Fibrinolysis Following Prostatic Surgery

THE JOURNAL OF UROLOGY

Vol. 77, No. 2, February 1957

Printed in U.S.A.

FIBRINOLYSIS FOLLOWING PROSTATIC SURGERY LOUIS J. LOMBARDO, JR.

From the Department of Urological Surgery, University of Southern California School of Medicine and Los Angeles County Hospital, Los Angeles, Calif.

Fibrinolysis is a term coined and apparently first used by Dastre 1 in 1893. Although this phenomenon of aseptic breakdown of whole blood clots in vitro has been known for over a century, it has only been in the past few years that the possible significance of increased plasma proteolytic activity in vivo has been recognized. The importance of fibrinolysis in the pathogenesis of some hemorrhagic diatheses has possibly been overlooked by earlier investigators because in its extreme form it occurs only rarely and with apparent irregularity. That urologists should be aware of fibrinolysis is evident by the fact that at the Los Angeles County Hospital in the past year the urological service recognized 5 cases in 302 transurethral procedures as compared ·with three cases in approximately 3500 general surgical procedures. The terminology for the current concepts of the proteolytic enzyme system of plasma is not standardized in the literature. Figure 1, proposed by Scott et al.,2 illustrates schematically the balanced enzyme system in plasma with delicate equilibrium between an active enzyme called plasmin (fibrinolysin) and its inhibitor called antiplasmin (antifibrinolysin). The precursor of plasmin (fibrinolysin) is termed plasminogen (profibrinolysin). Note that plasminogen and plasmin reside in the globulin fraction of the plasma and antiplasmin in the albumin fraction. The activation in pathological conditions of this plasma enzyme system may cause a complete breakdown of the hemostatic mechanism with resultant severe bleeding manifestations termed by Stefanini3 "fibrinolytic purpura." This hemorrhagic diathesis is probably due to enzymatic digestion not only of the fibrin clot but also of all other proteins involved in the process of blood coagulation. It is evident since the enzyme system is not fastidious in its lytic activity that this system is proteolytic rather than just fibrinolytic. Plasminemia is a term denoting an increased quantity of circulating plasmin. The exact details of the mechanism of abnormal plasma proteolytic activity are as yet undetermined. Fron, clinical and experimental studies it can be postulated that abnormal proteolytic activity may occur under a number of circumstances. These conditions are summarized by Scott, l\!Iatthews, Buttenvorth, and Frommeyer2 as follows: 1) activation of plasminogen as a result of the general alarm reaction; 2) activation of plasminogen as the result of release into the circulation of tissue activator substances; 3) entry into the circulation of proteolytic enzymes other than plasmin from sources such as the prostate or pancreas; 4) amniotic fluid embolism. Read at annual meeting of Western Section of American Urological Association San Francisco, Calif. April 30-.May 3, 1956. 1 Dastre, A.: Fibrinolyse clans le san. Arch. internat. physiol. norm. path., Par., 5: 661, 1893. 2 Scott, E. V. Z., .Matthews, W. F., Butterworth, C. E. and Frommeyer, W. B., Jr.: Abnormal plasma proteolytic activity; diagnosis and treatment. Surg., Gynec. & Obst., 99: 679, 1954. 3 Stefanini, Mario: Fibrinolysis and "fibrinolytic purpura." Blood, 7: 1044, 1952. 289

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LOUIS J. LOMBARDO, JR.

ALBUMIN FRACTION

GLOBULIN FRACTION

I

ACTH - - - - Cortisone

,-

l

ANTIPLASMINOGEN (?)--PLASMINOGEN s-

I

CHCls Ether Acetone)

r-

II(?.)

Activator Enzyme

i

Tissue Cells

iL--1-------Bacteria Streptokinase Staphyokinase

I

--+ANTIPLASMIN----- - PLASM IN

l

Semen Enzyme

~--------Prostate Trypsin I ~--------Pancreas

ll

1. Lysis of Fibrin

2. Proteolysis of Prothrombin, DEGRADATION Fibrinogen, --+ PRODUCTS Prothrombin Conversion Factors Casein, Gelatin, etc.

Fm. 1. Schema of plasma proteolytic enzymes and proposed mechanism of action of various compounds, bacteria and tissue products.

