The Complications of Therapy with Epsilon-Aminocaproic Acid

The Complications of Therapy with Epsilon-Aminocaproic Acid LT. COLONEL JAMES J. BERGIN, MC, D.S. ARMY*

Epsilon-aminocaproic acid (EACA), marketed in this country by Lederle as Amiear (aminocaproic acid), is a potent, synthetic, fibrinolytic inhibitor. The drug has been used and recommended in a wide variety of clinical circumstances. For the obstetrician, the list includes menorrhagia,46 abruptio placentae,9 and postpartum bleeding. 43 For the urologist, there is control of postprostatectomy hemorrhage. 30 , 45 The gastroenterologist encounters the drug in recurrent bleeding of cirrhotics. 19 The surgeon reads of its use in portacavapo and cardiac shunt 14 procedures. The drug has been advanced for hematuria, 6 , 30, 51 dental extractions,!' 41 and joint bleeding prophylaxis 17 in hemophilia; as well as bleeding associated with leukemia, aplastic anemia,33 and fibrinolysis therapy.32 Administration in bleeding diathesis of malignancy, particularly carcinoma of the prostate,4,25 has been reported. Benefit has been suggested in progressive systemic sclerosis,44 various allergic states, and treatment of dermatitides. 59 Indeed, continuous uncontrolled hemorrhage not responsive to the usual therapeutic modalities has been considered an indication for drug employment. l l Since the clinical states mentioned above are not uncommon nor infrequently encountered, detailed knowledge of the pharmacology of EACA and the potential hazards of administration is mandatory. PHARMACOLOGY

The pharmacology of epsilon-amino caproic acid has been carefully investigated by Alkjaersig,3 Ablondi,2 and Nilsson36 and reviewed by McNicoP7.29 and Sweeney. 53 It is a white, crystalline substance soluble in water and structurally closely related to lysine (Fig. 1). It is rapidly and predictably absorbed from the gastrointestinal tract with peak levels present in two hours. The intravenous route varies only in establishing similar

* Assistant

Chief, Department of Medicine, Fitzsimons General Hospital, Dcnver, Colorado

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JAMES J. BERGIN

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Lys i ne (alpha-epsilon-diaminocaproic acid) Figure 1. Structural formulas of Amicar and lysine.

levels within 30 minutes. The drug is readily distributed throughout the intravascular and extravascular spaces penetrating tissue cells and red blood cells. It is cleared by the kidney at approximately 75 per cent of the rate of creatinine. Between 60 and 90 per cent of the unchanged drug can be recovered from the urine in 12 hours. Using C-14labeled EA CA in man, .Tohnson23 confirmed that the excretion was primarily in the urine, although the breath did contain small amounts of labeled material as carbon dioxide. Since the kidney is the primary organ responsible for the excretion of the drug, appropriate caution should be exercised in the presence of renal failure, and the drug stopped or reduced depending upon the urine output. Prolonged administration is followed by gradual elimination of the drug over a 24 to 36 hour period. Effective drug levels will be present in the urine, less so in the plasma, after therapy has been discontinued. A blood level of 13 mg. per 100 ml. inhibits systemic plasminogen activation, whereas 130 mg. per 100 ml. is required for plasmin inhibition. A loading dose is necessary to attain a therapeutic blood level and continuing administration of the drug is needed to maintain adequate concentration. Five grams diluted in a vehicle, if given intravenously, is administered over 30 minutes, followed by 1 gram every hour to assure the 13 mg. level. The oral dosage is the same. The intensity and duration of therapy are dependent on the degree of fibrinolysis and the integrity of renal function.

