Effects Of Thrombin-activable Fibrinolysis Inhibitor And Hirudin On Fibrinolysis

With the development of economic and life level, cardiovascular disease, such asacute myocardial infarction and stroke, are one of the life-threatening disease thataffect more and more people each year.Thrombolysis is the main therapeutic approaches to treat thrombosis disease.Dispite of its tremendous clinical success, several major limitations of the therapy stillneed to be addressed. These include bleeding, inadequate reperfusion and thromboticreocclusion. Thus, identifying new therapeutic targets and developing new and safeand efficient thrombolytic agents are the focal points in the field of thrombolysis.The theme of focus on a new anticoagulant-hirudin a new discovered thrombosistherapeutic target-TAFI and TAFIa .The main researches and results are as followed:1. A HPLC/ESI-MS method to analysis and determined the main contaminants ofCPI from Sigma was developed. Solanine was determined as one of the maincontaminants of CPI sample. A RT-HPLC method to purify CPI sample was alsoestablished and the CPI of high purity was obtained.2. The in vitro thrombolysis induced by uPA show that hirudin is not only ananticoagulant but had a stronger stimulation effect than heparin on the clotolysisthrough inhibiting clot regeneration to reduce the temporary exhaustion of uPAand plasminogen and partly inhibiting TAFI activation.3. Through comparing the effects of soluble TM and HMEC treating on TAFIactivation, it was concluded that membrane-bound TM can activate TAFI as wellas soluble TM. TAFI activation could inhibit clotlysis obviously by reducing thegeneration of D-dimer and delaying clotlysis time and initiation time.4. A tPA dose-dependent effect on enhancement of clotlysis by inhibiting TAFIawas observed in the tPA-hirudin combination clotlysis in vitro, and it indicatedthe possibility of combination therapy of plasminogen activator, anticoagulantand TAFIa inhibitor in thrombolysis. A reverse relationship of the clotlysis timeand clotysis initiation time with the dose of TAFIa inhibitor was observed ininternal clotlysis tests in vitro. Low dose of tPA plus TAFIa inhibitor could reachthe same effect of the higher tPA dose. The results indicated that TAFI might havemore important value to patients with thrombophilia and TAFI might be a noveltarget of safe and efficient antithrombotic agents.