Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
T U B AMERICAN JOURNAL OF CLINICAL PATHOLOGY Vol. 41, No. 6, pp. 589-596 September, 1964 Copyright © 1864 by The Williams & Wilkins Co. Printed in U.S.A. T H E USE OF T H E SERIAL THROMBIN T I M E IN EVALUATING THERAPY WITH EPSILON AMINOCAPROIC ACID IN MASSIVE THROMBOLYSIS AND PROTEOLYSIS TSADORE BRODSKY, M.D., EVELYN ROSS, AND WILLIAM 0. RE ID, M.D. Department of Medicine, Section of Hematology, Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania The serial thrombin time (STT) method, originally developed by Wilhelm and associates,22 is an attractive test for thrombolysis and proteolysis because of its simplicity, rapidity, and convenience. The value of the STT has recently been emphasized by Ingrain and Matchett, 9 Reid and his associates,10' " and Tocantins and his colleagues.21 Ingram and Matchett demonstrated a linear relation between proportionate loss of clot weight and a proportionate increase in thrombin clotting time after adding increasing quantities of streptokinase-activated plasma.9 In the study reported below, the STT was used in conjunction with the euglobulin lysis time in order to evaluate epsilon aminocaproic acid (EACA) therapy in massive thrombolysis and proteolysis secondary to metastatic carcinoma of the prostate. The STT was a good measure of thrombolytic activity and correlated better than the euglobulin lysis time with the onset or cessation of bleeding during therapy with EACA. M A T E R I A L AND METHODS Pseudomonas polysaccharide (Piromen*) 50 Mg- per ml., was injected intravenously in a dose of 25 MgReceived, October 4, 1963; revision received January 13, 1964; accepted for publication March 2. Dr. Brodsky is Assistant Professor of Medicine, and Head of the Section of Hematology, Hahnemann Medical College and Hospital. Miss Ross is Research Associate in Hematology. Dr. Reid is Research Associate and Assistant Member, Cardeza Foundation, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania. This work was aided by the Public Health Service Grant H C3CS, Department of Health, Education, and Welfare, Bethesda, Maryland. * Travenol Laboratories Incorporated, Morton Grove, Illinois. EACAf was administered in the form of 500-mg. tablets or a parenteral preparation (250 mg. per ml.), or both. Parenteral EACA was administered in the form of a 10 per cent solution in 5 per cent glucose in water. Human thrombin (FibrindexJ) 50 units per vial was used in the STT. Coagulation studies included direct platelet count by means of the Brecher-Cronkite technic;4 clotting time in glass and silicone; 1-stage prothrombin time using human brain thromboplastin; 14 thrombotest; 13 Stypven time (to assay Factor X 3 ); Factor V;3 Factor All 1 0 assays, and thromboplastin generation test. 2 Fibrinogen levels were assayed by a semiquantitative method.10 Thrombolysis and proteolysis were studied by means of the whole blood clot lysis time. The euglobulin lysis time was performed with the methods of Buckell6 (normal range for this laboratory: 218 db 10 min.), and Iatridis and Ferguson7 (normal range for this laboratory: 371 ± 17 min.). The method of Iatridis and Ferguson was used only after the pyrogen stimulation and not during EACA therapy. The STT was performed by means of the modified method of Reid and associates.16, 17 Blood (4.5 ml.) was collected in an oxalated vacuum tube (Vacutainer No. 3206 BD) by means of a nontraumatic venipuncture. The blood was mixed thoroughly and immediately centrifuged at 3400 r.p.m. (International clinical centrifuge) for 5 min. After centrifugation, 1.4 ml. of plasma was distributed in 0.2-ml. aliquots into each of 7, 12- by 75-mm. test tubes (non-siliconized). The rack of tubes was placed in a water bath at 26 C. and tested in sequence at 0, 1, 2, 4, and 24 hr. as 589 f Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York. J Ortho Pharmaceutical Corporation, Raritan, New Jersey. 