MacFarlane and Biggs4 and Biggs, MacFarlane and Pilling 5 have shown that such stimuli as fear, exercise, trauma and parenteral adrenalin may initiate an increased plasmin activity. These investigators have demonstrated plasminemia in approximately one half of the preoperative patients they studied. In addition, their studies show that plasminemia occurs in approximately one half of postoperative patients without relation to the severity of the surgery. Tagnon and associates recorded fibrinolytic activity in cases of severe burns, hemorrhages and barbiturate poisoning. In view of these and other studies the alarm reaction of Selye is postulated as the basic mechanism for abnormal plasma proteolytic activity. Many studies support the postulation that plasminogen is activated as a result of release into the circulation of tissue activator substance. Lung tissue has been shown to be particularly capable of causing activation of plasminogen in the studies of Tagnon and Petermann 6 and Mathey et. al.7 Tagnon and Petermann also demonstrated an activator of plasminogen in many other organs. Astrup and 4 MacFarlane, R. G. and Biggs, R.: Observations on fibrinolysis, spontaneous activity with operations, trauma, etc. Lancet, 2: 863, 1946. 5 Biggs, R., MacFarlane, R. G. and Pilling, J.: Observations on fibrinolysin; experimental activity induced by exercise or adrenaline. Lancet, 1: 402, 1947. 6 Tagnon, H. J. and Petermann, M. L.: A proplasmin activator from mammalian tissue. J. Olin. Invest., 28: 814, 1949. 7 Mathey, J. J., Doumet, P., Soulier, J.P., LeBallogh, A.G. and Fayet, H.: Hemorrages graves au cours d'interventions thoraciques par incoagulabilite sanguine due a la fibrinolyse. Med. Acad. chir., 76: 977, 1950.

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291

Permin8 suggest that all tissue cells are capable of activation of plasminogen. Neoplastic tissue may also be capable of activation of plasminogen since Coon and Hodgson 9 reported a patient with bronchogenic carcinoma who had plasminemia. After surgical removal of the tumor the plasminemia disappeared. Abnormal proteolytic activity is postulated to occur following entry into the circulation of proteolytic enzyme from the pancreas or prostate. Proteolytic activity has been observed during or following pancreatic surgery. The clinical picture of proteolytic activity due to trypsin is not dissimilar to that due to plasmin. The work of Kaplan10 makes clear the differentiation of trypsin and plasmin. An enzyme originating in the prostate gland has been shmvn by the studies of Huggins and Neal 11 and V onKaulla and Shettles 12 to have the same proteolytic properties of plasmin. This semen enzyme system was found to have a precursor or proenzyme and an antienzyme. Tagnon et al.1 3 •14 have demonstrated that prostatic cancer tissue and metastatic prostatic carcinoma cells contain a proteolytic enzyme that is able to digest fibrinogen and fibrin. Tagnon points out the analogy of increased plasma proteolytic activity in extensive metastatic prostatic carcinoma to other such cases with an elevated serum acid phosphatase. Since a transient elevation of the serum acid phosphatase is noted following massage of the prostate gland it is not unreasonable to conjecture that the more severe trauma of a prostatic operation could result in the intravascular release of all other enzymes or enzyme activators produced by prostatic tissue. If sufficient enzyme or enzyme activators gain access to the bloodstream to neutralize the powerful inhibitors of proteolytic enzymes in the blood serum15 fibrinolysis may occur. The actual cause of fibrinolysis associated with prostatic surgery is unknown. The process may be entirely due to the intravascular release of the semen proteolytic system or due to intravascular release of enzyme activators from the prostate triggering the plasmin system. The pathogenesis in prostatic surgery may conceivably be the general alarm reaction with subsequent activation of plasminogen. METHODS

Coagulation time of venoils blood, The modified Lee-1Vhite method was used for determination of the coagulation time. 8 Astrup, T. and Permin, P. M.: Fibrinolysis in the animal organism. Nature, 159: 781, 1947. 9 Coon, W.W. and Hodgson, P. E': Fibrinolysis in surgery patients. Surg., Gynec. & Obst., 95: 717, 1952. 1 ° Kaplan, M. H.: Studies of streptococcal fibrinolysis: I, the dissimilarity of serum protease and trypsin as indicated by the separate specificities of their kinases, fibrinolysin and enterokinase. J. Clin. Invest., 25: 331, 1946. 11 Huggins, C. and Neal, W.: Coagulation and liquefaction of semen. J. Exp. Med., 76: 527, 1942. 12 Von Kaulla, K. N. and Shettles, L.B.: Relationship between human seminal fluid a,nd the fibrinolytic system. Proc. Soc. Exp. Biol. and Med., 83: 692, 1953. 13 Tagnon, H. J., Whitmore, W. F., Schulman, P. and Kravitz, S. C.: The significance of fibrinolysis occurring in patients with metastatic cancer of the prostate. Cancer, 6: 63, 1953. 14 Tagnon, H. J., Whitmore, W. F. and Shulman, N. R. Fibrinolysis in metastatic cancer of the prostate. Cancer, 5: 9, 1952. 15 Kaplan, M. H., Tagnon, H. J., Davidson, C. S. and Taylor, F. H. D.: Studies on blood coagulation: the nature and properties of a proteolytic enzyme derived from plasma. J. Clin. Investig., 21: 533, 1942.

