II Tissue plasminogen activator and plasminogen in the brain

II Tissue plasminogen activator and plasminogen in the brain

STATE-OF-THE-ART LECTURES 1 / I The current role of thrombolytic therapy in clinical practice VAN DE WERF F Thrombolytic therapy consists of intrav...

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I The current role of thrombolytic therapy in

clinical practice VAN DE WERF F

Thrombolytic therapy consists of intravenous infusion of plasminogen activators that dissolve the fibrin matrix ofa thrombus. Optimal reperfusion (TIMI flow grade 3) is obtained in 30% to 55% of the patients with the current fibrinolytic agents. The associated risk ofintracranial hemorrhage ranges from 0.5% to 0.9%. In an attempt to improve the efficacy (and safety) of thrombolysis many new fibrinolytic agents are currently being studied in phase II and III trials in patients with acute myocardial infarction. Plasminogen activators obtained from saliva of the vampire bat (DSPA 1 and DSPA2), recombinant single-chain urokinase-type plasminogen activator (rscu-PA), mutants and variants of rt-PA (r-PA or reteplase, a non-glycosylated recombinant plasminogen activator; TNK-tPA, a PAI-I resistant combination mutant of t-PA; n-PA (lanoteplase), a deletion mutant of tPA with an additional aminoacid substitution in kringle-1), and recombinant staphylokinase have already

been studied in patients or are ready to enter clinical investigation. The key results of these studies will be presented. A number of new antithrombotic co-therapies have also been tested over the last years or are currently being evaluated in patients with acute myocardial infarction: full-dose fibrinolytic therapy plus direct antithrombins like hirudin and hirulog; full-dose fibrinolytic therapy plus low molecular weight heparins; full-dose fibrinolytic therapy plus new antiplatelet agents (GPIIb/IIIa receptor-antagonists and thromboxane A2 synthase/receptor antagonists like ridogrel); reduced-dose fibrinolytic therapy plus GPIIb/IIIa receptor antagonists. The most intriguing new antithrombotic strategy at present is the use of abciximab in conjunction with a reduced dose of a fibrinolytic agent (alteplase and streptokinase in TIMI-14A and reteplase in SPEED).


II Tissue plasminogen activator and

plasminogen in the brain STRICKLAND S Department of Pharmacology and Program in Genetics, University at Stony Brook, Stony Brook, NY 11794-8651

ECM interaction via tPA/plasmin catalyzed degradation of laminin sensitizes hippocampal neurons to cell death.

Excess excitatory amino acids can provoke neuronal death in the hippocampus, and the extracellular proteases tissue plasminogen activator (tPA) and plasmin(ogen) have been implicated in this death. To investigate substrates for plasmin that might influence neuronal degeneration, extracellular matrix (ECM) protein expression was examined. Laminin is expressed in the hippocampus, and disappears after excitotoxin injection. Laminin disappearance precedes neuronal death, is spatially coincident with regions that exhibit neuronal loss, and is blocked by either tPA-deficiency or infusion ofa plasmin inhibitor, both of which also block neuronal degeneration. Preventing neuronal-laminin interaction by infusion of anti-laminin antibodies into tPA-deficient mice restores excitotoxic sensitivity to their hippocampal neurons. These results indicate that disruption of neuronal-


III TAFI (procarboxypeptidase b) compared to

the other inhibitors of the fibrinolytic system NESHE1M ME Departments of Biochemistry and Medicine, Queen's University, Kingston, ON, Canada

The fibrinolytic system can be down regulated by the serine protease inhibitors (SERPINS) PAI-I and tx2-antiplasmin (o~2AP). These are very fast acting, specific inhibitors that target plasminogen activators and plasmin. These SERPINS function to completely inhibit their target enzymes and they are consumed by the process of inhibition. The fibrinolytic system also can be down regulated by a fundamentally different mechanism involving the activation TAFI to the carboxypeptidase B-like enzyme TAFIa, which suppresses fibrinolysis by removing carboxy terminal lysine residues from partially degraded fibrin, thereby preventing the up regulation of plasminogen activation through plasmin-mediated positive feedback. TAFI is activated by thrombin at low levels in the presence of both soluble and cellassociated forms of thrombomodulin. The mechanism of the reaction is similar to that of protein C activation, although slightly more of the

thrombomodulin structure is needed for TAFI activation. TAFI also can be activated by thrombin, in the absence of thrombomodulin, at the high levels of thrombin generated after clotting through the intrinsic pathway of coagulation. Because TAFI is activated by thrombin or the thrombin-thrombomodulin complex, it defines a direct molecular link between the coagulation and fibrinolytic systems whereby activity in the former suppresses activity in the latter. Thus, TAFI, like PAl- 1 and ~2AP, has an essential role probably in maintaining an appropriate balance between fibrin formation and removal. In addition, from what is currently known about the activation of TAFI and the impact of TAFIa on fibrinolysis, one would anticipate that pharmaceutical modulation of TAFIa would be efficacious in enhancing the clot lysing potential of thrombolytics.