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Gross Hematuria Due to Dicumarol Therapy
THE JOURNAL OF UROLOGY
Vol. 65, No. 6, June 1951
Printed in U.S.A.
GROSS HEMATURIA DUE TO DICUMAROL THERAPY EUGENE S. GILMER
AND
LINUS W. HEWIT
Since 1942, numerous cases of hematuria due to dicumarol have been reported. NichoP analyzed 9,000 cases in which anticoagulant therapy was employed, using data obtained from a questionnaire, and reviewed 8,000 cases in the literature. In these 17,000 cases in which anticoagulants were used, the incidence of hemorrhage was 6 or 7 per cent with major hemorrhage in approximately 2 per cent; 26 deaths were due to hemorrhage, 15 in the first series attributed to the use of the anticoagulant and 11 due to hemorrhage in the second series. This author mentioned 8 additional deaths attributable to anticoagulants. In his study of 1,686 postoperative cases in which dicumarol therapy was used, Allen 2 noted that minor hemorrhage consisting of epistaxis, hematuria, petechiae and ecchymoses occurred in 3.1 per cent. He also reported 2 deaths owing to hemorrhage which may have been caused by dicumarol. In a later series of 1,983 postoperative cases reported by this author and his associates, minor hemorrhage occurred in 3.4 per cent and serious bleeding in 1.8 per cent. Smith and Mulligan3 reported that in their series of 2,353 cases hematuria occurred twice after dicumarol prophylaxis against venous thrombosis in women undergoing surgery. In the last 3 years we have observed 6 cases of gross hematuria caused, in our opinion, by the therapeutic use of dicumarol. We present them in the belief that they merit the attention of other urologists. We also include in this series a case of pulmonary embolism in which dicumarol therapy was not followed by hematuria, but prolonged prothrombin time persisted for more than 2 weeks. CASE REPORTS
Case 1. J. I. L., a white woman aged 63, was admitted to the Tampa Municipal Hospital on May 28, 1948 because of gross hematuria and thrombophlebitis of the left leg. Two weeks prior to admission she had been given 3 red capsules the first day, 2 the second and 1 each day thereafter until gross hematuria started 5 days before admission. The hematuria was accompanied by severe pain over the entire back and both flanks; it radiated to the lower part of the abdomen and to the epigastrium, simulating bilateral renal colic. Tenderness was elicited in the right flank, the urine was deeply bloody, the blood pressure was 130/80, the blood count indicated mild anemia, and thrombophlebitis of the veins of the left leg was present. Because it was not known what drug had been given, and because the first prothrombin time was reported normal, cystoscopy with pyelograms was performed the day after admission. The Read at annual meeting, Southeastern Section, American Urological Association, Gulfport, Miss., February 4, 1950. 1 Nichol, E. S., Falk, 0. P. J., Meneely, G. R. and Hull, E.: Symposium on anticoagulant therapy and cardiovascular disease. Panel discussion. South. Med. J., 42: 943-950, 1949. 2 Allen, E. V.: The clinical use of anticoagulants; report of treatment with dicumarol in 1,686 postoperative cases. J. A. M.A., 134: 323-329, 1947. Allen, E. V., Hines, E. A., Jr., Kvale, W. F. and Barker, N. W.: The use of dicumarol as an anticoagulant: experience in 2,307 cases. Ann. Int. Med., 27: 371-381, 1947. 3 Smith, G. Van S. and Mulligan, W. J.: Dicumarol prophylaxis against venous thrombosis in women undergoing surgery. Surg., Gynec. & Obst., 86: 461-464, 1948. 1143
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ElJGENE S. GILMER AND LINUS W. HEvVIT
urine from the bladder was grossly bloody with a few small clots present. The vesical mucosa was normal, and blood was seen coming from both ureteral orifices. Roentgen examination of the kidneys, ureters and bladder gave no evidence of calculi. The pyelogram of the left kidney and ureter was normal. In the upper two thirds of the pelvis and superior calyx of the right kidney a homogeneous filling defect was demonstrated. It had the appearance of a blood clot or tumor (fig. 1, A). On the day after admission, the prothrombin time was 82 seconds, and we then concluded the drug given before admission "'as dicumarol. Since hematuria was
FIG. 1. Case 1. A, pyelogram showing homogeneous filling defect that gives appearance of blood clot or tumor in upper two thirds of pelvis and superior calyx of right kidney. B, normal pyelogram following vitamin K therapy.