590 BRODSKY BT TABLE 1 N O R M A L VALUES OF S E R I A L T H R O M B I N TIME IN SECONDS Immediate 1-hr. 2-hr. 4-hr. 24-hr. 5.2 G.l 10.0 64.9 ± 0.45* ± 0.54 ± 2.63 ± 33.80 >240 * Mean ± s t a n d a r d deviation. follows: 1 ml. of 0.85 per cent saline solution was added to a vial of Fibrindex and 0.2 ml. of this solution was added at each given time interval. The tube was then tilted gently through an arc of approximately 80 degrees from the vertical to the horizontal and back at least 90 times per min. The time required for a coagulum to form was recorded with a stop-watch. If no coagulum formed within 4 min., the test was discontinued and the result recorded as greater than 4 min. ( > 4 ' ) . Normal values for the STT in our laboratory are listed in Table 1. The most significant determinations are those made immediately, at 1 hr., and at 2 hr. The normal values are in close agreement with those reported by Reid and his associates.17 In this paper only the immediate and the 1-hr.. STT results are reported, inasmuch as the values at these times correlated quickly and accurately with the response to EACA therapy and provided a good measure of thrombolysis. REPORT OF CASE A 72-year-old white man was admitted to Hahnemann Hospital in April 1963, with massive epistaxis and hematuria. The patient was known to have carcinoma of the prostate gland for 10 years. The diagnosis was established by means of biopsy following a transurethral resection. During this time he was treated with diethylstilbestrol 5 mg. t.i.d. The patient refused orchiectomy. In February 1963, he developed mild hematuria that subsided spontaneously. At that time he was admitted to Hahnemann Hospital, and roentgenograms revealed extensive osteoblastic metastases involving the pelvis, lumbar spine, and ribs. Therapy with estrogens was continued. The patient Vol. 41 AL. still refused orchiectomy. The pertinent physical findings consisted of pallor, tachycardia, and obvious epistaxis and hematuria. The hemoglobin was 5.8 Gm. per 100 ml., white blood cell count 8500 per cu. mm. The differential was within normal limits. The BUN was 15 mg. per 100 ml., serum calcium was 10 mg. per 100 ml., and phosphorus 4 mg. per 100 ml. The serum alkaline phosphatase and serum acid phosphatase were 19 and 3.0 Bodansky units, respectively. Therapy was immediately instituted with EACA as indicated in the results below. During the first 24 hr., the patient received 2 units of whole blood after the institution of EACA therapy. After the cessation of bleeding, bone marrow studies performed from both the sternum and posterior iliac crest demonstrated invasion of the marrow with metastatic carcinoma cells. Forty four days after the patient's admission to the hospital, treatment with EACA was discontinued and no additional bleeding occurred. The patient was discharged from the hospital 62 days after admission. RESULTS Studies of blood coagulation prior to tire start of therapy with EACA are summarized in Table 2. The clotting times in glass and silicone were normal, but thrombolysis was greatly increased in view of the 10-min. whole blood clot lysis time. By means of the assay methods used in this study, there was an apparent decrease in the 1-stage prothrombin time; thrombotest; Factors V, VII, X, and fibrinogen. The platelet count was elevated and the thromboplastin generation test was normal. Forty-two hours after the start of treatment with EACA, the blood coagulation factors returned to almost normal limits and there was a significant drop in the platelet count. Within 62 hr., all of the blood coagulation factors had returned to normal. The STT, the euglobulin lysis times, and their variations during bleeding