Lysis of fibrin was first recognized by MORGAGNI in 1769, observing a liquid blood in a patient of acute death, and the phenomenon was named as fibrinolysis by DASTRE in 1893. In 1937, MACFARLANE recognized in a patient after cholecystectomy that the blood clot was lysed completely in the following morning. Since then, much attention has been paid clinically on fibrinolysis and it has been said to occur in case receiving a large amount of blood transfusion, shock, cancer, obstetric diseases, hemophilia, various drug poisonings, allergic diseases, after irradiation and after the operations of lung, pancreas and prostate. In our department, also, the similar phenomenon was recognized often in association with cardiac surgery using the artificial heart-lung machine, and a difficulty in hemostasis was encountered postoperatively. We have been studying, therefore, on fibrinolysis in open heart surgery.</p

Fujiyama, Noboru

Morimoto, Setsuo

Ohmoto, Takechiyo

Shigemoto, Hirosada

Shimizu, Hiroshi

Sunada, Terutake

English

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 22, Issue 6 1968 Article 3DECEMBER 1968Studies on an antifibrinolytic agenttrans-AMCHATerutake Sunada∗ Hiroshi Shimizu† Setsuo Morimoto‡Hirosada Shigemoto∗∗ Noboru Fujiyama†† Takechiyo Ohmoto‡‡∗Okayama University,†Okayama University,‡Okayama University,∗∗Okayama University,††Okayama University,‡‡Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Studies on an antifibrinolytic agenttrans-AMCHA∗Terutake Sunada, Hiroshi Shimizu, Setsuo Morimoto, Hirosada Shigemoto,Noboru Fujiyama, and Takechiyo OhmotoAbstractLysis of fibrin was first recognized by MORGAGNI in 1769, observing a liquid blood ina patient of acute death, and the phenomenon was named as fibrinolysis by DASTRE in 1893.In 1937, MACFARLANE recognized in a patient after cholecystectomy that the blood clot waslysed completely in the following morning. Since then, much attention has been paid clinicallyon fibrinolysis and it has been said to occur in case receiving a large amount of blood transfusion,shock, cancer, obstetric diseases, hemophilia, various drug poisonings, allergic diseases, afterirradiation and after the operations of lung, pancreas and prostate. In our department, also, thesimilar phenomenon was recognized often in association with cardiac surgery using the artificialheart-lung machine, and a difficulty in hemostasis was encountered postoperatively. We have beenstudying, therefore, on fibrinolysis in open heart surgery.∗PMID: 4240920 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOLActa Med. Okayama 22. 331-337 (1968)STUDIES ON AN ANTIFIBRINOLYTIC AGENTTRANS-AMCBATerutake SUNADA, Hiroshi SHIMIZU, Setsuo MORIMOTO, HirosadaSHIGEMOTO, Noboru FUJIYAMA & Takechiyo OHMOTODepartment of Surgery, Okayama University Medical School, Okayama,Japan (Director: Prof. Terutake Sunada)Received for publication, October 19, 1968Lysis of fibrin was first recognized by MORGAGNI in 1769, observinga liquid blood in a patient of acute death, and the phenomenon wasnamed as fibrinolysis by DASTRE in 1893. In 1937, MACFARLANE recognizedin a patient after cholecystectomy that the blood clot was lysed completelyin the following morning. Since then, much attention has been paidclinically on fibrinolysis and it has been said to occur in case receiving alarge amount of blood transfusion, shock, cancer, obstetric diseases, hemo-philia, various drug poisonings, allergic diseases, after irradiation andafter the operations of lung, pancreas and prostate.In our department, also, the similar phenomenon was recognizedoften in association with cardiac surgery using the artificial heart-lungmachine, and a difficulty in hemostasis was encountered postoperatively.We have been studying, therefore, on fibrinolysis in open heart surgery.For prophylaxis and treatment of fibrinolysis, various substances havebeen used for a long time, such as fibrinogen, fresh blood, serum albuminfraction, anti-hemophilic globulin, soy-bean inhibitor, cortisone, platelettransfusion and various hemostatics. However, in 1954, OKAMOTO intro-duced e-aminocaproic acid (EACA) which was found to have a strongFig. 