still profuse after cystoscopy, 25 mg. vitamin K (Synkayvite) was given intravenously, and 10 mg. was administered intramuscularly every 3 hours over a period of 2 days until 130 mg. was given. The urine ,vas clear in 24 hours after the first dose of vitamin K. A second pyelogram on the right side was obtained prior to the patient's discharge from the hospital and was normal (fig. 1, B). Case 2. J. J.M., a white man aged 20, was admitted to the Tampa Municipal Hospital on July 22, 1949 because of thrombophlebitis of the left leg. He was given 1,800 mg. dicumarol over a period of 15 days. On the fourteenth day of dicumarol therapy, he had severe bilateral renal colic, pain over the entire abdomen, particularly in the epigastrium, and gross hematuria. The prothrombin time at this time was 1 minute and 21 seconds. The renal colic lasted 48 hours and required morphine for relief. The patient was given 50 mg. vitamin K
GROSS HEMATURIA DUE TO DICUMAROL THERAPY
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(Synkayvite) intravenously on August 9, and 30 mg. intravenously the following day. The renal colic promptly disappeared, the urine became clear within 48 hours, and the prothrombin time returned to normal without delay. This patient was given too much dicumarol from the start and should have received vitamin K therapy when the prothrombin time fell below 20 per cent of normal. He was a healthy young man, and therefore the response to vitamin K was prompt. Case 3. L. M. T., a white man aged 72, was admitted to the Tampa Municipal Hospital on October 16, 1947 with symptoms of prostatism and acute urinary retention. After preliminary drainage by catheter, transurethral prostatic resection was performed with little hemorrhage, and the catheter was removed on the fourth postoperative day. On this date, the patient had a small pulmonary embolism which was first diagnosed as pleurisy, and on the tenth postoperative day definite thrombophlebitis of the veins of the left leg was noted. Immediately, bilateral ligation of the femoral vein was performed. Over a period of 7 days following the ligation, 600 mg. dicumarol was given, and on the seventh day of dicurnarol therapy and the fourteenth postoperative day following transurethral prostatic resection, there developed gross hematuria, which persisted for 10 days. The urine was red in color, there were no clots, and it was not necessary to insert an indwelling catheter for its control. The prothrombin time was only slightly prolonged, and vitamin K therapy was not used. We do not believe that the hematuria was due to necrosis in the prostatic fossae. Case 4- J. A. A., a white man aged 67, was admitted to the Tampa Municipal Hospital on February 4, 1947 with an acute anterior myocardial infarction confirmed by electrocardiogram. Acute urinary retention developed shortly after admission, and an 18F Foley catheter was inserted into the bladder. A total of 700 mg. dicumarol was given over a period of 5 days. Gross hematuria began on the fifth day of therapy and continued for 12 days, being excessive for 4 days. The prothrombin time at the onset of hematuria was 1 minute and 5 seconds. On February 14, 10 days after the hematuria started, the prothrombin time was 6 minutes and 54 seconds. The patient was given 25 mg. vitamin K (Synkayvite) intravenously. On February 18, when the prothrombin time had become more prolonged, bleeding became excessive, and the patient went into shock. At that time, 50 mg. vitamin K was given intravenously, followed by 10 mg. intramuscularly every 4 hours for 6 doses. Bleeding subsided 48 hours after the large dose of vitamin K was given intravenously. Daily prothrombin time determinations were obtained and were reported normal 5 days prior to cysto-urethroscopic examination, which was performed on February 24. The cysto-urethroscopic examination at that time revealed that the vesical mucosa was inflamed throughout. There was considerable oozing from the wall of the bladder, and an area of ulceration at the vesical neck bled freely. A grade 2 enlargement of the median and lateral lobes of the prostate was present, and the prostatic bed appeared nodular and pearly white. A diagnosis of carcinoma of the prostate with ulceration in the prostatic urethra was made. The prostate was hard, nodular and fixed per rectum. Following the cystourethroscopic examination on February 25, there was considerable hemorrhage
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EUGENE S. GILMER AND LINUS W. HEWIT
for 48 hours, but it was controlled by 25 mg. vitamin K given intravenously. The patient was discharged 1 week later. In this case, even when a small dose of dicumarol had been given, the prothrombin time was so prolonged that it was difficult to bring it within normal limits with vitamin K therapy. Also, considerable hemorrhage continued for 48 hours even though the prothrombin time had been normal for 5 days prior to cysto-urethroscopic examination. If we had used larger doses of vitamin K in the beginning, we believe the results would have been much better. Case 5. J. W.W., a white man aged 70, was admitted to the Tampa Municipal Hospital on November 12, 1947 because of acute urinary retention due to benign prostatic hyperplasia. An indwelling catheter was inserted. On the fourteenth day after admission thrombosis of the right femoral vein developed, and bilateral ligation of the femoral vein was performed. Over a period of 4 days, 700 mg. dicumarol was given orally. The prothrombin time 4 days after cessation of dicumarol therapy was 1 minute and 51 seconds, and 