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Postoperative Bleeding Associated with Levodopa Therapy
Vol. llO, November
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
Printed in U.S.A.
POSTOPERATIVE BLEEDING ASSOCIATED WITH LEVODOPA THERAPY VICTOR E. AGUSTA, JAY Y. GILLENWATER
AND
J. DOUGLAS MANN
From the Departments of Urology and Neurology, University of Virginia School of Medicine, Charlottesville, Virginia
The use of levodopa in the treatment of parkinsonism has been a major breakthrough in the relief of symptoms from this debilitating disease. As the number of patients given levodopa increases, the urologist will encounter more patients on this drug because of the occasionally associated neurogenic bladder and bladder outlet obstruction. There are reports of numerous complications of levodopa therapy, including gastrointestinal, cardiovascular, mental and laboratory abnormalities.1-• However, there have been no reports of possible bleeding diathesis in these patients. We encountered 2 patients taking levodopa who had excessive bleeding after prostatectomy. We report herein the hematologic alterations in these 2 patients as well as studies cm 20 patients with parkinsonism who were receiving levodopa and who had not been operated upon. CASE REPORTS
Case 1. D. R., UVH 48 70 91, a 73-year-old white man, was hospitalized on March 12, 1972 with urethritis secondary to an indwelling Foley catheter. He was first seen 3 months previously with bilateral hydronephrosis secondary to benign prostatic hypertrophy and a spastic neurogenic bladder from severe parkinsonism. He had been on levodopa therapy (1.25 gm. per day) for 2 years. The patient was initially treated with a punch cystocath and the Foley catheter was removed. On March 16 a bladder full of clots was noted with no obvious bleeding points. Laboratory data revealed a partial thromboplastin time (PTT) of 40.9/22-34, prothrombin time (PT) 13/12 and normal bleeding time, fibrinogen and liver function tests. The patient received 3 units of blood but continued to bleed. On March 18 the PTT was 37.4/22-34 and the PT 13/12. The levodopa was stopped and on Accepted for publication June 29, 1973. Read at annual meeting of American Urological Association, New York, New York, May 13-17, 1973. Supported by United States Public Health Service Training Grant 5 TOl AM 05489 and the Mr. and Mrs. Howell E. Jackson Urology Research Fund. 1 Martin, W. E.: Adverse reactions during treatment of Parkinson's disease with levodopa. J .A.M.A., 216: 1979, 1971. 'McDowell, F.: Symposium on levodopa in Parkinson's disease. Clinical and pharmacological aspects. Clinical laboratory abnormalities. Clin. Pharmacol. Ther., 12: 335, 1971. 3 Clark, L. 8.: Autoimmune hemolytic anemia in relation to L-DOPA therapy. Amer. J. Med. Technol., 38: 38, 1972. 'Jenkins, A. C. and Schwieger, A. C.: Therapeutic guidelines and side effects encountered during L-DOPA therapy in 100 cases of Parkinsonism. Med. J. Aust., 2: 693, 1971.
574
March 21 with the PTT 31.4/22-34, the patient underwent transurethral resection of the prostate and received 4 more units of blood preoperatively and postoperatively. On April 7 the patient underwent suprapubic cystostomy because of continuous oozing and incontinence despite a PTT of 33.7 /22-34 and PT of 12/12. He was discharged from the hospital on April 12 on 750 mg. per day levodopa. However, the patient was rehospitalized several days later with severe bleeding from the supra pubic tube with clots in the bladder. He had received 2 units of blood at another hospital and the hematoTABLE
1. Adverse effects of levodopa
Gastrointestinal: Nausea and vomiting Cardiovascular: Postural hypotension Dysrhythmia Palpitations Pulmonary emboli Neurological: Dyskinesia Mental disturbances: Insomnia Depression Anxiety Suicide attempt Laboratory abnormalities: Elevated liver enzymes Leukopenia Positive Coombs' test Elevated BUN, uric acid
crit was 24 per cent. He received 2 more units of blood. The PTT was 39.6/22-24 and PT 13/12. Levodopa was stopped but on April 17 the PTT remained elevated at 42.4/22-34 and PT 12/12. The bleeding finally stopped on April 20 and repeated PTT and PT studies remained normal. The patient was discharged from the hospital without levodopa. Case 2. A. N., UVH 67 84 03, a 65-year-old white man with known parkinsonism since 1970, had been on 4 gm. per day levodopa for the previous 6 months. He had a history of prolonged bleeding from cuts and easy bruisability for the previous 6 months; the dose of levodopa was reduced to 2 gm. per day 6 days before hospitalization because of facial and upper extremity dyskinesia. He was hospitalized on June 28, 1972 for symptoms of prostatism. The preoperative PTT was 41.9/22-24 and PT was 14.5/11.5 with normal fibrinogen and bleeding time. The levodopa was stopped and on June 29 the patient underwent suprapubic prostatectomy with a blood loss of
POSTGP.ERATIVE BLEEDIF-..1G
TABLE
2. Laboratory studies in post-prostatectoniy patients Hematologic Studies
Pts.