and EACA therapy are illustrated graphically in Figures 1 and 2. The values are plotted on a semilogarithmic scale for purposes of convenience in presentation of data and not to imply a first-order reaction. Prior to the start of EACA therapy, the June 196J, 591 AMIN0CAPR01C ACID THERAPY TABLE 2 COAGULATION PROFILES Platelet count Thromboplastin tion test genera- 1-stage prothrombin time Thrombotest Factor V (accelerator globulin) Factor VJI (proconvertin) Stypven time (Factor X) Estimation of semiquantitative fibrinogen Clotting time (in glass) Clotting time (in silicone) Whole blood clot lysis time BEFORE AND D U R I N G EPSILON AMINOCAPROIC ACID (EACA) 0 Mr.* 18 Hr. 42 Hr. 62 Hr. 504,000 251,000 237,000 230,000 100% (7.0 sec. in 3 min.) 23% 30% 43% 100% (7.4 sec. in 4 min.) 41% 34% 73% 100% (9.8 sec. in 3 min.) 55% 43% 74% 100% (10.8 sec. in 5 min.) S9% 50% 00% 54% 81% 88% 100% THERAPY Normal Values 150,000400,000 S0-100% 80-100% 40-100% 70-100% S0-100% 30.0 sec. <75 mg. 18.G sec. 75-125 mg. 10.9 sec. 75-125 mg. 15.2 sec. 125 mg. 13-15 sec. 125 mg. 13 min. 23 min. 10 min. 8 min. 30 sec. 15 min. 0 sec. 13 min. 7 min. 45 sec. 19 min. 0 sec. 24 hr. 9 min. 30 sec. 17 min. 0 sec. >24 hr. 8-12 min. 10-20 min. 24 hr. Immediately before s t a r t of EACA therapy. STT was greatly prolonged immediately and at 1 hr. (54 sec. and >240 sec, respectively). The euglobulin lysis time was unobtainable because of failure of a clot to form.1 Lack of a coagulum with the euglobulin lysis time is recorded as 0 in Figures 1, 2, and 3. The patient was treated initially with 5 Gm. of parenteral EACA. The EACA was infused in 30 min. and bleeding stopped promptly in approximately 20 to 30 min., at which time blood transfusions were started. Three hours after the first infusion of EACA, the STT immediate was 18 sec. and 1 hr. >240 sec. The euglobulin lysis time was still unobtainable. Severe bleeding again developed and another 5 Gm. of parenteral EACA were administered over a 30-min. period, and again the bleeding was controlled. In addition to the parenteral EACA, 2 Gm. of oral EACA were administered to the patient every 4 hr. Although the epistaxis stopped, mild hematuria continued until the STT immediate and 1 hr. reached normal limits. This occurred approximately 18 to 20 hr. after the start of treatment. It is of interest that at this point the euglobulin lysis time was still reduced and did not return to normal limits until approximately 32 to 40 hr. after the start of treatment. In 4 days, the EACA dosage was reduced to 1 Gm. every 6 hr. (Fig. 2). Six days later, there was a sharp rise in the STT and reduction in euglobulin lysis time. Within 24 hr., epistaxis and hematuria developed. Five grams of parenteral EACA were administered and the oral dose increased to 1 Gm. every 3 hr. The oral dosage was continued for 48 hr. and then reduced to 1 Gm. every 6 hr. Five days later the STT again became elevated, the euglobulin lysis time becoming unobtainable. EACA dosage was increased to 2 Gm. every 4 hr. in an attempt to prevent hemorrhage, but severe bleeding again developed and 5 Gm. of parenteral EACA was administered. EACA was then continued in an oral dose of 8 Gm. per day for the next 12 days, and the dosage was then reduced to 6 Gm. daily. Slight elevations in the 1-hr. STT occurred on the 29th, 40th, and 47th day after admission. These elevations were not associated with any significant bleeding. EACA was discontinued on the 44th day and there was a sharp reduction in euglobulin lysis time as well as an increase in the 1-hr. STT. Slight hematuria occurred, but there was no 592 BRODSKY ET NO II J EL Vol. 41 AL. SLEEPING a EUGLOBULIN CLOT LYSIS THROMBIN TIMEfimmedwte reading) THROMBIN TIMEIc™ hour main,) I.V. DOSAGE 16 20 24 HOURS FIG. 1. Effect of epsilon aminocaproic acid (EACA) on serial thrombin time (STT) and euglobulin lysis time for first 48 hr. of therapy. * Lower limit of normal for euglobulin lysis time—2 standard deviations from mean; normal range, 218 ± 10.0 min. ** Upper limit of normal for STT at 1 hr.—3 standard deviations from the mean; normal range, 6.1 ± 0.54 sec. massive bleeding. The hematuria subsided spontaneously, no further therapy with EACA being required. Seven days after stopping EACA, a dose of pyrogen was injected, and a typical response was noted. There was a conspicuous rise in temperature, white blood cell count, and significant reduction in the euglobulin lysis time. The results of pyrogen stimulation are illustrated graphically in Figure 3. The euglobulin lysis time remained reduced for 48 hr. On the first day there was only a slight rise in the 1-hr. STT, but by the second day the immediate and 1-hr. STT were elevated. At this point the euglobulin lysis time was unobtainable. The STT immediate and 1-hr. became normal in 24-hr. In this experiment the euglobulin lysis times were performed by means of the Buckell as well as the Iatridis methods. There was no significant difference in the results. In Figure 3, only the results of the Buckell method are illustrated. Mild hematuria occurred within 24 hr. after injection, but the bleeding stopped spontaneously. There was no change in the blood coagulation factors at this time. Injection of pyrogen into 4 normal controls resulted in a characteristic response, with reduction in euglobulin lysis time, and no change in the STT. DISCUSSION A hemorrhagic state in patients with prostatic carcinoma secondary to abnormal June 1964 593 AMINOCAPHOIC ACID THERAPY NO , HO BLEEDING, B * > BLEEPINGg BLEE D I N G EUGLOBULIN CLOT LYSIS THROMBIN TlMEpmf'ediott reading) THROMBIN TIMEtor* nojr reading) I.V. DOSAGE ORAL DOSAGE 240 D A Y S Fro,. 2. Effect of epsilon aminocaproic acid (EACA) on serial thrombin time (STT), euglobulin lysis time, and clinical course from the 3rd to 51st clays of treatment. "fibrinolytic activity" has been well documented.20 Sherry and associates18 have suggested that the terms "fibrinolysis" and "fibrinolytic activity" are misleading and should be restricted to the action of proteolytic enzymes upon the protein fibrin. In this paper the term "thrombolysis" describes the entire mechanism or activity by which thrombi are lysed and the term "proteolysis" describes the series of changes produced by plasmin or other proteolytic enzymes acting upon susceptible plasma proteins.18 In the past, the term "fibrinolysis" was used to encompass thrombolysis, fibrinolysis, and proteolysis. Present theory suggests that when plasminogen is activated in the plasma (soluble phase), the resulting plasmin is rapidly neutralized by antiplasmin, whereas plasminogen activation in a clot (gel phase) leads to thrombolysis. 6 In abnormal hemorrhagic states, excess free plasmin in the plasma causes fibrinolysis, proteolysis, and severe coagulation defects.13 It is of interest that the prostate gland is known to contain high levels of soluble plasminogen activator. 18 In the example described in this paper, massive thrombolysis and proteolysis were present. Prior to EACA therapy the coagulation profile demonstrated decreased levels of fibrinogen, prothrombin, Factor V, Factor VII, and Factor X. The decreased levels of the above factors could be explained on the basis of: (1) initial hypofibrinogenemia, (2) fibrinolytic activity during performance of the assay procedure, and (3) release of anti-thrombin 6 (fibrinogen polymerization inhibitor) during fibrinolysis.17 A direct proteolytic effect on the individual coagulation factor must also be considered. Severe thrombolysis was 594 BRODSKY ET Vol. 41 AL. n NO BLEEDING i NO _, : -BLEEDING..; NO BLEEDING •120 2 •EUGLOBULIN CLOT LYSIS 'THROMBIN TIMEl immediate reading) •THROMBIN TIME lone hour reading) BO 27 21 \ 15 9 ',(^Ofc>— DAY 51 OAY 52 DAY 53 FIG. 3. Effect of administration of pyrogen on the STT, euglobulin lysis time, and clinical course for 48 hr. * Lower limit of normal for euglobulin lysis time—2 standard deviations from mean; normal range, 218 ± 10.0 min. ** Upper limit of normal for STT at 1 hr.—3 standard deviations from the mean; normal range, 6.1 ± 0.54 sec. indicated by the whole blood clot lysis time, euglobulin lysis time, and STT. The platelet count was elevated and the first stage of coagulation, as measured by the thromboplastin generation test, was normal to accelerated. Hyperplasminemia is associated with proteolysis and results in a decrease in fibrinogen, prothrombin, Factor V, and complement.6 Although it would seem, on the basis of the above findings, that abnormal activation of the plasminogen-plasmin system was entirely responsible for the hemorrhagic state, a second explanation must also be considered. It is possible that the release of a thromboplastic substance into the circulation might also lead to a hemorrhagic state by causing intravascular clotting with resultant defibrination and consumption of coagulation factors. Prior to the start of EACA the platelet count was elevated and the thromboplastin generation test was slightly accelerated. This might suggest a hypercoagulable state in the first stage of coagulation; however, it would be difficult to explain depressions of Factor VII and X on the basis of intravascular clotting. These 2 factors are activated by clotting. In a case of prostatic carcinoma presented by Rapaport and Chapman, 16 the second explanation was believed to be the major factor in the hemorrhagic state because of the demonstration of hypercoagulability in the presence of hypofibrinogenemia. June 1964 595 AMINOCAPHOIC ACID THERAPY It is possible that activation of the plasminogen-plasmin system as well as release of thrornboplastic substance into the circulation is responsible for the hemorrhagic state in this case. Recent studies by Iatridis and Ferguson7 have demonstrated that Hageman Factor will activate not only the coagulation system but also the plasminogen-plasmin system, as measured by means of the euglobulin lysis time. In this study, with the exception of a slightly elevated platelet count prior to therapy, we were unable to demonstrate definitely a hypercoagulable state. All studies indicated that thrombolysis and proteolysis were the major factors in the abnormal bleeding. EACA, a potent and specific inhibitor of plasminogen activators such as streptokinase, stopped the bleeding almost immediately.19 Within 24 hr. depressed clotting factors returned to normal levels. The inhibitory effect of EACA on plasmin is almost negligible.19 EACA was first administered parenterally but, because of the rapid renal clearance, oral EACA was instituted. Oral administration is highly effective because the drug is rapidly and predictably absorbed from the gastrointestinal tract. Peak plasma levels are obtained approximately 2 hr. after a single oral dose.11,12 The 2 technics used serially to follow this patient's disordered thrombolytic activity were the euglobulin lysis time and the STT. The euglobulin lysis time has been frequently used as a measure of over-all plasma "fibrinolytic activity," but recent studies have demonstrated that it is a qualitative and perhaps even quantitative measure of plasminogen activators. 8 After the start of EACA, the STT correlated well with the cessation of bleeding, but the euglobulin lysis time remained decreased for approximately 40 hr. Each episode of subsequent bleeding requiring increased dosage of EACA was preceded by an increase in the STT. Cessation of bleeding coincided with an immediate decrease in the STT, but the euglobulin lysis time remained reduced for approximately 24 hr. The pyrogen injection resulted in an immediate significant reduction in the euglobulin lysis time, but only a slight increase in the 1-hr. STT occurred. Both the euglobulin lysis time and the immediate and 1-hr. STT were abnormal 24 hr. later. This was associated with minimal hematuria. The euglobulin lysis time was still reduced and the STT was well within normal limits 48 hr. later. Injection of pyrogen into 4 apparently normal persons in our laboratory resulted in a significant reduction in the euglobulin lysis time but no change in the STT. I t is apparent that the STT does not correlate well with the euglobulin lysis time, during spontaneous thrombolysis and proteolysis or during pyrogen-induced activation of the plasminogen-plasmin system. The euglobulin lysis time is probably a much more sensitive test for plasminogen activator than the STT. However, significant elevation in plasminogen activator will result in an elevation of the STT, probably because of production of net excess of circulating proteolytic and thrombolytic enzyme. The lack of correlation between the euglobulin lysis time and the STT might be expected, inasmuch as the former test measures primarily plasminogen activator, whereas actual proteolytic and thrombolytic activity in man as detailed in this case by the STT, is a complex process involving both plasminogen activation and inhibition by anti-plasmin. The complex nature of the STT may explain its better correlation with bleeding than the euglobulin lysis time. Although it is unlikely, the differences between the euglobulin lysis time and STT could be explained by removal of the EACA during the precipitation of the euglobulin fraction. Therefore, the euglobulin lysis time may be conducted in the absence of and STT in the presence of EACA. The STT may be particularly useful in following therapy in cases of thrombolysis and proteolysis treated with EACA. Present evidence tends to support the Irypothesis that the STT is a good over-all measure of thrombolysis and proteolysis, and that this test can be performed with great speed, convenience, and accuracy. SUMMARY A patient with massive thrombolysis and proteolysis secondary to metastatic car- 596 BRODSKY cinoma of the prostate gland was treated with epsilon aminocaproic acid (EACA). The effect of therapy was evaluated by means of clinical course, euglobulin lysis time, and serial thrombin time (STT). The STT coincided better than the euglobulin lysis time with cessation or onset of bleeding and the necessity for varying doses of EACA. The STT is regarded as being a rapid, convenient, and accurate test for evaluating thrombolysis, proteolysis, and a concomitant hemorrhagic diathesis. SUMMAKIO IN REFERENCES 1. ALKJABRSIG, N . : Laboratory control of t h e thrombolytic s t a t e . In R O B E R T S , H . R., AND GERATZ, J . D . : Conference on Thrombolytic Agents—Hematology Study Section. Chapel Hill, N . C : University of N o r t h Carolina, 1960, p p . 136-145. 2. B I G G S , R., AND D O U G L A S , A. S.: T h e t h r o m b o - test. J . Clin. Path., 3. B I G G S , R., AND M A C F A K L A N E , R . G.: H u m a n Blood Coagulation and I t s Disorders. Springfield: Charles C Thomas, 19G2, p p . 388-389. 4. B R E C H E R , G., AND C R O N K I T E , E . P . : Vol. U AL. 7. I A T R I D I S , S. G., AND F E R G U S O N , J . H . : Effect of surface and H a g e m a n factor in t h e endogor spontaneous activation of enous the fibrinolytic system. T h r o m . D i a t h . Haemorrh., 6: 411-423, 1961. 8. I A T R I D I S , S. G., AND F E R G U S O N , J . H . : Effect of physical exercise on blood clotting and fibrinolysis. J. Appl. Physiol., 18: 337-344, 1963. 