Tissue plasminogen activator

The natural thrombolytic process is illustrated in Figure 12.11. Plasmin is a protease that catalyses the proteolytic degradation of fibrin 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 disulfide linkages.

tPA (also known as fibrinokinase) represents the most important physiological activator of plasminogen. 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 five structural domains, each of which has a specific 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 fibrinolytic activity.

Table 12.6 The five domains that constitute human tPA, and the biological function of each domain tPA domain Function

Finger domain (F domain)

Protease domain (P domain)

Epidermal growth factor domain (EGF domain)

Kringle-1 domain (K1 domain) Kringle-2 domain (K2 domain)

Promotes tPA binding to fibrin with high affinity Displays plasminogen-specific proteolytic activity Binds hepatic receptors, thereby mediating hepatic clearance of tPA from blood Associated with binding to the hepatic receptor Facilitates stimulation of tPA's proteolytic activity by fibrin

Figure 12.11 (a) The fibrinolytic system, in which tPA proteolytically converts the zymogen plasminogen into active plasmin, which in turn degrades the fibrin strands, thus dissolving the clot. tPA and plasminogen both bind to the surface of fibrin strands (b), thus ensuring rapid and efficient activation of the thrombolytic process

Figure 12.11 (a) The fibrinolytic system, in which tPA proteolytically converts the zymogen plasminogen into active plasmin, which in turn degrades the fibrin strands, thus dissolving the clot. tPA and plasminogen both bind to the surface of fibrin strands (b), thus ensuring rapid and efficient activation of the thrombolytic process

Fibrin contains binding sites for both plasminogen and tPA, thus bringing these into close proximity. This facilitates direct activation of the plasminogen at the clot surface (Figure 12.11). This activation process is potentiated by the fact that binding of tPA to fibrin (a) enhances the subsequent binding of plasminogen and (b) increases tPA's activity towards plasminogen by up to 600-fold.

Overall therefore, activation of the thrombolytic cascade occurs exactly where it is needed, i.e. on the surface of the clot. This is important, as the substrate specificity of plasmin is poor, and circulating plasmin displays the catalytic potential to proteolyse fibrinogen, factor V and factor VIII. Although soluble serum tPA displays a much reduced activity towards plasminogen, some free-circulating plasmin is produced by this reaction. If uncontrolled, this could increase the risk of subsequent haemorrhage. This scenario is usually averted because circulating plasmin is rapidly neutralized by anther plasma protein, a2-antiplasmin (a 70 kDa single-chain glycoprotein that binds plasmin very tightly in a 1:1 complex). In contrast to free plasmin, plasmin present on a clot surface is very slowly inactivated by o^-antiplasmin. The thrombolytic system has thus evolved in a self-regulating fashion, which facilitates efficient clot degradation with minimal potential disruption to other elements of the haemostatic mechanism.

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