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THE COMPLICATIONS OF THERAPY WITH EpSILON-AMINOCAPROIC ACID

THE FIBRINOLYTIC SYSTEM

It was inevitable that the investigation of clot formation would be followed by similar efforts defining fibrinolysis, that is, the dissolution of blood clots. 12 , 22, 60 Fibrinolysis involves the enzymatic conversion of plasminogen to plasmin by an activator substance present in tissues, blood or urine. The inactive substance, plasminogen, has an affinity for fibrin assuring an ample supply within a formed thrombus. The active material, plasmin, a proteolytic enzyme, is capable of digesting not only fibrin but also accelerator globulin, antihemophiliac globulin and other proteins. The source of blood activation is the vascular endothelium according to Warren 58 and Todd 54 (Fig. 2). Fibrinolysis, which maintains vascular patency, is subject to counterbalance. Plasma contains large amounts of antiplasmins which rapidly neutralize frce plasmin. Since the clot contains low concentrations of antiplasmins, clot dissolution at the site of the thrombus may proceed actively as systemic effect is inhibited. This local action with inhibition of systemic effect is ideal for hemostasis. Epsilon-aminocaproic acid effectively blocks plasminogen activation by competitive inhibition. 3 Since body kinases, such as plasminogen activator, are known to act specifically on lysine and arginine bonds, it is postulated that the structural similarity of EACA to lysine and arginine permits this synthetic compound to compete with plasminogen as an enzymatic substrate for activator substance. Once plasmin formation has been blocked, the remaining plasmin is rapidly neutralized by endogenous antiplasmins

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The fibrinolytic system.

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JAMES

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BERGIN

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Fibrinolytic antagonists.

and fibrinolytic activity is abolished. The products of fibrinogen and fibrin proteolysis are spontaneously cleared from the circulation with a half life of nine hours 59 (Fig. 3).

COMPLICATIONS

Nonthrombotic Drug Toxicity Setting aside the consequences of inhibiting fibrinolysis, other side effects will be considered. A dosage schedule in excess of the recommended human level has produced subendocardial hemorrhage, focal subendocardial thickening and occasional myocardial degeneration in animals. 38 This complication has not been encountered in man. Incorporation of lysine into protein of the rat diaphragm preparation has been reported to be significantly inhibited. 29 This disruption of protein metabolism is a theoretical contraindication to the long-term use of the drug in children. Daily injection of EACA in pregnant rats caused a variety of teratogenic defects in embryos. Whether or not human defects under similar circumstances will be produced has not been determined. Until more data have been accumulated, the drug probably should not be used during pregnancy, especially during the first trimester.1° Nasal stuffiness, abdominal discomfort,4 hypotension,5 conjunctival suffusion,28 nausea and vomiting,4 diarrhea,5 maculopapular rash,28 and pruritic morbilliform rash 34 have been noted in humans receiving recommended amounts.

Hemorrhagic Diathesis Generalized unremitting bleeding not responsive to standard surgical methods of tamponade has been referred to as a hemorrhagic diathesis. The sudden or subacute onset of bleeding from all traumatized areas, ostia, serosal spaces, viscera and facial planes is often accompanied by delayed

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clot formation or a poor clot which fragments easily. The disorder has been reported in a variety of clinical situations (Table 1). INTRAVASCULAR COAGULATION. If bleeding is due to isolated pathological fibrinolysis, 7 that is, accelerated, deleterious destruction of formed clots and impaired clot retraction, EACA is an ideal drug to arrest the process. However, the conversion of fibrinogen to fibrin by formed thrombin may consume essential clotting factors with subsequent hemorrhage. In this circumstance, the accelerated coagulation of blood triggers fibrinolysis as a protective response. Therapy is logically directed to alleviate the thrombotic tendency and not the clot lysis. Animal experimentation has demonstrated the value of induced hypocoagulability as a protection from widespread intravascular coagulation and hemorrhage. 39 . 40, 42 The concept of using an anticoagulant as therapy for a bleeding diathesis becomes less alarming when the importance of preventing hypercoagulability is appreciated. In 1963 von Francken67 and Verstraete 65 reported the value of administering heparin to patients bleeding from a variety of clinical circumstances. In the presence of a hemorrhagic diathesis, Verstraete66 recommended heparin as a diagnostic test for defibrination secondary to intravascular coagulation. If accelerated clotting is primary, improvement is to be anticipated. Merskey31 commented on the value of heparin, but not of warfarin, in controlling intravascular clotting and preventing secondary fibrinolysis in his discussion of the simultaneous occurrence of accelerated clotting and clot lysis. He warned against fibrinolytic inhibition in this circumstance because unimpeded disseminated thrombosis might follow.

Thrombotic Complications Gans13 explored the potential hazard of thrombosis as a complication of EACA therapy in animal experiments. He infused a group of dogs with thrombin and another with thrombin and EACA. The ten dogs receiving only thrombin demonstrated increased fibrinolytic activity, but survived the experimental period. No thrombi, gross or microscopic, were present Table 1.

The Clinical Setting for Hemorrhagic Diathesis

Cold exposure Burns Hemorrhagic shock Extensive trauma Cirrhosis Thoracic surgery Amniotic fluid embolism Abruptio placentae Fetal death syndrome Portacaval shunt Cystoscopy Tetralogy of Fallot

Prostatic carcinoma Anoxemic death Cardiopulmonary bypass Incompatible blood transfusion Fibrinolytic therapy Leukemia Snake bite Sh wartzman phenomenon Metastatic cancer Sarcoidosis Polycythemia vera Endotoxin shock

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JAMES J. BERGIN

on sacrifice. Four of the ten animals receiving thrombin and EACA succumbed before termination of the experiment and had microscopic evidence of pulmonary emboli, edema and atelectasis. It has been estimated that over 1000 patients have received EACA.63 Generalized thrombosis is a lethal complication and is not likely to be reported, but survey of the literature reveals a number of such circumstances encountered following the use of the drug. N aeye36 described a patient with prostatic carcinoma who developed a hemorrhagic diathesis. After treatment with steroids and EACA the hemorrhage ceased, but the patient developed widespread intravascular thrombosis. The author postulated that the EACA inhibited fibrinolysis, thus unmasking a process of intravascular coagulation which had initiated the hemorrhagic diathesis. Dameshek,62 in commenting on a patient with disseminated lymphosarcoma, stated that thrombotic manifestations developed when EACA was given as treatment for the hemorrhage. Fletcher12 remarked in a footnote that the reluctance to report therapeutic complications is evidenced by his learning, after limited inquiry, of five cases of post-treatment thrombosis following EACA. Lewis24 reported on cirrhotics receiving EACA, none of whom had a generalized bleeding tendency. One patient developed clinical evidence suggesting a splenic vein thrombosis following EACA and steroids. The author incriminated the steroids. Sharp47 observed widespread intravascular thrombosis and death after EACA was used to neutralize fibrinolysis occurring after open heart surgery. A similar experience was recorded by Gibbon,15 who encountered two patients treated with EACA for fibrinolysis after heart-lung bypass. Both died of massive clotting. Although not further elucidating, Gollub 16 reported having seen immediate and unexplained death when EACA dosage had exceeded 12 grams a day. McNicopo reported the use of EACA in a hemophiliac with hematuria. Renal colic developed and subsequent serial intravenous urograms showed a nephrogram effect on the involved side. It was speculated that the thrombus containing EA CA was not subject to normal lysis (plasmin activated by urokinase) and remained in the renal pelvis. The same author26 further described the hazard of failure of lysis of such a clot in a patient surviving open heart surgery. Subsequent bleeding was immediately controlled by EACA; however, the patient later expired with a clotted hemothorax and hemopericardium. The theoretical contraindications to the use of a fibrinolytic blocking agent have been considered. As clinical experience has accrued, it would appear that the use of EACA alone in various hemorrhagic circumstances has been associated with subsequent lethal intravascular clotting. Further, clotted blood containing EACA has compromised life because of resistance to normal lysis. Bleeding into critically situated spaces should be controlled, if at all possible, before the drug is administered.

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COMBINED THERAPY

Rapid, economical, and dependable laboratory methods of determining the exact extent of fibrinolysis and degree of intravascular coagulation are needed for the immediate investigation of hemorrhagic diatheses and for direction of therapy. Unfortunately, such methods are not presently available. The interdependence of clot lysis and clot formation has been stressed in a number of recent publications. 18 , 21, 48 It is doubtful that either system exists without the other in physiological or pathological states. Concurrent treatment of accelerated clotting and pathological clot lysis has been beneficial. 8 Heparin was administered at the level of 0.5 mg./kg. to interfere with pathological intravascular coagulation and to protect against a thrombotic tendency from EACA. Immediately following heparinization, EACA was given to block plasminogen activation. Circulatory volume was restored with fresh whole blood. It was further recommended that, if the hemorrhage persisted, the level of fibrinogen should be determined and this factor replenished if found deficient. The technique was applied to two patients, one of whom suffered a bleeding diathesis after the repair of a congenital heart defect. The other had generalized bleeding following surgical excision of an ectopic tubal pregnancy. Cessation of bleeding occurred promptly without clinical evidence of thrombosis and with survival of both patients. Table 2 includes the recommended therapy of an uncontrolled generalized hemorrhagic diathesis encountered in the appropriate clinical setting. The method of treatment exploits to the patient's advantage the antagonistic qualities of heparin and EACA. Heparin is an anticoagulant, but when used in moderate amounts it does not compromise normal hemostasis. Therefore, heparin is used to protect the patient should the fibrinolysis be secondary to intravascular coagulation. Heparin is also mildly antifibrinolytic. EACA is intensely antifibrinolytic, but it does not interfere with normal hemostasis. When generalized bleeding is a result of fibrinolysis, EACA is dramatically effective. However, blocking fibrinolysis may precipitate generalized thrombosis unless EACA is preceded by

Table 2.

Therapy

of Hemorrhagic

Diathesis

1. Administer 0.5 mg. per kilogram of heparin intravenously every 6 hours. 2. Follow heparinization with 5 gm. of EACA intravenously over 30 minutes and 500 mg. every hour thereafter until hemorrhage is controlled. 3. Maintain stability of the circulatory system with fresh whole blood. 4. If bleeding persists after the 5 gm. of EACA, determine the fibrinogen level. If the fibrinogen level is less than 100 mg./lOO ml., administer 4 gm. of fibrinogen intravenously.

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JAMES J. BERGIN

prophylactic administration of heparin. Since the half life of EACA36 and heparin37 are quite similar, the effective duration of therapy is comparable.

SUMMARY Epsilon-aminocaproic acid is a potent inhibitor of the activation of plasminogen to plasmin. Minor side effects such as nasal stuffiness, abdominal discomfort, hypotension, conjunctival suffusion, nausea and vomiting, diarrhea, maculopapular rash, and pruritic morbilliform rash have been recorded. The drug is specific in blocking fibrinolytic activation allowing circulating plasmins to be neutralized by antiplasmins while fibrin and its end-products are spontaneously cleared. Inhibiting fibrinolysis associated with accelerated intravascular coagulation removes an essential mechanism protecting against widespread thrombosis. As clinical experience with EACA has accrued, this lethal complication of disseminated thrombosis has been encountered. Combined therapy, utilizing heparin to interfere with pathological intravascular coagulation and to protect against a thrombotic tendency from EACA, and utilizing EA CA to block plasminogen activation, has been found practical in a limited number of cases.

REFERENCES 1. Abe, T., Sato, A., Kazama, N., and Matsumara, T.: Therapeutic effect of epsilonaminocaproic acid on hemophilia. In Proc. Internat. Soc. Hemato!., Ninth Congress, Mexico, 1962, Vo!. 2, p. 720. Mexico City: Universidad Nacional Autonoma de Mexico, 1964. 2. Ablondi, F. B., Hagen, J. J., Philips, M., and de Renzo, E. C.: Inhibition of plasmin and trypsin in the streptokinase activated fibrinolytic system by epsilon-aminocaproic acid. Arch. Biochem. 82: 153, 1959. 3. Alkjaersig, N., Fletcher, A. P., and Sherry, S.: Epsilon-aminocaproic acid: An inhibitor of plasminogen activation. J. Bio!. Chem. 234: 832, 1959. 4. Andersson, L., and Nilsson, I. M.: Effect of epsilon-aminocaproic acid on fibrinolysis and bleeding conditions in prostatic disease. Acta chir. scandinav. 121: 291, 1961. 5. Andersson, L., Nilsson, I. M., and Olow, B.: Fibrinolytic activity in man during surgery. Thromb. Diath. Haemorrh. 7: 391, 1962. 6. Barkhan, P.: Haematuria in a haemophiliac treated with epsilon-aminocaproic acid. Lancet 287: 1061,1964. 7. Beller, F. K., Douglas, G. W., Debrovher, C. H., and Robinson, R.: The fibrinolytic system in amniotic fluid embolism. Am. J. Obst. & Gynec. 87: 48, 1963. 8. Bergin, J. J., Crosby, W. H., and Jahnke, E. J.: Massive bleeding with fibrinolysis: Management with heparin and epsilon-aminocaproic acid. Milit. Med. 131: 340, 1966. 9. Bonnar, J., and Crawford, J. M.: Hemorrhagic diathesis due to abruptio placentae: Treated by fibrinogen, epsilon-aminocaproic acid, and hysterotomy. Lancet 288: 241, 1965. 10. Council on Drugs: An antIfibrinolytic agent: Aminocaproic acid J .A.M.A. 191: 145, 1965. 11. Deysine, M., and Cliff ton, E. E.: Mechanism of action of epsilon-aminocaproic acid in the control of hemorrhage. Ann. New York Acad. Sc. 115: 291, 1964.

