Some Complexities of Multiple Inhibitor Interactions in Fibrinolytic Systems

Abstract

SummaryHuman or canine fibrin polymers which are structurally altered by the combined action of plasmin and EACA show an increased resistance to digestion by trypsin, but not to digestion by chymotrypsin. These observations support the concept that EACA inhibition of fibrinolysis is to a variable extent a function of structural changes in the substrate, and that the changes may be related to the susceptibility of lysyl- and arginyl-sites attacked by plasmin and trypsin, but not by chymotrypsin.In plasma, the fibrin modification reactions mediated by plasmin + EACA are analogous to those in purified systems, with quantitative differences resulting from the presence of other inhibitors, and perhaps from earlier gelation of the developing polymers.This complexity of the action of EACA must be taken into account in comparing its effects with those of other inhibitors, which also have variable and non-linear effects related to prevention of autodigestion of plasmin, antagonistic or potentiative combinations of inhibitors, and interference with substrate conversion.

Rotational diffusion analysis of the conformational alterations produced in plasminogen by certain antifibrinolytic amino acids

“…Maxcerning synthetic inhibitors of fibrinolysis. Okamoto and well and Allen (1966) and Maxwell et al (1968) have shown colleagues have demonstrated that various aromatic sulf-that e-aminocaproic acid alters the structure of fibrin, leading hydryl compounds as well as various homologs of e-amino-to a diminished capacity for digestion by plasmin. Also, it has caproic acid, p-aminomethylbenzoic acid, and 4-amino-been postulated that e-aminocaproic acid is an antiplasmin methylcyclohexane-1-carboxylic acid were antifibrinolytic.…”

“…plasmin, thus manifesting its antifibrinolytic activity. Maxwell and Allen (1966) and Maxwell et al (1968) have shown that e-aminocaproic acid alters the structure of fibrin, leading to a diminished capacity for digestion by plasmin. Also, it has been postulated that e-aminocaproic acid is an antiplasmin (Okamoto, 1959).…”

Studies on the Mechanism of Action of Synthetic Antifibrinolytics

“…This "antiactivator activity" of the antifibrinolytics was first described by Alkjaersig et al (1959) and repeatedly confirmed later (for review see Markwardt and Landmann 1967). Results from our own laboratory (Landmann 1967) as well as those from others (Donaldson 1964;Godal and Theodor 1965;Egeblad 1966;Maxwell and Allen 1966;Maxwell et al 1968;Ambrus et al 1968;Lukasiewicz et al 1968;Lukasiewicz and Niewiarowski 1968;Iwamoto et al 1968;Abiko and Iwamoto 1970) do not correspond with that generally accepted mechanism of action. The present study was, therefore, undertaken.…”

“…Nevertheless, the extremely strong inhibitory action of the antifibrinolytics compared with that of benzamidine derivatives in the lysis of plasma clots induced by urokinasc or streptokinase is not completely understood. Presumably phenomena which increase the activity of antifibrinolytics like potentiation by plasma inhibitors (Maxwell et aL 1967(Maxwell et aL , 1968(Maxwell et aL , 1970Abiko and Iwamoto 1970) and also fibrin stabilization (Lukasiewicz et al 1968;Lukasievvicz and Ni.ewiarowski 1968) contribute to this striking effect.…”

Substrate Composition and the Effect of ε-Aminocaproic Acid on Tissue Plasminogen Activator and Urokinase-induced Fibrinolysis

“…EACA forms a complex with plasmin (Skoza et al 1968) and it is a competitive inhibitor of plasmin (Brockway and Castellino 1971). High concentrations of EACA may also alter the fibrin clot changing its susceptibility to plasmin digestion (Ambrus et al 1970;Lukasiewicz et al 1968 ;Maxwell et al 1968) and influencing lysis induced by urokinase (Egeblad 1966).…”