Hematocrit
DR.* first hospitalization: On levodopa Off levodopa
PTT
:is
[±Q]t
3;3
33.7
DR,second hospitalization: On levodopa Off levodopa
24 31
~t
AN: On levodopa Off levodopa
44 34
[TI]Jt
40-45
Normal
PT
Liver Function Test
Platelets
Fibrinogen
SGOT
470 >500
15 10:lt
13 12
:J04 320
X l()'
1:3 12
:J6) 314
X
10'
X
10'
>500 >500
14.5 13
305 250
X
22. l
10 3 10 3
Not done Not done
22-34 secs.
11-12 secs.
33
> 150
X
X
10'
X l()'
>300 mg.%
Bilirubin
Alkaline Phosphatase
Total Protein
OJi
7:l
0.2
54
8.4 7.6
6.7 5.4
Not done
Not done
35 :J3
0.5 0.6
60 51
<60
< 1.2
< 100
6.5-8.0
* Bleeding times normal.
t Elevated. TABLE
3. Laboratory studies on 20 asymptomatic outpatients
Levodopa dose: 1 to 6 gm. per day Hematologic studies: CBC, PT, PTT, platelets* Liver function tests: Bilirubin, LDH, SGOT, alkaline phosphatase,-1 total protein Cone! usion: 5% (l/20) abnormal prothrombin time 20% ( 4/20) abnormal alkaline phosphatase
* One patient with elevated prothrombin time.
t Four patients with elevated alkaline phosphatase.
TABLE
4. Recommended preoperative evaluation of
patients on levodopa History of bleeding tendency Laboratory screen: CBC Prothrombin time (PT) Partial thromboplastin time (PTT) Liver function tests If bleeding studies are abnormal: Stop levodopa 24-48 hours preoperatively Readminister levodopa only after all bleeding has stopped and catheters have been removed
1,600 cc and brisk the ooeration. The hematocrit decreased from 44 to 34 p~r cent 1 unit of blood. One 22.1/22-34 and the vvas not until the urine cleared and he was I-Ie ,vas gm.
DISCUSSION
Numerous authors have reported abnormal liver function tests, serum gl utamic oxaloacetic transaminase with therapy. 2· ' However, there have been no specific reports of abnormal measurements of PT or PTT in patients given levodopa. Positive Coombs' test, 3
decreased hematocrit of unknown cause and leukopenia 2 are the only hematological abnormalities described. An extensive review of the literature revealed only 2 reports of abnormal bleeding. Ivl.artin's review alluded to 1 patient with a bleeding gastric ulcer. 1 Kruse-Larsen and Garde described 2 women with uterine bleeding and unremarkable dilatation and curettage in whom bleeding after cessation of 5 Table l lists the known ---r----· of Our patients had moderately elevated PTT and only marginally elevated PT with normal liver function tests and other heniatological screening (table 2). The PTT measures the total clotting mechanism (except for platelets and factor VII) and is analogous to coagulation time. The PT indirectly measures the prothrombin the conversion of prothrombin to thrombin. We studied 20 ---~----~- on sured the complete blood count count, phatase and total protein with ratio. 1 of 20 showed an increased PT (table 3), As 4 patients had elevated liver function tests. However, none had abnormal PTT studies_ It is must be studied. before an abnormal PTT is found. In any case, abnormal unusual with The elevated PTT found in our patients may have been D. R. had elevated PTT values after reinstifrom his first of easy bruisability and bleeding on doses of The PTT in this patient became normal after cessation of nP,rPtrnrP the bleeding diathesis may be dose-related. 5 Kruse-Larsen, C. and Garde, K.: Postmenopausal bleeding: another side-effect of levodopa. Lancet, 1: 707, 1971.
576
AGUSTA, GILLENWATER AND MANN
Since the PTT and PT may be elevated in patients with liver disease and it is known that levodopa can cause hepatic dysfunction as seen by elevated liver enzymes, the abnormal bleeding we encountered may be secondary to the effect of levodopa on liver metabolism. It is possible that the bleeding diathesis from levodopa occurs through another mechanism. Although the mechanism of action for levodopa in parkinsonism is not entirely clear, some authors have postulated that it supplies the brain with increased catecholamine precursors. 6 Conversely, other investigators think that it may interfere with the peripheral synthesis of catecholamine stores. 1 • 7 Card and Schiff reported on 5 of 7 patients taking reserpine who had abnormal post-prostatectomy bleeding. 8 They thought that this was related to the depletion of catecholamine stores caused by 6 Axelrod, J. and Weinshilboum, R.: Catecho-lamines. New Engl. J. Med., 287: 237, 1972. 7 Stern, G. M. and Hunter, K. R.: Parkinsonism and the hypotension caused by L-DOPA. Amer. Heart J., 82: 570, 1971.