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LOUIS J. LOMBARDO, JR.

Plasma fibrinogen concentration. The modified Ware and Seegers16 method was used for determination of the plasma fibrinogen concentration. Histopathology of prostatic tissiw. In addition to the routine histopathology available at our hospital, the tissues in these cases, where practical, were studied by the blended tissue method of Ludden and Jensen. 17 This was undertaken to leave little doubt that fibrinolysis had occurred in benign prostatic hypertrophy. The following 5 case reports illustrate hypofibrinogenemia and afibrinogenemia in transurethral prostatic resections. One case occurred in adenocarcinoma of the prostate and 4 cases in benign prostatic hypertrophy. CASE REPORTS

Case 1. G. T., a 70-year-old white man, was admitted to the hospital because of urinary obstruction due to benign prostatic hypertrophy. Under spinal anesthesia a transurethral resection of the prostate gland was performed. Thirty grams of tissue were removed in one hour. Whole blood was started near the end of the procedure because of uncontrolled oozing from the prostatic fossa. No open venous sinuses were identified. Immediately after operation the clotting time was 60 minutes and the clot completely lysed in 3 hours. The patient continued to bleed through the urethral catheter and all modes of catheter traction upon the prostatic fossa failed to abate the bleeding. Blood loss was replaced with whole blood. The sites of venipuncture, venesection and the site of lumbar puncture for the spinal anesthetic oozed profusely. A few hours postoperatively urethroscopy was performed to possibly identify bleeding points. Again generalized oozing from the prostatic fossa was noted and not controlled by fulguration. Toluidine blue and fibrinogen were not available for administration at this time. A fibrinogen determination 20 hours postoperatively was 106 mg. per cent. During the postoperative course the patient received 5,400 milliliters of whole blood. The blood pressure progressively declined and 22 hours postoperatively the patient expired. Case 2. R.H., a 75-year-old white man, was admitted to the hospital because of acute urinary retention due to benign prostatic hypertrophy. Under spinal anesthesia a transurethral resection of the prostate gland was performed. Toward the end of the resection the patient had an acute asthmatic attack controlled by intravenous ephedrine and aminophyllin. Twenty four grams of prostatic tissue were resected. Venous sinuses were opened near the end of the procedure, but bleeding was easily controlled by catheter traction. The blood pressure and pulse were stable throughout surgery. Subsequently the blood pressure progressively declined and profuse bleeding developed through the urethral catheter. This bleeding was not controlled by traction; therefore, urethroscopy was performed. Fulguration would not control the generalized oozing from the prostatic fossa. A blood sample was found to have no fibrinogen and no heparin. A blood sample at this time did not clot in one hour. The patient expired 4½ hours postoperatively before any fibrinogen was instituted. Ware, A.G. and Seegers, W. H.: Arch. Biochem., 13: 231, 1947. Ludden, T. E. and Jensen, R. E.: Histologic diagnosis of cancer by study of blended tissues with particular reference to adenocarcinoma of prostate. J. Urol., 72: 57, 1954. 16 17

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Case 3. J. F., an 81-year-old white man, was admitted to the hospital because of acute urinary retention due to a small fibrotic benign prostate. Under spinal anesthesia a transurethral resection of the prostate gland and bladder neck was performed. The obstruction ,vas relieved with resection of only 7 gm. tissue. Good hemostasis was acquired at surgery, but during the operation the patient had acute precordial pain. An electrocardiogram at this time showed no changes from one taken preoperatively. The blood pressure remained stable until 2 hours postoperatively at which time there was an increase in blood pressure to 150/70 from a baseline of 110/70. Three hours postoperatively profuse bleeding through the urethral catheter developed and the patient vomited coffee ground emesis positive for blood. Bleeding from the oral mucous membranes was also noted at this time. A blood sample 4 hours postoperatively contained no fibrinogen. In further support for the diagnosis of plasminemia it was found that the patient's plasma lysed a normal hmnologous blood clot and also lysed his own blood clot. Therapy therafter consisted of whole blood transfusions, toluidine blue and 6 gm. fibrinogen (1 gm. hourly for the subsequent 6 hours). At 18 hours postoperatively the plasma fibrinogen concentration was 100 mg. per cent. The patient expired 19 hours postoperatively. Case 4- P. G., a 70-year-old white man, was admitted to the hospital because of acute urinary retention and hematuria 2 days before admission. The hematuria completely subsided on ind·welling catheter drainage and a complete urological workup revealed no genitourinary disease other than benign prostatic hypertrophy. Under spinal anesthesia a transurethral resection of the prostate gland was done. In 70 minutes 47 gm. ·were resected. Near the end of the procedure the capsule was perforated. A cystogram revealed extraperitoneal extravasation. The blood pressure had remained stable throughout surgery with the administration of 600 ml. whole blood. The patient's general condition was satisfactory and there was no unusual bleeding. A cystostomy and drainage of the prevesical space were undertaken immediately. As the skin was being closed the patient vomited bright red blood and the sites of recent venipunctures began bleeding. Also profuse bleeding developed through the urethral catheter. At this time the patient's plasma fibrinogen concentration was 141 mg. per cent and his clotting time was 20 minutes. In 1 hour the clot was corn.pletely lysed. Intravenous therapy consisted of toluidine blue, 6,800 ml. whole blood and 1 gm. fibrinogen administered every hour for the subsequent 6 hours. Vasopressors ·were also employed to maintain the blood pressure. Subsequently, the blood pressure declined and the patient expired 22 hours postoperatively. Case 5. S. H., an 82-year-old white man, was admitted to the hospital because of elevated residual urine due to adenocarcinoma of the prostate gland proven by Silverman needle biopsy. The patient had been previously on estrogen therapy 2 months. No metastatic disease was evident by chest film or bony survey films. Under spinal anesthesia a transurethral resection of the prostate gland removed 14 gm. tissue. During the resection venous sinuses were entered, but good hemostasis was acquired and the patient maintained a normal blood pressure. This case was oper:i,ted upon at a time when a study of fibrinogen concen-

294

LOUIS J. LOMBARDO, JR. TABLE

1. Effects of hyperheparinemia and plasminemia on blood clotting

Hyperheparinemia

Plasminemia

1. Coagulation time is usually delayed

2. Small amounts of the patient's blood will delay the coagulation time of normal blood 3. Addition of small amounts of thrombin will usually produce a clot 4. If a clot forms it does not lyse

1. Coagulation time may be normal or may be infinitely delayed 2. The patient's blood will not delay the coagulation time of normal blood

3. If blood does not clot spontaneously thrombin will not cause clotting 4. If a clot forms it will partially or completely lyse within 24 hours

trations was being done. In this study fibrinogen determinations were done preoperatively, 1 hour following the administration of the anesthetic and 4 hours after the anesthetic. The preoperative fibrinogen concentration was 280 mg. per cent and the 1 hour postanesthetic plasma fibrinogen concentration was 336 mg. per cent. Almost simultaneously with the report from the laboratory of the 4-hour postanesthetic blood sample containing no fibrinogen the patient suffered profuse bleeding through the urethral catheter and a blood pressure drop. Treatment immediately instituted consisted of toluidine blue, whole blood transfusions and 1 gm. of fibrinogen every hour for the subsequent 5 hours. Bleeding through the urethral catheter gradually decreased. The plasma fibrinogen concentration 24 hours postoperatively was 340 mg. per cent. Within this postoperative period 5,600 milliliters of whole blood were given. At 48 hours postoperatively the drainage through the urethral catheter was grossly clear of blood. At 72 hours the plasma fibrinogen concentration was 340 milliliters per cent. The patient has been followed 3 months postoperatively without recurrence of bleeding. DIAGNOSIS

