| The fibrinolytic system also limits excessive fibrin formation
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| page 74 |  | | page 75 |
The coagulation system acts to form fibrin; the fibrinolytic system acts to limit excessive formation of fibrin (both intra- and extravascular) through plasmin-mediated fibrinolysis. Circulating plasminogen binds to fibrin via lysine-binding sites; it is converted to active plasmin by plasminogen activators. Tissue-type plasminogen activator (tPA) is synthesized by endothelial cells; it normally circulates in plasma in low basal concentrations (5 ng/mL), but is released into plasma by stimuli that include venous occlusion, exercise, and epinephrine . Together with plasminogen, it binds strongly to fibrin, which stimulates its activity (the Km for plasminogen decreases from 65 to 0.15μmol/L in the presence of fibrin), thereby localizing plasmin activity to fibrin deposits. Excessive tPA activity in plasma is normally prevented by an excess of its major inhibitor, plasminogen activator inhibitor type 1 (PAI-1), which is synthesized by both endothelial cells and hepatocytes. Urinary-type plasminogen activator (uPA) circulates in plasma both as an active single-chain precursor form, uPA (scuPA, pro-urokinase) and as a more active two-chain form (tcuPA, urokinase). One activator of scuPA is surface-activated coagulation factor XII, which therefore
links the coagulation and fibrinolytic systems. The major components of the fibrinolytic system are illustrated in Table 6.4 and Figure 6.7.
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Excessive formation of plasmin is normally prevented by:
- binding of 50% of plasminogen to histidine-rich glycoprotein (HRG);
- rapid inactivation of free plasmin by its major inhibitor, α2-antiplasmin.
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| The physiologic importance of PAI-1 and α2-antiplasmin is illustrated by the increased bleeding tendency that is associated with the rare cases of their congenital deficiencies (see Table 6.1); the excessive plasma plasmin activity which results from the deficiencies has the effect of lysing hemostatic plugs.
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Table 6-4.
Properties of fibrinolytic system components. |
| Body_ID: None |
| Properties of fibrinolytic system components |
| Body_ID: T006004.50 |
| Component (synonym) | Molecular weight | Plasma concentration (mg/dL) |
| Body_ID: T006004.100 |
| Plasminogen | 92000 | 0.2 |
| Body_ID: T006004.150 |
| Tissue-type plasminogen activator, tPA | 65000 | 5 (basal) |
| Body_ID: T006004.200 |
| Urinary-type plasminogen activator type 1, uPA | 54000 | 20 |
| Body_ID: T006004.250 |
| Plasminogen activator inhibitor type 1, PAI-1 | 48000 | 200 |
| Body_ID: T006004.300 |
| Antiplasmin (α2 antiplasmin) | 70000 | 700 |
| Body_ID: T006004.350 |
| THROMBOLYTIC TREATMENT IN MYOCARDIAL INFARCTION |
| Occlusion of a coronary artery by thrombus causes death of that part of the heart muscle which is supplied by the artery (myocardial infarction). In acute myocardial infarction, the patient typically experiences severe, substantial chest pain. Many such patients are candidates for thrombolytic treatment with a plasminogen activator drug, given intravenously (there are some exceptions). Prompt thrombolysis dissolves the coronary artery thrombus, reduces the size of the infarct, and reduces the risk of complications, including death and heart failure. Aspirin is also given routinely in acute myocardial infarction, to inhibit the platelet component of the developing coronary artery thrombus. |
| Comment. Thrombolytic drugs include tissue-type and urinary-type plasminogen activators (tPA and uPA) (Fig. 6.7), produced by recombinant gene technology, or their synthetic variants. Worldwide, the most commonly used thrombolytic drug is streptokinase (a plasminogen activator produced by streptococci), because of its lower cost. All thrombolytic drugs can cause bleeding (see Table 6.1), as a result of lysis of hemostatic plugs in addition to the target thrombi. |
| Figure 6.7 The fibrinolytic system. Plasminogen can be activated to plasmin by uPA (urokinase), tPA, or streptokinase. uPA and tPA are inhibited by plasminogen activator inhibitor type 1 (PAI-1). Plasmin is inhibited by antiplasmin. Plasmin degrades fibrin to fibrin degradation products (FDP). HMWK, high-molecular-weight kininogen; scuPA, pro-urokinase; tcuPA, urokinase; tPA, tissue-type plasminogen activator. |
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