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12. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: Fibrinolytic mechanisms and the development of thrombolytic therapy. Am. J. Med. 33: 738, 1962. 13. Gans, H.: Thrombogenic properties of epsilon-aminocaproic acid. Ann. Surg. 163: 175, 1966. 14. Gans, H., Lillehei, C. W., and Krivit, W.: Problems in hemostasis during open heart surgery. Ill. Epsilon-aminocaproic acid as an inhibitor of plasminogen activator activity. Ann. Surg. 155: 268, 1962. 15. Gibbon, J. H., and Camishion, R. C.: Problems in hemostasis with extracorporal apparatus. Ann. New York Acad. Sc. 115: 195,1964. 16. Gollub, S.: Panel Discussion. Ann. New York Acad. Sc. 115: 299,1964. 17. Gordon, A. M., McNicol, G. P., Dubber, A. H. C., McDonald, G. A., and Douglas, A. S.: Clinical trial of epsilon-aminocaproic acid in severe hemophilia. Brit. M. J. 1: 1632, 1965. 18. Grannis, G. F., and Kazal, L. A.: The fibrinotic index and evidence for a balanced regulation of coagulation activities. Thromb. Diath. Haemorrh. 14: 52, 1965. 19. Grossi, C. R, Moreno, A. H., and Rousselot, L. M.: Studies on spontaneous fibrinolytic activity in patients with cirrhosis of the liver and its inhibition by epsilonaminocaproic acid. Ann. Surg. 153: 383, 1961. 20. Gros~i, C. E., Rousselot, L. N., and Panke, W. F.: Hemorrhagic diathesis during and after portacaval shunt in patients with cirrhosis of liver: Their recognition and management. Am. J. Gastroentero!. 41: 117, 1964. 21. Hardaway, R. M.: Blood coagulation changes after shock and transfusion of incompatible blood. Ann. New York Acad. Sc. 115: 151,1964. 22. Johnson, A. J., and Newman, J.: The fibrinolytic system in health and disease. Seminars Hemat. 1: 401, 1964. 23. Johnson, A. J., Skoza, L., and Clause, E.: Observations on epsilon-amino caproic acid. Thromb. Diath. Haemorrh. 7: 203, 1962. 24. Lewis, J. H., and Doyle, A. P.: Effects of epsilon-amino caproic acid on coagulation and fibrinolytic mechanisms. J.A.M.A. 188: 56, 1964. 25. Malcolm, D., and O'Connor, J. J.: Generalized fibrinolytic bleeding following cystoscopy in a patient with carcinoma of the prostate. J. Uro!' 90: 458, 1963. 26. McNicol, G. P.: Disordered fibrinolytic activity and its control. Scottish M. J. 7: 266, 1962. 27. McNicol, G. P., and Douglas, A. S.: Epsilon-aminocaproic acid and other inhibitors of fibrinolysis. Brit. M. J. 20: 233, 1964. 28. McNicol, G. P., Fletcher, A. P., Alkjaersig, N., and Sherry, S.: Impairment of hemostasis in urinary tract: Role of urokinase. J. Lab. & Clin. Med. 58: 34, 1961. 29. McNicol, G. P., Fletcher, A. P., Alkjaersig, N., and Sherry, S.: Plasma amino acid chromatography with ion exchanged resin loaded paper: Assay of epsilon-aminocaproic acid. J. Lab. & Clin. Med. 59: 7, 1962. 30. McNicol, G. P., Fletcher, A. P., Alkjaersig, N., and Sherry, S.: Use of epsilonamino caproic acid, potent inhibitor of fibrinolytic activity, in management of postoperative hematuria. J. Uro!' 86: 829, 1961. 31. Merskey, C., Johnson, A. J., Pert, J. H., and Wohl, H.: Pathogenesis of fibrinolysis in defibrination syndrome. Effect of heparin administration. Blood 24: 701, 1964. 32. Meyer, J. S.: Lysis of cerebrovascular blood clots. New York J. Med. 62: 3750, 1962. 33. Mikata, I., Hasegawa, M., Igarashi, I., Shirakura, N., Hoshida, M., and Toyama, K.: Variations of plasmin in the hemorrhagic blood diseases. Keio J. Med. 8: 279, 1959. 34. Mohler, as cited by Sweeney, W. M.: Aminocaproic acid, an inhibitor of fibrinolysis. Am. J. M. Sc. 249: 576, 1965. 35. Naeye, R. L.: Thrombotic state after hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood 19: 694, 1962. 36. Nilsson, I. M., Sjoerdsma, A., and Waldenstrom, J.: Antifibrinolytic activity and metabolism of epsilon aminocaproic acid in man. Lancet 1: 1322, 1960. 37. Olsson, P.: Exogenous heparin and the heparin co-factor: Experimental and clinical studies. Acta chir. scandinav. (Suppl.) 319: I, 1963. 38. Peck, as cited by Sweeney, W. M.: Aminocaproic acid, an inhibitor of fibrinolysis. Am.J.M.Sc.249:576,1965.

