Clot lysis induced by a monoclonal antibody against alpha 2-plasmin inhibitor.
A monoclonal antibody (MoAb) to alpha 2-plasmin inhibitor designated JTPI-1 inhibited antiplasmin activity by interfering with formation of alpha 2-plasmin inhibitor (alpha 2-PI)-plasmin complex. With this MoAb, we observed plasma clot lysis in vitro and evaluated the potential of JTPI-1 to serve as a new therapeutic agent for thrombolysis. After adding 125I-labeled fibrinogen to plasma, clots were made by adding thrombin and calcium and were then resuspended in normal plasma containing various concentrations of JTPI-1. The presence of JTPI-1 enhanced release of the soluble 125I-labeled fibrin degradation fragment from the clots in a dose-dependent manner. With tissue plasminogen activator (t-PA)-depleted plasma, we showed that induction of clot lysis by JTPI-1 was dependent on fibrin-bound endogenous t-PA. Regulation of fibrinolysis initiated on the fibrin surface by fibrin-bound t-PA and plasminogen is mediated by alpha 2-PI cross-linked to fibrin by activated factor XIII. JTPI-1 bound to this cross-linked alpha 2-PI neutralized its activity and induced partial digestion of fibrin by plasmin. This resulted in additional binding of Glu-plasminogen to fibrin during the incubation. When 1.2 mumol/L JTPI-1 and 5 U/mL exogenous t-PA were present in the suspending plasma, the rate of clot lysis was essentially the same as that induced by 60 U/mL exogenous t-PA alone. These results suggest that JTPI-1 may be useful in reducing the amount of t-PA administered for thrombolytic therapy.
Sakata
Y
Y
Division of Hemostasis and Thrombosis, Jichi Medical School, Tokyo, Japan.
Eguchi
Y
Y
Mimuro
J
J
Matsuda
M
M
Sumi
Y
Y
D000911:Antibodies, Monoclonal / Q000276:immunology*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis; D005343:Fibrinolytic Agents; D006801:Humans; D066298:In Vitro Techniques; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000276:immunology*
D000911:Antibodies, Monoclonal; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator