Tridegin, a Novel Peptidic Inhibitor of Factor XIIIa from the Leech, Haementeria ghilianii, Enhances Fibrinolysis In Vitro

Abstract

SummaryTridegin is a potent inhibitor of factor Xllla from the leech, Haementeria ghilianii, which inhibits protein cross-linking. It modifies plasmin-mediated fibrin degradation as shown by the absence of D-dimer and approximately halves the time for fibrinolysis. Plasma clots formed in the presence of Tridegin lyse more rapidly when either streptokinase, tissue plasminogen activator or hementin is added 2 h after clot formation. The effect of Tridegin is markedly increased if clots are formed from platelet-rich plasma. Platelet-rich plasma clots are lysed much more slowly by the fibrinolytic enzymes used and if Tridegin is present, the rate of lysis returns almost to that of platelet- free clots. These studies indicate the important role of platelets in conferring resistance to commonly used fibrinolytic enzymes and suggest that protein cross-linking is an important step in this effect. Moreover they indicate that Tridegin, a small polypeptide, may have potential as an adjunct to thrombolytic therapy.

Differences in the inhibition of coagulation factor XIII-A from animal species revealed by Michael Acceptor– and thioimidazol based blockers

“…A comparable effect was described for Tridegin, a leech-derived natural peptidic FXIIIa-inhibitor [31]. Tridegin reduces clot stability and enhances fibrinolysis in vitro [32,33]. Table 3 Summary of k 2nd -values [10 3 M −1 s −1 ] for the inactivation of rFXIII-A species.…”

Pharmacokinetic studies of a novel 1,2,4-thiadiazole derivative, inhibitor of Factor XIIIa, in the rabbit by a validated HPLC method

“…These observations have been corroborated in vivo in the animal models of arterial [6,7] and venous thrombosis [8]. Potent FXIIIa inhibitors have been isolated from natural sources, such as Tridegin [9] and alutacenoic acids [10], or obtained synthetically, such as halodihyroisooxazoles [11,12], 2-((2-oxopropyl)thio)imidazolium [3] and cyclopropenone derivatives [10].…”

New Antithrombotic Drugs

“…190 Tridegin, a peptide isolated from the giant Amazon leech, Haementeria ghilianii , is a specifi c inhibitor of factor XIIIa and enhances fi brinolysis in vitro when added before clotting of fi brinogen. 191,192 Destabilase, a leech enzyme that hydrolyzes cross-links, provides an alternative approach to reversing the consequences of factor XIIIa-mediated fi brin crosslinking. 193,194 Neither of these agents has been tested in humans.…”