Gut, 1970, 11, 585-587 Epsilon-aminocaproic acid therapy in ulcerative Gut: first published as 10.1136/gut.11.7.585 on 1 July 1970. Downloaded from

R. H. SALTER' AND A. E. READ From the Department ofMedicine, Bristol Royal Infirmary

SUMMARY On the supposition that excessive fibrinolysis at the rectal mucosal level may contribute to the pathogenesis of , 11 patients with this condition, in whom rectal bleeding was the predominant feature, were given a course of epsilon-aminocaproic acid therapy. Six patients responded dramatically to this treatment, there was a partial response in two, no effect in two others, and one patient found it necessary to discontinue the treatment after 48 hours because of the severity of side effects.

Rectal bleeding and diarrhoea are the cardinal level might contribute in some way to the patho- http://gut.bmj.com/ symptoms ofulcerative colitis (Goligher, de Dom- genesis of ulcerative colitis. Kwaan, Cocco, and bal, Watts, and Watkinson, 1968). Anaemia is Mendeloff (1964), in a study of the localization common in patients with ulcerative colitis and of plasminogen activator inrectalmucosa, showed haematological studies have shown that blood that in five out of six patients with active ulcer- loss and of iron are the major ative colitis there was an abnormally high con- factors in its production (Ormerod, (1968). centration of plasminogen activator at the site By the measurement of the fall in total body of the crypt abscesses, whereas in eight patients radioactivity after the parenteral administration with quiescent colitis the distribution of plas- on September 29, 2021 by guest. Protected copyright. of 59Fe, Stack, Smith, Jones, and Fletcher 1969) minogen activator in the rectal mucosa con- showed that the amount of blood lost per formed to the normal vascular fibrinolytic in 17 patients with idiopathic proctocolitis is pattern. Also Nilsson, Anderson, and Bjorkman related to the activity of the disease, as judged by (1966), in an account of their clinical experiences the sigmoidoscopic appearance of the rectal with epsilon-aminocaproic acid (EACA), de- mucosa, and the extent of the disease, as judged scribed seven patients with ulcerative colitis in by barium examination. They also found whom rectal bleeding continued despite conven- that a rectal loss of 50 to 150 ml of blood a week tional therapy. The fibrinolytic activity of the was common, even when the patient saw no peripheral venous blood was not increased in any blood in the faeces and the rectal mucosa did not of these patients, yet EACA controlled the bleed- appear haemorrhagic on sigmoidoscopy. ing in all. Unfortunately, side effects in the form Rectal bleeding may be the most obvious of nausea and diarrhoea, whether the EACA was feature of ulcerative colitis, and apart from pro- given orally or intravenously, made it impossible ducing anaemia, usually causes the patient con- to continue with this form of treatment. These siderable alarm. Conventional medical treatment, observations, together with the findings of Cox, although aimed at the prompt termination of an Poller, and Thomson (1967) that excessive gastric acute attack, includes no measures intended fibrinolytic activity may play a role in the patho- specifically to stop rectal bleeding. genesis of gastric ulceration, prompted an inves- Nevertheless, there is some evidence to suggest tigation into the role of fibrinolysis in ulcerative that excessive fibrinolysis at the rectal mucosal colitis, the results of which will be reported else- Received for publication 29 October 1969. where. Part of the project was designed to assess 'Present address: Cumberland Infirmary, Carlisle. the efficacy of EACA in the control of rectal 586 R. H. Salter and A. E. Read examination. All the patients fulfilled the follow- Patient Age Sex Total Extent Average Associated Sigmoidoscopic diarrhoea, (years) Duration of Bowel Treatment Grading' ing criteria: (1) Despite