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39. Penick, G. D., Roberts, H. R., Webster, W. P., and Brinkhous, K. M.: Hemorrhagic states secondary to intravascular clotting: An experimental study of their evolution and prevention. Arch. Path. 66: 708, 1958. 40. Penick, G. D., Taylor, C. B., Huffines, W. D., Roberts, H. R., Wilson, S. G., and Brinkhous, K. M.: Comparative study of responses of normal and hemophiliac drugs to local cold injury. USAF School of Aviation Med. Rep. 6: 1, 1963. 41. Reid, W. 0., Lucas, O. N., Francisco, J., Geisler, P. H., and Erslev, A. J.: Use of epsilon-aminocaproic acid in management of dental extractions in hemophilia. Am. J. M. Sc. 248: 184, 1964. 42. Roberts, H. R., Penick, G. D., Webster, W. P., and Brinkhous, K. M.: Prevention of hemorrhage with anticoagulants-an exploratory study of a paradox. Ann. New York Acad. Sc. 115: 67,1964. 43. Roth, F.: Orientierung uber die Wirkung der .-Aminocapronsaure in der Geburtshilfe und Gynakologie. Ther. Umsch. 9: 358, 1962. 44. Rotstein, J., Gilbert, M., and Estrin, I.: Antifibrinolytic drug in treatment of progressive systemic sclerosis. J.A.M.A. 184: 517, 1963. 45. Sack, E., Spaet, T. H., Gentile, R. L., and Hudson, P. B.: Reduction of postprostatectomy bleeding by epsilon-amino caproic acid. New England J. Med. 266: 541,1962. 46. Sato, S., Ishibashi, Y., Endo, T., Watahabe, T., and Nakajima, K.: Clinical use of epsilon-amino caproic acid on metropathia hemorrhagica. Keio J. Med. 8: 267, 1959. 47. Sharp, A. A.: Pathological fibrinolysis. Brit. M. Bull. 20: 240,1964. 48. Sherry, S., Fletcher, A. P., and Alkjaersig, N.: Fibrinolytic bleeding and its controls. Am. Heart J. 67: 425, 1964. 49. Sherry, S., Fletcher, A. P., and Alkjaersig, N.: Fibrinolytic bleeding and its management. Ann. New York Acad. Sc. 115: 481,1964. 50. Stafford, J. L. (Ed.): Fibrinolysis. Brit. M. Bull. 20: 171,1964. 51. Steiger, M. D., White, J. G., and Krivit, W.: Epsilon-aminocaproic acid for hematuria in hemophilia. J. Lancet 82: 421, 1962. 52. Stokes, J., Hufnagel, C. A., Dameshek, W., and Ratnoff, O. D.: Blood fractions in clinical medicine. Postgrad. Med. 31: 492, 1962. 53. Sweeney, W. M.: Aminocaproic acid, an inhibitor of fibrinolysis. Am. J. M. Sc. 249: 576, 1965. 54. Todd, A. S.: Localization of fibrinolytic activity in tissues. Brit. M. Bull. 20: 210, 1964. 55. Verstraete, M., Vermylen, C., Amery, A., and Robyn, G.: Heparin treatment of bleeding following intravascular coagulation. Lancet 1: 446, 1963. 56. Verstraete, M., Vermylen, C., Vermylen, J., and Vandenbroucke, J.: Excessive consumption of blood coagulation components as cause of hemorrhagic diathesis. Am. J. Med. 38:899, 1965. 57. von Francken, I., Johansson, L., Olsson, P., and Zetterqvist, E.: Heparin treatment of bleeding: Clinical observations. Lancet 1: 70, 1963. 58. Warren, B. A.: Fibrinolytic activity of vascular endothelium. Brit. M. Bull. 20: 213, 1964. 59. Yokoyama, K., and Hatano, H.: Clinical use of epsilon-amino caproic acid in eczema or other kinds of skin diseases suspected to be allergic. Keio J. Med. 8: 303,1959. Fitzsimons General Hospital Denver, Colorado