10 mg. vitamin K (Synkayvite) was given intramuscularly every 4 hours for 5 days, a total of 300 mg. On December 9, eleven days after dicumarol was discontinued, the prothrombin time was reported normal, and transurethral prostatic resection was performed. All prostatic tissue was resected, and bleeding was profuse and not entirely controlled when the patient left the operating table. Hemorrhage from the urethra continued for 20 days postoperatively. It required 1,500 cc blood in divided doses to keep up the hemoglobin and red blood cell count. Few blood clots were seen in the urine following the operation, but the urine was red in color during this time. Postoperatively, the patient was given 10 mg. vitamin K intramuscularly every 4 hours for 8 days, a total of 480 mg. When he was discharged on the twenty-sixth day after the operation, the urine was clear. Bleeding was profuse for 20 days after transurethral resection in spite of normal prothrombin time before surgery. Vitamin K was given as directed in the literature at that time. We realize now that the amount was entirely inadequate and that this vitamin should have been given in much larger doses intravenously. There may have been hepatic damage or renal insufficiency which was not recognized. This case illustrates that when an ulcerative lesion of the urinary tract is present, it may bleed for 20 days. We think this bleeding was caused by dicumarol. Case 6. B . F . H ., a white man aged 78, was admitted to the Tampa Municipal Hospital on February 23, 1948 with acute urinary retention due to benign prostatic hyperplasia and a large left scrotal hernia. On February 27, herniorrhaphy was performed on the left side, and on March 5, thrombophlebitis developed in the left leg. Over a period of 7 days before and following ligation of the right femoral vein, 1,200 mg. dicumarol was given. Eight days after the last dose of dicumarol was administered, the prothrombin time was reported normal, and transurethral prostatic resection was performed. After resection of 10 gm. tissue generalized oozing developed and became so profuse that it was necessary to stop the operation. Red urine oozed for 7 days, necessitating frequent irrigations, and the indwelling catheter was not removed
GROSS HEMATURIA DUE TO DICUMAROL THERAPY
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until the eighth postoperative day. A second transurethral resection was performed 15 days following the first resection, and again bleeding at the time of operation was profuse, but the urine cleared in 48 hours. The prothrombin time was reported normal prior to the second resection. The patient was discharged 8 days after the second resection. He returned to the hospital 2 months later with severe jaundice and died as a result of pathologic changes in the liver. No vitamin K therapy was given to this patient. We do not know why there was bleeding following the first resection when the prothrombin time was reported normal. Case 7. W.W. G., a white man aged 86, was admitted to St. Joseph's Hospital on April 19, 1947 with a diagnosis of pulmonary embolism, probably due to thrombosis in the pelvic veins. After admission he was incontinent of urine, and a retention catheter was inserted. Over a period of 3 days, 600 mg. dicumarol was given. Hematuria did not develop, but it is interesting to note that the prothrombin time remained prolonged for a period of 15 days in spite of vitamin K (Synkayvite) therapy. Only 10 mg. of the vitamin was given twice a day for 5 days. This patient was senile and debilitated and may have had renal or hepatic damage. These factors probably account for the prolonged prothrombin time which continued over a period of 15 days. In view of our previous experience with dicumarol, we thought that prostatic surgery should be postponed. DISCUSSION
The first 2 cases reported illustrate the typical symptoms of bilateral renal colic which may occur in cases of hematuria caused by dicumarol. Also, they particularly stress the unusual feature of pain referred to the epigastrium when bilateral renal colic is present. In both of these cases the patient obviously received an overdose of dicumarol and responded favorably to vitamin K therapy. The patient was, however, in good physical condition in both instances. It is now known that the amounts of vitamin K which were recommended and first used were entirely inadequate. According to Allen,2 30 to 60 mg. vitamin K injected intravenously should be used when hemorrhage due to dicumarol is present. Had we used larger doses in the beginning and given them intravenously, we probably would not have had the difficulty encountered with this drug. One need fear no ill effects from large doses of vitamin K as Heindl, Anderson and Friedlander4 reported a case in which the patient received 585.6 mg. hykinone intravenously over a period of 8 days with no unfavorable results. In debilitated patients, it seems to take 7 to 21 days for the body to eliminate all the effects of dicumarol. Rosenbloom and Crane 5 reported a case in which hematuria persisted 14 days after withdrawal of dicumarol. They used synthetic vitamin Kin large amounts to control the hemorrhage, but this therapy proved ineffective. Falk1 concluded that the use of dicumarol is contraindicated in the presence 4 Heindl, I. A., Anderson, B. G. and Friedlander, R. D.: Acute idiopathic hypoprothrombinemia, response to massive doses of vitamin K. Ann. Int. Med., 29: 347-356, 1948. 5 Rosenbloom, D. and Crane, J. J.: Massive hematuria due to dicumarol overdosage. J. A. M. A., 132: 924-925, 1946.