1c-aminocaproic acid (EACA)331CH2-NH2ICH/ ""CH2 CH2I ICH2 CH2"" /CHICOOHTrans-l-aminomethyl-cyclohexane-4-carl::oxylic acid (AMCHA)1Sunada et al.: Studies on an antifibrinolytic agent trans-AMCHAProduced by The Berkeley Electronic Press, 1968332 T. SUNADA, H. SHIMIZU, S. MORIMOTO, H. SHIGEMOTO, N. FUJIYAMA & T. OHMOTOanti-fibrinolytic action, and then it has been widely used as a therapeuticagent. Then, OKAMOTO et at. (1965) introduced a trans-stereoisomer of4.aminomethyl cyclohexane carboxylic acid (AMCRA) which has strongeranti-fibrinolytic activity than EACA (Fig. 1).We used AMCRA both experimentally and clinically in 23 cases, andcompared its activity with that of EACA.(A) Experimental evaluation(1) ThrombelastographyOne hundred units of streptokinase (SK) was added to 1 ml of normalcitrated plasma, and then calcium ion was added to observe the throm.belastograms (TEG). The plasma having 3 minutes of the lysis time wasused for the experiments. EACA or AMCRA was added in various con-centrations before 100 unitsjml of SK was mixed to plasma for the purposeof obtaining TEG (Photographs 1, 2, Table 1).The lysis time of the SK activated plasma containing 1 l~gjml ofPhotograph 11. SK lOOu/ml+EACA lO/-lg/ml added2. SK lOOu/ml+EACA 25/-lg/ml added3. SK lOOu/ml+EACA 50/-lg/ml addedPhotograph 22. SK 100u/ml+AMCHA 0.1 ng/ml added2. SK 100u/ml+AMCHA 1.0/-lg/ml added3. SK lOOu/ml+AMCHA 1O.0/-lg/ml addedTable 1Solutions added to the plasmak Lysis time-----Ir rnaSK EACAIAMCHA (min.) (min.) (mm) (min.)(u/ml) (/-lg/ml) (/-lg/ml)100 0 0I5.0 / 2I3.0100 10 0 5.0 / 12 I 10.0100 25 0 5.0 6.0 21Ilong100 50 0 4.0 10.0 25 /100 0 0.1 4.0 / 6 I 4.5I100 0 1.0 4.0 3.5 31I39.0100 0 10.0 4.0 8.0 28 /2Acta Medica Okayama, Vol. 22 [1968], Iss. 6, Art. 3http://escholarship.lib.okayama-u.ac.jp/amo/vol22/iss6/3Trans-AMCHA, an Antifibrinolytic Agent 333AMCHA (39 minutes) varies in between that of the SK activated plasmacontaining 101J.gjml of EACA (10 minutes) and that of the SK activatedplasma containing 25 fl.g/ml of EACA (immeasurably prolonged). Thus,the activity of AMCHA is 10-25 times stronger than that of EACA.(2) Euglobulin lysis timeEuglobulin fraction was prepared from the normal citrated plasmaby the method of VON KAULLA. Five units of SK was added to 1 ml of theeuglobulin solution, and thrombin was added to produce the clotting.Then, the clot dissolved in a few minutes. On the next experiment, variousconcentrations of EACA or AMCHA were added to the euglobulin solutionin advance, and then 5 units/ml of SK was added to determine the clotlysis time.When each value was plotted on the logarithmic graphs, EACA andAMCHA showed straight lines in parallel (Fig. 2). The activity ratio of0.5 1.0 2.0mg/cc0.05 0.1s::....8-4) 1008.... 50....,l/l 30.... 20l/l>- 10....4) 5s::....-::l.00....bO::l~ Concentration of AMCHA orEACAFig. 2AMCHA and EACA is, therefore, the same at any concentration. Theratio of normal 3 samples was 5.3, 5.3 and 5.6 times, respectively. Theaverage value among 3 determinations was 5.4 in their activity.(B) Evaluation on clinical casesAmong 3218 major surgical operations done in our department forthe past 7 years excluding cardiac surgery, increased fibinolysis wasrecognized only in 8 cases (0.25 % i. e. esophageal carcinoma 1, gastriccarcinoma with Banti's syndrome 1, coarctation of the aorta 1, thoracicaneurysm 1, pulmonary tuberculosis 1, bronchiectasis 2, Werlhof's disease3Sunada et al.: Studies on an antifibrinolytic agent trans-AMCHAProduced by The Berkeley Electronic Press, 1968334 T. SUNADA, H. SHIMIZU, S. MORIMOTO, H. SHIGEMOTO, N. FUJIYAMA & T. OHMOTO1). On the contrary, increased fibrinolysis in open heart surgery was seenin 7 out of 29 cases (24. 