CLINICAL TRIAL OF EPSILON-AMINOCAPROIC ACID IN SEVERE HAEMOPHILIA.

Abstract

The main components of the fibrinolytic enzyme system are plasminogen, plasmin, activators, and inhibitors. Plasminogen, a naturally occurring plasma globulin, is converted by activators to plasmin, an enzyme which can digest many proteins, including fibrinogen and fibrin, prothrombin, factor V, and antihaemophilic globulin. Under physiological circumstances it is thought that natural inhibitors in the plasma restrict plasmin to digestion of fibrin, but in pathological fibrinolytic (hyperplasminaemic) states plasma proteins, including fibrinogen and antihaemophilic globulin, are digested. Activators of plasminogen include a plasma activator, trace quantities of which are probably responsible for physiological fibrinolytic activity, a urinary activator named urokinase, and activators of bacterial origin?for example, streptokinase. E.A.C.A., a potent competitive inhibitor of plasminogen activa tion (Alkjaersig et al., 1959), was first used in man by Sherry et al. (1959), who found it effective in inhibiting plasma fibrino lytic activity induced by a variety of plasminogen activators. The value of E.A.C.A. in the treatment of pathological fibrinolytic states has recently been reviewed by McNicol and Douglas (1964), who also discuss the pharmacology and toxicity of E.A.C.A. E.A.C.A., a synthetic amino-acid which closely resembles lysine in structure, is rapidly absorbed when taken by mouth. Peak plasma levels are found about two hours after a single oral dose. Urinary excretion is also rapid, the greater part of a single dose being recovered unchanged in the urine in 12 hours. The action of E.A.C.A. as an inhibitor of plasminogen activation is seen with plasma concentrations above 1 mg./100 ml. The first report of the use of E.A.C.A. in haemophilia was from McNicol et al. (1961a) who, during a study of the bene ficial effect on post-operative haemostasis of E.A.C.A. given to produce local inhibition of urokinase activity in the urinary tract, gave E.A.C.A. to a high-grade haemophiliac with haematuria. The haematuria ceased with E.A.C.A. administra tion, but at the same time the patient developed renal colic and was found subsequently to have permanent loss of function in one kidney, presumably because of ureteric blockage with unlysable clot. Steiger et al. (1962) and Barkhan (1964) have also reported successful control of haematuria in three patients and one patient respectively with haemophilia, without any adverse effects on renal function. Abe et al. (1962) and Reid et al. (1964) report favourably on the use of E.A.C.A. for other haemorrhagic complications in small numbers of haemophiliacs. On theoretical grounds there are reasons for considering that E.A.C.A. might have a beneficial systemic effect in the treatment of high-grade haemophilia, in addition to control of local