9. INGRAM, G. I . E . , AND M A T C H E T T , M . O.: T h e "serial thrombin t i m e " method for measuring fibrinogenolytic activity in plasma. N a t u r e , 188: 674-675, 1960. 10. L E N A H A N , J . G., AND P H I L L I P S , G. E . : In Seminar on t h e Coagulation of Blood. Morris Plains, N . J.: Warner-Lambert R e search I n s t i t u t e , 1902, p . 26. 11. M C N I C O L , G. P . , F L E T C H E R , A. P . , A L K J A E R SIG, N . , AND S H E R R Y , S.: T h e use of epsilon INTERLINGUA Un patiente con massive thrombolyse e proteolyse secundari a carcinoma metastatic del glandula prostatic esseva tractate con acido epsilon-aminocaproic. Le effecto del therapia esseva evalutate per medio del curso clinic, le tempore del lyse de euglobulina, e del serial tempore de thrombina. Le tempore serial de thrombina coincideva melio que le tempore del lyse de euglobulina con le cessation o initiation de sanguination e le necessitate de variar le doses de acido epsilon-aminocaproic. Le serial tempore de thrombina es reguardate como un rapide, commode, e accurate test pro le evalutation de thrombolyse, proteolyse, e un concomitante diathese hemorrhagic. plastin generation 6: 23-29, 1953. ET Mor- phology and enumeration of human blood platelets. J . Appl. Physiol., 3 : 365-377, 1950. 5. BUCKELL, M . : T h e effect of citrate on euglobin methods of estimating fibrinolytic activity. J. Clin. P a t h . , 11: 403-405, 1958. 6. FLETCHER, A. P . : Pathophysiology of throm- aminocaproic acid, a p o t e n t inhibitor of fibrinolytic activitj', in the management of postoperative hematuria. J . Urol., 86: 829-837, 1961. 12. M C N I C O L , G. P . , F L E T C H E R , A. P . , A L K J A E R SIG, N . , AND S H E R R Y , S.: T h e a b s o r p t i o n , distribution, and excretion of e-aminocaproic acid following oral or intravenous administration t o m a n . J . L a b . & Clin. Med., 59: 15-24, 1962. 13. O W R E N , P . A . : Thrombotest—a new method for controlling anticoagulant therapy. Lancet, 2 : 754-758, 1959. 14. Q U I C K , A. J., STANLEY-BROWN, M . , AND BANCROFT, F . W.: A s t u d y of t h e coagulation defect in hemophilia a n d in jaundice. Am. J . M . S c , 190: 501-511, 1935. 15. R A P A P O R T , S. I., AND CHAPMAN, C. G.: Co- existent hypercoagulability and acute hypofibrinogenemia in a p a t i e n t with prostatic carcinoma. A m . J . Med., 27: 144-153, 1959. 16. R E I D , W. O.: T h e relationship of liver insufficiency to fibrinolytic hemorrhage as demonstrated by the serial thrombin time. M e tabolism,'12: 631-641, 1963. 17. R E I D , W. O., SOMLYO, A. V., SOMLYO, A. P . , AND CUSTER, R. P . : T h e role of t h e platelet in fibrinolysis with a sensitive test for fibrinolytic activity. Am. J . Clin. P a t h . , 37: 561-566, 1962. 18. SHERRY, S., FLETCHER, A. P., A N D ALKJAER- SIG, N . : Fibrinolysis and fibrinolytic act i v i t y in m a n . Physiol. R e v . , 39: 343-382, 1959." 19. SHERRY, S., F L E T C H E R , A. P . , A L K J A E K S I O , N . , AND SAWYER, W. D . : e-aminocaproic acid: a p o t e n t anti-fibrinolytic agent. A. Am. Physicians, 72: 62-70, 1959. Tr. 20. T A G N O N , H. J., W H I T M O R E , W. F . , SCIIULMAN, P . , AND K R A V I T Z , S. C . : Significance of fibrinolysis occurring in p a t i e n t s with m e t a s t a t i c cancer of t h e p r o s t a t e . Cancer 6: 63-67, 1953. 21. TOCANTINS, L. M . , R E I D , W. O., S I L V E R , M . J., AND KAZAL, L. A.: C u r r e n t problems in hemostasis, in press. bolysis. In R O B E R T S , H . R., AND G E R A T Z , 22. W I L H E L M , D . L., M I L E S , A. A., AND M A C K A Y , J. D . : Conference on Thrombolytic Agents —Hematology S t u d y Section. Chapel Hill, N . C : University of N o r t h Carolina, 1960, pp. 148-159. M. E . : Enzyme-like globulins from serum reproducing the vascular phenomenon of inflammation. Brit. J . Exper. P a t h . , 36: 82-104, 1955.