1%), as reported previously. Since we started touse EACA prophylactically after the completion of the extracorporealcirculation, increased fibrinolysis have been able to prevent in consecutive250 cases. Through our various experiments, 0.25 gjkg of body weight ofEACA was reported to be adequate. Instead of using EACA, AMCHAwas given in two groups, receiving Ij5 dosis of EACA (0.05gjkg) and 1/10that of EACA (0.025 gjkg) after perfusion (Tables 2, 3).(1) Appearance of fibrinolysisWhole blood clot lysis and TEG were used for the evaluation. Noneof the cases receiving EACA and AMCHA showed increased fibrinolysis.(2) Comparison of the amount of blood discharge through the intra-thoracic drainThe amount of blood discharge through the drain was measured at12 hours after the surgery and at the time of removing the drain in 18cases without EACA and AMCHA, in 11 cases receiving 0.25 gjkg ofEACA, in 12 cases receiving 0.05 gjkg of AMCHA and in 11 casesreceiving 0.025 gjkg of AMCHA. The amount of blood discharge decreas.ed in the order of non.treated group, EACA group, 0.025 gjkg AMCHAgroup and 0.05 gjkgAMCHA group. At 12 hours after the operation, theamount of blood discharge in EACA group was 42.2 % less than that ofTable 2No.1 Nam, I Ag' I Sox I Diagnosis Operation•Perfusion I Lowestt " (") temperaturelme mm. (OC)IIM.K. II F I VSD Closure of the defect I 76 20.82 M.1. 5 F I VSD Closure of the defect 32 27.031 K.O.I9 F Aortic stenosis Dilatation of the I 151 20.2o"'um41 K.A. 19 F VSD Closure of the defect 13 28.65 M.H. 17 M Ruptured aneurysm Closure of the defect 70 21.6of Valsalva's sinus6 A.H. 3 F ASD Closure of the defect 10 33.77 M.M, 6 F VSD Closure of the defect 16 34.08 T.F. 16 M Right ventricular Radical operationI86 22.8aneurysm9 B.N. 17 M Mitral stenosis Commissurotomy 31 33.610 E.K. 11 F Mitral steno- Valuloplasty 81 33.4insufficiencyII Y.l'. 12 F VSD Closure of the defect 87 26.0I121 M.T. 16 MiASD Closure of the defect 18 33.84Acta Medica Okayama, Vol. 22 [1968], Iss. 6, Art. 3http://escholarship.lib.okayama-u.ac.jp/amo/vol22/iss6/3Trans-AMCHA, an Antifibrinolytic AgentTable 3335No.1 Namo I Ago ISoxIDiagnosis Operation P"fu,ion I Low,,'f (.) temperaturelme mm. (OC)13 T.A. I 35 M Mitral insufficiency Valvuloplasty 100 30.214 R.A.I5 M VSD Closure of the defect 88 27.815 S.N. 16 F ASD Closure of the defect 16 32.016 Y.N. 19 M VSD Closure of the defect 36 27.617 T.!. 21 M Aortic steno- Transplantation of 236 24.3insufficiency the valveMitral stenosis Commissurotomy18 T.O. 5 F ASD Closure of the defect 9 33.819 0.0. 26 M Aortic steno- Transplantation of 184 26.9insufficiency the valveMitral stenosis Commissurotomy20 T.O. 7 M ASD Closure of the defect 15 33.621 Y.M. 14 F ASD Closure of the defect 7 33.522 A.H. 7 M VSD Closure of the defect 31 32.223 M.U. IS M VSD Closure of the defect 22 34.5non-treated group; in 0.025 gjkg AMCHA group 12.5 % less than that ofEACA group; in 0.05 gjkg AMCHA group 17.8 % less than that of0.025 gjkg AMCHA group. The total amountof blood discharges obtaineduntil the removal of the drain showed the similar changes. Namely, theamount of blood discharge in EACA group was 26.3 % less than that ofnon-treated group; in 0.025gjkg AMCHA group 34.1 % less than that ofEACA group, in 0.05 gjkg AMCHA group 17.3 % less than that of 0.025rn1/kg30'"000.--<..0'-H Q)0 0.0....., :-.t:: ro::i..t::0 u6 til....-< '"02010(a) (b)o non-treated_ EACA 0.25 g/kggivenEZZJ 0.025 g/kg AMCHAgivenk::::::.'J 0.05. g/kg AMCHAgivenFig. 