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EUGENE S. GILMER AND LINUS W . HEWIT
of hepatic damage, renal disease and blood dysoriasias, following operations on the central nervous system, and when there is a history of gastro-intestinal hemorrhage in the past, active peptic ulcer, menorrhagia or bloody stools from any source in the recent past. From our experience we believe that dicumarol should not be used when a urethral catheter is necessary or when there is any ulcerative lesion of the urinary tract. It should not be used when any type of prostatectomy is contemplated. If the drug has been used prior to prostatectomy, a period of at least 21 days should elapse before surgery. SUMMARY
Hematuria following the use of dicumarol is not uncommon. Seven cases are reported, in 6 of which gross hematuria followed therapy with this drug. In the seventh case the prothrombin time was prolonged for 15 days despite vitamin K therapy. When gross hematuria due to dicumarol is present, vitamin K should be given intravenously in large doses. Dicumarol probably should not be administered when an indwelling catheter is necessary or when prostatectomy by any method is contemplated. Gross hematuria may persist for a period of 7 to 21 days following dicumarol therapy if an ulcerative lesion of the urinary tract is present.
706 Franklin St., Tampa 2, Fla.
Vol. 65, No. 6, June 1951
Printed in U.S.A.
GROSS HEMATURIA DUE TO DICUMAROL THERAPY EUGENE S. GILMER
AND
LINUS W. HEWIT
Since 1942, numerous cases of hematuria due to dicumarol have been reported. NichoP analyzed 9,000 cases in which anticoagulant therapy was employed, using data obtained from a questionnaire, and reviewed 8,000 cases in the literature. In these 17,000 cases in which anticoagulants were used, the incidence of hemorrhage was 6 or 7 per cent with major hemorrhage in approximately 2 per cent; 26 deaths were due to hemorrhage, 15 in the first series attributed to the use of the anticoagulant and 11 due to hemorrhage in the second series. This author mentioned 8 additional deaths attributable to anticoagulants. In his study of 1,686 postoperative cases in which dicumarol therapy was used, Allen 2 noted that minor hemorrhage consisting of epistaxis, hematuria, petechiae and ecchymoses occurred in 3.1 per cent. He also reported 2 deaths owing to hemorrhage which may have been caused by dicumarol. In a later series of 1,983 postoperative cases reported by this author and his associates, minor hemorrhage occurred in 3.4 per cent and serious bleeding in 1.8 per cent. Smith and Mulligan3 reported that in their series of 2,353 cases hematuria occurred twice after dicumarol prophylaxis against venous thrombosis in women undergoing surgery. In the last 3 years we have observed 6 cases of gross hematuria caused, in our opinion, by the therapeutic use of dicumarol. We present them in the belief that they merit the attention of other urologists. We also include in this series a case of pulmonary embolism in which dicumarol therapy was not followed by hematuria, but prolonged prothrombin time persisted for more than 2 weeks. CASE REPORTS
Case 1. J. I. L., a white woman aged 63, was admitted to the Tampa Municipal Hospital on May 28, 1948 because of gross hematuria and thrombophlebitis of the left leg. Two weeks prior to admission she had been given 3 red capsules the first day, 2 the second and 1 each day thereafter until gross hematuria started 5 days before admission. The hematuria was accompanied by severe pain over the entire back and both flanks; it radiated to the lower part of the abdomen and to the epigastrium, simulating bilateral renal colic. Tenderness was elicited in the right flank, the urine was deeply bloody, the blood pressure was 130/80, the blood count indicated mild anemia, and thrombophlebitis of the veins of the left leg was present. Because it was not known what drug had been given, and because the first prothrombin time was reported normal, cystoscopy with pyelograms was performed the day after admission. The Read at annual meeting, Southeastern Section, American Urological Association, Gulfport, Miss., February 4, 1950. 1 Nichol, E. S., Falk, 0. P. J., Meneely, G. R. and Hull, E.: Symposium on anticoagulant therapy and cardiovascular disease. Panel discussion. South. Med. J., 42: 943-950, 1949. 2 Allen, E. V.: The clinical use of anticoagulants; report of treatment with dicumarol in 1,686 postoperative cases. J. A. M.A., 134: 323-329, 1947. Allen, E. V., Hines, E. A., Jr., Kvale, W. F. and Barker, N. W.: The use of dicumarol as an anticoagulant: experience in 2,307 cases. Ann. Int. Med., 27: 371-381, 1947. 3 Smith, G. Van S. and Mulligan, W. J.: Dicumarol prophylaxis against venous thrombosis in women undergoing surgery. Surg., Gynec. & Obst., 86: 461-464, 1948. 1143
1144
ElJGENE S. GILMER AND LINUS W. HEvVIT
urine from the bladder was grossly bloody with a few small clots present. The vesical mucosa was normal, and blood was seen coming from both ureteral orifices. Roentgen examination of the kidneys, ureters and bladder gave no evidence of calculi. The pyelogram of the left kidney and ureter was normal. In the upper two thirds of the pelvis and superior calyx of the right kidney a homogeneous filling defect was demonstrated. It had the appearance of a blood clot or tumor (fig. 1, A). On the day after admission, the prothrombin time was 82 seconds, and we then concluded the drug given before admission "'as dicumarol. Since hematuria was
FIG. 1. Case 1. A, pyelogram showing homogeneous filling defect that gives appearance of blood clot or tumor in upper two thirds of pelvis and superior calyx of right kidney. B, normal pyelogram following vitamin K therapy.
still profuse after cystoscopy, 25 mg. vitamin K (Synkayvite) was given intravenously, and 10 mg. was administered intramuscularly every 3 hours over a period of 2 days until 130 mg. was given. The urine ,vas clear in 24 hours after the first dose of vitamin K. A second pyelogram on the right side was obtained prior to the patient's discharge from the hospital and was normal (fig. 1, B). Case 2. J. J.M., a white man aged 20, was admitted to the Tampa Municipal Hospital on July 22, 1949 because of thrombophlebitis of the left leg. He was given 1,800 mg. dicumarol over a period of 15 days. On the fourteenth day of dicumarol therapy, he had severe bilateral renal colic, pain over the entire abdomen, particularly in the epigastrium, and gross hematuria. The prothrombin time at this time was 1 minute and 21 seconds. The renal colic lasted 48 hours and required morphine for relief. The patient was given 50 mg. vitamin K
GROSS HEMATURIA DUE TO DICUMAROL THERAPY
1145
(Synkayvite) intravenously on August 9, and 30 mg. intravenously the following day. The renal colic promptly disappeared, the urine became clear within 48 hours, and the prothrombin time returned to normal without delay. This patient was given too much dicumarol from the start and should have received vitamin K therapy when the prothrombin time fell below 20 per cent of normal. He was a healthy young man, and therefore the response to vitamin K was prompt. Case 3. L. M. T., a white man aged 72, was admitted to the Tampa Municipal Hospital on October 16, 1947 with symptoms of prostatism and acute urinary retention. After preliminary drainage by catheter, transurethral prostatic resection was performed with little hemorrhage, and the catheter was removed on the fourth postoperative day. On this date, the patient had a small pulmonary embolism which was first diagnosed as pleurisy, and on the tenth postoperative day definite thrombophlebitis of the veins of the left leg was noted. Immediately, bilateral ligation of the femoral vein was performed. Over a period of 7 days following the ligation, 600 mg. dicumarol was given, and on the seventh day of dicurnarol therapy and the fourteenth postoperative day following transurethral prostatic resection, there developed gross hematuria, which persisted for 10 days. The urine was red in color, there were no clots, and it was not necessary to insert an indwelling catheter for its control. The prothrombin time was only slightly prolonged, and vitamin K therapy was not used. We do not believe that the hematuria was due to necrosis in the prostatic fossae. Case 4- J. A. A., a white man aged 67, was admitted to the Tampa Municipal Hospital on February 4, 1947 with an acute anterior myocardial infarction confirmed by electrocardiogram. Acute urinary retention developed shortly after admission, and an 18F Foley catheter was inserted into the bladder. A total of 700 mg. dicumarol was given over a period of 5 days. Gross hematuria began on the fifth day of therapy and continued for 12 days, being excessive for 4 days. The prothrombin time at the onset of hematuria was 1 minute and 5 seconds. On February 14, 10 days after the hematuria started, the prothrombin time was 6 minutes and 54 seconds. The patient was given 25 mg. vitamin K (Synkayvite) intravenously. On February 18, when the prothrombin time had become more prolonged, bleeding became excessive, and the patient went into shock. At that time, 50 mg. vitamin K was given intravenously, followed by 10 mg. intramuscularly every 4 hours for 6 doses. Bleeding subsided 48 hours after the large dose of vitamin K was given intravenously. Daily prothrombin time determinations were obtained and were reported normal 5 days prior to cysto-urethroscopic examination, which was performed on February 24. The cysto-urethroscopic examination at that time revealed that the vesical mucosa was inflamed throughout. There was considerable oozing from the wall of the bladder, and an area of ulceration at the vesical neck bled freely. A grade 2 enlargement of the median and lateral lobes of the prostate was present, and the prostatic bed appeared nodular and pearly white. A diagnosis of carcinoma of the prostate with ulceration in the prostatic urethra was made. The prostate was hard, nodular and fixed per rectum. Following the cystourethroscopic examination on February 25, there was considerable hemorrhage
1146
EUGENE S. GILMER AND LINUS W. HEWIT
for 48 hours, but it was controlled by 25 mg. vitamin K given intravenously. The patient was discharged 1 week later. In this case, even when a small dose of dicumarol had been given, the prothrombin time was so prolonged that it was difficult to bring it within normal limits with vitamin K therapy. Also, considerable hemorrhage continued for 48 hours even though the prothrombin time had been normal for 5 days prior to cysto-urethroscopic examination. If we had used larger doses of vitamin K in the beginning, we believe the results would have been much better. Case 5. J. W.W., a white man aged 70, was admitted to the Tampa Municipal Hospital on November 12, 1947 because of acute urinary retention due to benign prostatic hyperplasia. An indwelling catheter was inserted. On the fourteenth day after admission thrombosis of the right femoral vein developed, and bilateral ligation of the femoral vein was performed. Over a period of 4 days, 700 mg. dicumarol was given orally. The prothrombin time 4 days after cessation of dicumarol therapy was 1 minute and 51 seconds, and 10 mg. vitamin K (Synkayvite) was given intramuscularly every 4 hours for 5 days, a total of 300 mg. On December 9, eleven days after dicumarol was discontinued, the prothrombin time was reported normal, and transurethral prostatic resection was performed. All prostatic tissue was resected, and bleeding was profuse and not entirely controlled when the patient left the operating table. Hemorrhage from the urethra continued for 20 days postoperatively. It required 1,500 cc blood in divided doses to keep up the hemoglobin and red blood cell count. Few blood clots were seen in the urine following the operation, but the urine was red in color during this time. Postoperatively, the patient was given 10 mg. vitamin K intramuscularly every 4 hours for 8 days, a total of 480 mg. When he was discharged on the twenty-sixth day after the operation, the urine was clear. Bleeding was profuse for 20 days after transurethral resection in spite of normal prothrombin time before surgery. Vitamin K was given as directed in the literature at that time. We realize now that the amount was entirely inadequate and that this vitamin should have been given in much larger doses intravenously. There may have been hepatic damage or renal insufficiency which was not recognized. This case illustrates that when an ulcerative lesion of the urinary tract is present, it may bleed for 20 days. We think this bleeding was caused by dicumarol. Case 6. B . F . H ., a white man aged 78, was admitted to the Tampa Municipal Hospital on February 23, 1948 with acute urinary retention due to benign prostatic hyperplasia and a large left scrotal hernia. On February 27, herniorrhaphy was performed on the left side, and on March 5, thrombophlebitis developed in the left leg. Over a period of 7 days before and following ligation of the right femoral vein, 1,200 mg. dicumarol was given. Eight days after the last dose of dicumarol was administered, the prothrombin time was reported normal, and transurethral prostatic resection was performed. After resection of 10 gm. tissue generalized oozing developed and became so profuse that it was necessary to stop the operation. Red urine oozed for 7 days, necessitating frequent irrigations, and the indwelling catheter was not removed
GROSS HEMATURIA DUE TO DICUMAROL THERAPY