associated Gut: first published as 10.1136/gut.11.7.585 on 1 July 1970. Downloaded from of Disease Frequency rectal bleeding was the most pronounced symp- Disease Process (per 24 hours) tom, being clearly visible at each bowel action. (2) There was no significant change in the sympto- 1 69 F 3 years Left2 6 None Moderate 2 15 M 1 year Rectum 3 Sulphasalazine Moderate matology for at least two weeks before the start (0.5 g tds) of EACA therapy. (3) The patients were either 3 18 F 11 years Rectum 6 Sulphasalazine Moderate EACA (10 g tds) receiving no therapy at the time of the 4 73 M 1 year Left 12 None Moderate trial, or if treatment had been previously in- 5 44 M i year Left 8 None Severe stituted this had not been altered for the preced- 6 34 M 21 years Rectum 2 Sulphasalazine Moderate (10 g tds) ing two weeks and was continued unchanged 7 43 M 11 years Rectum 8 Sulphasalazine Moderate during the period of EACA administration. (1.0 g tds) Prednisolone The age of the patients ranged from 14 to 73 enema nocte years and these data, together with the details as 8 51 F 10 years Rectum 10 None Severe to the duration, extent, frequency of bowel action, 9 51 F 4 years Left 6 None Severe 10 14 M 6 weeks Left 6 None Severe sigmoidoscopic grading, and associated therapy, 11 64 M 20 years Rectum 8 None Severe are summarized in Table I. All the patients were seen before the EACA Table I Details ofpatients studied trial when the clinical features and sigmoido- 'Mild, moderate, or severe according to the classification of scopic appearance of the rectal mucosa were Goligher et al (1968). recorded. The latter was graded as normal, mild, 2'Left' indicates that the descending and sigmoid colon is involved as well as the rectum. moderate, or severe according to the classifica- tion of Goligher et al (1968). Peripheral venous blood samples were taken for haemoglobin Patient Haemoglobin Euglobulin Euglobulin Effects Side Ebects (g/100 ml) Lysis Time' Lysis Time estimation in all and for assessment of the (before (seventh day euglobulin lysis time in six, the method of EACA of treatment) therapy) Chakrabarti, Bielawiec, Evans, and Fearnley (1968) being used. This gives a normal range for 1 10-7 6-66 3-33 Bleeding cleared None within 48 hours euglobulin lysis of approximately60to 300minutes 2 109 5-55 1.0 No effect on bleeding None or 3 to 16 arbitrary units, this figure being derived 3 11.0 8-33 3-33 No effect on bleeding Nausea by multiplying the reciprocal of the time in 4 10-5 4-76 1.0 Bleeding cleared None within 48 hours minutes by 1,000 (Sherry, Lindemeyer, Fletcher, 5 11.9 1.0 1 0 Bleeding cleared None and Alkjaersig, 1959). http://gut.bmj.com/ within 48 hours 6 10-7 6-66 3-33 Bleeding less but not Slight The patients were then given a supply of EACA completely cleared nausea and syrup sufficient for a seven-day course at a dose giddiness g four times daily and were asked to report 7 11-7 - - Bleeding less but not None of 6 completely cleared back on the seventh day of treatment, having 8 11-7 - - Bleeding cleared Nausea carefully observed during the preceding six days within 48 hours 9 9-0 - - EACA discontinued after 48 hours whether there was any change in the severity of because of severe nausea and the diarrhoea and rectal bleeding and whether vomiting on September 29, 2021 by guest. Protected copyright. 10 11-8 - - Bleeding cleared Nausea and they had noticed any other effects of treatment. within 48 hours vomiting At this visit the symptoms and results ofsigmoido- 11 11-5 - - Bleeding cleared None scopy were again recorded and the euglobulin within 48 hours lysis time of the peripheral venous blood was re- Table II Results estimated in six patients. The EACA treatment was discontinued and appropriate alterations 'The euglobulin lysis is expressed as arbitrary units obtained by multiplying the reciprocal of time in minutes by 1,000 (Sherry were made to the therapeutic regime if required. et al, 1959).