3 Amount of blood discharge after operation(a): 12 hours(b): until the removal of drain5Sunada et al.: Studies on an antifibrinolytic agent trans-AMCHAProduced by The Berkeley Electronic Press, 1968336 T. SUNADA, H. SHIMIZU, S. MORIMOTO, H. SHDEMOTO, N. FUJIYAMA & T.OHMOTOg/kg AMCHA group. Thus, AMCHA appeared to be more effective thanEACA, and 0.05 g/kg AMCHA was the most adequate dose (Fig. 3).(3) Comparison of englobulin lysis timeHypothermia with extracorporeal circulation was used more in 0.05g/kg AMCHA group than in 0.025 g/kg AMCHA group. Therefore, theformer group showed shortening of the lysis time before the administrationof AMCHA. On the administration of AMCHA, it varied from 30 min.to 60 min. in 0.05g/kg AMCHA group, and from 82 min. to 114 min. in0.025 g/kg AMCHA group. However, they all returned to normal value1 hour after the operation (Fig. 4).Euglobulin lysis timeFig. 4a: preoperativeb: post-thoracotomyc: during extracorporeal circulationd: after extracorporeal circulatione: after AMCHA givenf: after protamine giveng: I hour after operationQ) more than 2008..... 180.....e f gabc d60120rn.....rn>..-(DISCUSSION AND CONCLUSIONOn comparing the effects of EACA and AMCBA on fibrinolysis inthis experiment, TEG showed that AMCHA was 10-25 times more thanEACA. While in measuring the euglobulin lysis time it revealed thatAMCBA was 5.4 times more effective than EACA. In thrombelasto.graphy, the plasma was used, in which inhibitors for fibrinolysis werealso included. In euglobulin lysis time test, however, it was measuredwith euglobulin fraction which contained no inhibitors. Besides such a6Acta Medica Okayama, Vol. 22 [1968], Iss. 6, Art. 3http://escholarship.lib.okayama-u.ac.jp/amo/vol22/iss6/3Trans-AMCHA, an Antifibrinolytic Agent 337difference of methods, there are some differences in the mechanism oftheir actions, so their effect might have been different with methods used.Other authors also reported that AMCHA was 5-26 times more effectivethan EACA.When AMCHA was used in a dose of 1/5 that of EACA (0.05 g/kg)or 1fl 0 (0.025 g/kg) on cardiac surgery using artificial heart-lung machine,the amount of blood discharge through the intrathoracic drain was lessthan in the group receiving EACA. Euglobulin lysis time became shortenedmore in 0.05 g/kg AMCHA group than in 0.025 g/kg AMCHA group,probably due to hypothermia combined with extracorporeal circulation,while the amount of blood discharge was decreased in the former group.This appeared to be due to a large dose of AMCHA used after extracorpo-real circulation.Thus, through the experimental results and clinical experiences, it isconcluded that AMCHA is very strong anti.fibrinolytic agent which in.hibits the increased fibrinolytic activity after extracorporeal circulationand the dose of AMCHA being 1/5-1/10 that of EACA is adequate.REFERENCES1. T. SUNADA et ai.: Knowledge on antihemophilic human blasma (AHP). The Diagnosis& Treatment (Jap.) 50, 183, 19622. T. SUNADA et ai.: Fibrinolysis in extracorporeal circulation .. · Causes and Treatments· ..Clinical Surgery (Jap.). 19, 178, 19643. H. SHIGEMOTO: Studies on fibrinolysis in surgery-with special reference to thrombelasto-graphy. Okayama Igakkai Zasshi (Jap.) 74, 869, 19627Sunada et al.: Studies on an antifibrinolytic agent trans-AMCHAProduced by The Berkeley Electronic Press, 1968

Studies on fibrinolysis in surgery-with special reference to thrombelastography.

SUNADA et ai.: Fibrinolysis in extracorporeal circulation ..· Causes and Treatments·..

SUNADA et ai.: Knowledge on antihemophilic human blasma (AHP).

Studies on an antifibrinolytic agent trans-AMCHA

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Studies on an antifibrinolytic agent trans-AMCHA

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