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until the eighth postoperative day. A second transurethral resection was performed 15 days following the first resection, and again bleeding at the time of operation was profuse, but the urine cleared in 48 hours. The prothrombin time was reported normal prior to the second resection. The patient was discharged 8 days after the second resection. He returned to the hospital 2 months later with severe jaundice and died as a result of pathologic changes in the liver. No vitamin K therapy was given to this patient. We do not know why there was bleeding following the first resection when the prothrombin time was reported normal. Case 7. W.W. G., a white man aged 86, was admitted to St. Joseph's Hospital on April 19, 1947 with a diagnosis of pulmonary embolism, probably due to thrombosis in the pelvic veins. After admission he was incontinent of urine, and a retention catheter was inserted. Over a period of 3 days, 600 mg. dicumarol was given. Hematuria did not develop, but it is interesting to note that the prothrombin time remained prolonged for a period of 15 days in spite of vitamin K (Synkayvite) therapy. Only 10 mg. of the vitamin was given twice a day for 5 days. This patient was senile and debilitated and may have had renal or hepatic damage. These factors probably account for the prolonged prothrombin time which continued over a period of 15 days. In view of our previous experience with dicumarol, we thought that prostatic surgery should be postponed. DISCUSSION
The first 2 cases reported illustrate the typical symptoms of bilateral renal colic which may occur in cases of hematuria caused by dicumarol. Also, they particularly stress the unusual feature of pain referred to the epigastrium when bilateral renal colic is present. In both of these cases the patient obviously received an overdose of dicumarol and responded favorably to vitamin K therapy. The patient was, however, in good physical condition in both instances. It is now known that the amounts of vitamin K which were recommended and first used were entirely inadequate. According to Allen,2 30 to 60 mg. vitamin K injected intravenously should be used when hemorrhage due to dicumarol is present. Had we used larger doses in the beginning and given them intravenously, we probably would not have had the difficulty encountered with this drug. One need fear no ill effects from large doses of vitamin K as Heindl, Anderson and Friedlander4 reported a case in which the patient received 585.6 mg. hykinone intravenously over a period of 8 days with no unfavorable results. In debilitated patients, it seems to take 7 to 21 days for the body to eliminate all the effects of dicumarol. Rosenbloom and Crane 5 reported a case in which hematuria persisted 14 days after withdrawal of dicumarol. They used synthetic vitamin Kin large amounts to control the hemorrhage, but this therapy proved ineffective. Falk1 concluded that the use of dicumarol is contraindicated in the presence 4 Heindl, I. A., Anderson, B. G. and Friedlander, R. D.: Acute idiopathic hypoprothrombinemia, response to massive doses of vitamin K. Ann. Int. Med., 29: 347-356, 1948. 5 Rosenbloom, D. and Crane, J. J.: Massive hematuria due to dicumarol overdosage. J. A. M. A., 132: 924-925, 1946.
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EUGENE S. GILMER AND LINUS W . HEWIT
of hepatic damage, renal disease and blood dysoriasias, following operations on the central nervous system, and when there is a history of gastro-intestinal hemorrhage in the past, active peptic ulcer, menorrhagia or bloody stools from any source in the recent past. From our experience we believe that dicumarol should not be used when a urethral catheter is necessary or when there is any ulcerative lesion of the urinary tract. It should not be used when any type of prostatectomy is contemplated. If the drug has been used prior to prostatectomy, a period of at least 21 days should elapse before surgery. SUMMARY
Hematuria following the use of dicumarol is not uncommon. Seven cases are reported, in 6 of which gross hematuria followed therapy with this drug. In the seventh case the prothrombin time was prolonged for 15 days despite vitamin K therapy. When gross hematuria due to dicumarol is present, vitamin K should be given intravenously in large doses. Dicumarol probably should not be administered when an indwelling catheter is necessary or when prostatectomy by any method is contemplated. Gross hematuria may persist for a period of 7 to 21 days following dicumarol therapy if an ulcerative lesion of the urinary tract is present.
706 Franklin St., Tampa 2, Fla.