two forms: a single-chain polypeptide (type I tPA) and a two-
chain structure (type II) proteolytically derived from the single-chain structure. The two-chain
form is the one predominantly associated with clots undergoing lysis, but both forms display
fi brinolytic activity.
Table 12.6
The fi ve domains that constitute human tPA, and the biological function of each domain
tPA domain
Function
Finger domain (F domain)
Promotes tPA binding to fi brin with high affi nity
Protease domain (P domain)
Displays plasminogen-specifi c proteolytic activity
Epidermal growth factor domain (EGF domain)
Binds hepatic receptors, thereby mediating hepatic
clearance of tPA from blood
Kringle-1 domain (K
1
domain)
Associated with binding to the hepatic receptor
Kringle-2 domain (K
2
domain)
Facilitates stimulation of tPA's proteolytic activity by
fi brin
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