After the well defined hemorrhagic diatheses are excluded, hyperheparinemia and plasminemia should be considered in the differential diagnosis of excessive bleeding during or following operative procedures. Table 1 outlines the effects of hyperheparinemia and plasminemia on blood clotting. The diagnosis can be made by careful observation of the blood while determining the modified LeeWhite coagulation time. This test, of course, should be started before any therapy is instituted since therapy may obscure the test. It should be emphasized that therapy need not be delayed while this test is being run since considerable time may elapse while the future integrity of the clot is being decided. When the blood is obtained for this test a specimen may also be obtained for determination of the plasma fibrinogen concentration. During observation of the blood any one of the following phenomena may occur in plasrninemia: 1) the coagulation time may be normal with ensuing partial lysis of the clot; 2) the coagulation time may be normal with ensuing complete lysis of the clot; or 3) there may be no coagulation. Hyperheparinemia will not cause lysis of the blood clot; therefore,

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if a clot forms, hyperheparinemia is ruled out. From this it is evident that the blood in both hyperheparinemia and plasminem.ia may not clot. To differentiate the two in such a condition a small amount of thrombin is added. Thrombin ,vill usually produce a clot in hyperheparinemia. TREATMENT

We can not predicate the therapy of fibrinolysis occurring in prostatic surgery with the experience of only 5 cases. Cases 3, 4, and 5 were treated similarly with whole blood, fibrinogen and toluidine blue. Apparently one of the most important factors is early recognition. Once fibrinolysis is suspected and the blood samples are drawn the therapy should be started empirically. If the blood sample does not clot and there is difficulty in immediately distinguishing hyperheparinemia and plasminemia, an antiheparin such as toluidine blue should be given. The recommended dosage of toluidine blue is 5 mg. per kilogram of body weight. If a blood sample 30 minutes after injection of toluidine blue does not clot or demonstrates a prolonged coagulation time, this is strong evidence that one is not dealing with hyperheparinemia. When either a normal coagulation time or a delayed coagulation time is demonstrated, therapy must also be instituted for plasminemia. Our therapy has consisted of the intravenous administration of whole blood and fibrinogen. "\Vhole blood acts upon the abnormal plasma proteolytic activity both directly and indirectly. The direct action is in the supplementation of the patient's plasma. with antiplasmin content of normal plasma found in the albumin fraction. A disadvantage of whole blood is its normal content of plasminogen or plasmin found in the globulin fraction. With more plasminogen available to the patient's enzyme activating system the abnormal proteolytic activity could be augmented. The indirect action of whole blood on plasminemia or fibrinolysis is in the supplementation of substrate in the form of fibrinogen, prothrombin and other coagulation factors. We have used 1 gm. fibrinogen every hour until clinical evidence of lessening of bleeding. Fibrinogen is given to supply large amounts of substrate. "\Ve have had no experience in the treatment of plasminemia with low salt human serum albumin, but this appears to be an advisable mode of direct attack. It is in the albumin fraction of blood that antiplasmin resides. With the administration of albumin it is possible to supply the patient directly with concentrated antiplasmin which opposes the proteolytic action of excessive plasmin. The recommended dosage of low salt human serum albumin is 100 ml. every hour until there is clinical evidence of lessening of bleeding. One may ask why serum albumin is used in fibrinolysis thought to be caused by prostatic proteolytic enzyme since it is not known whether the albumin fraction of the serum contains an antienzyme for the prostatic proteolytic enzyme. Until there is further evidence and conclusions are drawn as to the identity of the prostatic proteolytic enzyme and plasmin it would seem advisable to administer serum albumin to any patient with abnormal proteolytic bleeding.

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LOUIS J. LOMBARDO, JR.

Stefanini and Gendel18 and Solomon and Stefanini19 have reported striking and prompt falls in plasma proteolytic activity ,vith the use of cortisone or corticotrophin in patients with excessive fibrinolysis. We have not evaluated this therapy in our cases. In summary the important factors in treatment should include early recognition of abnormal bleeding, early empirical therapy, whole blood in amounts to maintain blood volume and blood pressure, neutralization of the proteolytic enzyme with serum albumin and fibrinogen, and employ cortisone or corticotrophin to increase the circulating antienzyme. SUMMARY

A clinical and laboratory summary of the findings in 5 cases of fibrinolysis following surgical removal of the prostate is presented. Simple laboratory procedures are suggested to alert the surgeon of this impending complication and the present methods of treatment are briefly discussed. 18 Stefanini, M. and Gendel, B. R.: Influence of fibrinolysin on the survival in vivo of various coagulation factors and favorable effect of cortisone on "fibrinolytic purpura." Clin. Res. Proc., 1: 5, 1953. 19 Solomon, L. andStefanini, M.: Control of bleeding manifestations in "fibrinolytic states" by corticotropin and cortisone. Clin. Res. Proc., 2: 33, 1954.