bleeding in patients with ulcerative colitis in Results whom this was a prominent feature. The results form the basis of this report. The results are summarized in Table II. All of the patients were anaemic before the EACA trial. Six patients reported that rectal bleeding had Patients and Methods cleared within 48 hours of starting the therapy and remained absent for the remainder of the Eleven outpatients took part in this study, the course of treatment. Also there was no immediate diagnosis of ulcerative colitis being made on the recurrence of bleeding after stopping EACA basis of clinical features and the sigmoidoscopic therapy. Two patients reported a considerable appearance of the rectal mucosa. The extent of reduction in rectal blood loss and two patients the disease process was assessed by barium enema noted no significant change. One patient found 587 Epsilon-aminocaproic acid therapy in ulcerative colitis it necessary to discontinue the EACA treatment In the patients who failed to respond, the

after 48 hours because of the severity of side disease process was confined to the rectum and Gut: first published as 10.1136/gut.11.7.585 on 1 July 1970. Downloaded from effects. rectosigmoid regions. This was a disappointing finding as haemorrhage is often a feature of idiopathic and recurrent iron-deficient EUGLOBULIN LYSIS anaemia is common. Why oral EACA therapy No increase in the fibrinolytic activity of the should have been so ineffective in this group is peripheral venous blood was demonstrated in again difficult to explain. the six patients in whom the euglobulin lysis The fact that the euglobulin lysis time before time was estimated. The repeat euglobulin lysis treatment was begun was within the normal time estimated on the seventh day of therapy range in five of the six patients studied, and also showed a considerable reduction but not a com- the observation that although rectal bleeding was plete abseice of fibrinolytic activity of the peri- quickly abolished there was still some demon- pheral venous blood, except in case 5 where the strable fibrinolytic activity in the peripheral value before treatment was also low. venous blood, suggests that the bleeding may be caused at least in part by a local release of plas- minogen activator. This again suggests that local SIDE EFFECTS EACA treatment might be expected to be bene- Six patients reported no side effects and ficial and this form of therapy is surely worth a four patients complained of various combina- trial. tions of nausea, vomiting, and giddiness but were It must be emphasized that this study was in nevertheless able to complete the course of treat- no way intended to be a full clinical trial and no ment. One patient complained of such severe attempt was made to quantitate the rectal blood nausea and faintness that it was necessary to dis- loss, the effect of therapy being judged solely by continue the treatment after 48 hours. None of observation ofthepatient. Despitethese limitations the patients noticed any increase in the the results are sufficiently impressive to merit the frequency of bowel action and no thrombotic consideration of EACA therapy in any case of episodes occurred during the course of treatment. ulcerative colitis where rectal bleeding is a pre- dominant feature.

Discussion http://gut.bmj.com/ These results confirm those of Nilsson et al (1966) This work forms part of a dissertation to be sub- and show that antifibrinolytic therapy with mitted by one of us (R.H.S.) for the M.D. degree EACA is an extremely effective method of con- of the University of London. trolling rectal bleeding in certain patients with ulcerative colitis, despite the fact that the pre- treatment fibrinolytic activity of the peripheral venous blood was not increased. References on September 29, 2021 by guest. Protected copyright. In all seven patients studied by Nilsson et al Chakrabarti, R., Bielawiec, M., Evans, J. F., and Fearnley, G. R. (1966) the EACA, whether given orally or intra- (1968). Methodological study and a recommended tech- venously, had to be discontinued because of the nique for determining the euglobulin lysis time. J. clin. Path., 21, 698-701. severity of side effects, these being predominantly Cox, H. T., Poller, L., and Thomson, J. M. (1967). Gastric nausea and diarrhoea. In the patients constituting fibrinolysis. A possible aetiological link with peptic ulcer. Lancet, 1, 1300-1302. the present series the average frequency of bowel Goligher, J. C., Dombal, F. T. de, Watts, J. McK., and Watkin- action per 24 hours was unaffected by EACA sin, G. (1968). Ulcerative Colitis. Bailli6re, Tindall, and five certainly found nausea Cassell, London. therapy, although Kwaan, H. C., Cocco, A., and Mendeloff, A. I. (1964). Histologic troublesome, one so much so that the treatment demonstration of plasminogen activation in rectal biopsies had to be discontinued. The reason for this from patients with active ulcerative colitis. J. Lab. clin. Med., 64, 877. difference is difficult to understand as the daily Nilsson, I. M., Anderson, L., and Bjorkman, S. E. (1966). Epsilon- dose of oral EACA used in this study (24 g) was aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years' clinical experience. Acta med. scand., 180, not significantly different from that of Nilsson Suppl., 448. et al (1966). Ormerod, T. P. (1968). Anaemia in ulcerative colitis. Proc. roy. It is possible that as an alternative to EACA Soc. Med., 61, 931. Sherry, S., Lindemeyer, R. I., Fletcher, A. P., and Alkjaersig, N. another antifibrinolytic drug may become (1959). Studies on enhanced fibrinolytic activity in man. available which has less troublesome side effects. I. clin. Invest., 38, 810-822. Stack, B. H. R., Smith, T., Jones, J. H., and Fletcher, J. (1969). Also, the possibility oflocal EACA therapy in the Blood and iron loss in colitis. Proc. roy. Soc. Med., 62, form of retention enemata is worth considering. 497.