reserpine. A similar mechanism may be contributing to the bleeding diathesis caused by levodopa in our patients but this has not been previously described. We believe that all patients on levodopa therapy should undergo a careful hematologic investigation, including history, laboratory studies, PT and PTT before undergoing an operation (table 4). If abnormalities are noted levodopa therapy should be discontinued until the patient is well into convalescence. SUMMARY
Two patients on levodopa therapy had abnormal bleeding associated with prostatectomy and had elevated PTT. This is an unusual complication of levodopa therapy. We believe that bleeding studies should be part of the routine preoperative evaluation of any patient on levodopa therapy for parkinsonism. 8 Card, D. J. and Schiff, M., Jr.: Possible role of reserpme in post-prostatectomy hemorrhage. J. Urol., 107: 97, 1972.
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
Printed in U.S.A.
POSTOPERATIVE BLEEDING ASSOCIATED WITH LEVODOPA THERAPY VICTOR E. AGUSTA, JAY Y. GILLENWATER
AND
J. DOUGLAS MANN
From the Departments of Urology and Neurology, University of Virginia School of Medicine, Charlottesville, Virginia
The use of levodopa in the treatment of parkinsonism has been a major breakthrough in the relief of symptoms from this debilitating disease. As the number of patients given levodopa increases, the urologist will encounter more patients on this drug because of the occasionally associated neurogenic bladder and bladder outlet obstruction. There are reports of numerous complications of levodopa therapy, including gastrointestinal, cardiovascular, mental and laboratory abnormalities.1-• However, there have been no reports of possible bleeding diathesis in these patients. We encountered 2 patients taking levodopa who had excessive bleeding after prostatectomy. We report herein the hematologic alterations in these 2 patients as well as studies cm 20 patients with parkinsonism who were receiving levodopa and who had not been operated upon. CASE REPORTS
Case 1. D. R., UVH 48 70 91, a 73-year-old white man, was hospitalized on March 12, 1972 with urethritis secondary to an indwelling Foley catheter. He was first seen 3 months previously with bilateral hydronephrosis secondary to benign prostatic hypertrophy and a spastic neurogenic bladder from severe parkinsonism. He had been on levodopa therapy (1.25 gm. per day) for 2 years. The patient was initially treated with a punch cystocath and the Foley catheter was removed. On March 16 a bladder full of clots was noted with no obvious bleeding points. Laboratory data revealed a partial thromboplastin time (PTT) of 40.9/22-34, prothrombin time (PT) 13/12 and normal bleeding time, fibrinogen and liver function tests. The patient received 3 units of blood but continued to bleed. On March 18 the PTT was 37.4/22-34 and the PT 13/12. The levodopa was stopped and on Accepted for publication June 29, 1973. Read at annual meeting of American Urological Association, New York, New York, May 13-17, 1973. Supported by United States Public Health Service Training Grant 5 TOl AM 05489 and the Mr. and Mrs. Howell E. Jackson Urology Research Fund. 1 Martin, W. E.: Adverse reactions during treatment of Parkinson's disease with levodopa. J .A.M.A., 216: 1979, 1971. 'McDowell, F.: Symposium on levodopa in Parkinson's disease. Clinical and pharmacological aspects. Clinical laboratory abnormalities. Clin. Pharmacol. Ther., 12: 335, 1971. 3 Clark, L. 8.: Autoimmune hemolytic anemia in relation to L-DOPA therapy. Amer. J. Med. Technol., 38: 38, 1972. 'Jenkins, A. C. and Schwieger, A. C.: Therapeutic guidelines and side effects encountered during L-DOPA therapy in 100 cases of Parkinsonism. Med. J. Aust., 2: 693, 1971.
574
March 21 with the PTT 31.4/22-34, the patient underwent transurethral resection of the prostate and received 4 more units of blood preoperatively and postoperatively. On April 7 the patient underwent suprapubic cystostomy because of continuous oozing and incontinence despite a PTT of 33.7 /22-34 and PT of 12/12. He was discharged from the hospital on April 12 on 750 mg. per day levodopa. However, the patient was rehospitalized several days later with severe bleeding from the supra pubic tube with clots in the bladder. He had received 2 units of blood at another hospital and the hematoTABLE
1. Adverse effects of levodopa
Gastrointestinal: Nausea and vomiting Cardiovascular: Postural hypotension Dysrhythmia Palpitations Pulmonary emboli Neurological: Dyskinesia Mental disturbances: Insomnia Depression Anxiety Suicide attempt Laboratory abnormalities: Elevated liver enzymes Leukopenia Positive Coombs' test Elevated BUN, uric acid
crit was 24 per cent. He received 2 more units of blood. The PTT was 39.6/22-24 and PT 13/12. Levodopa was stopped but on April 17 the PTT remained elevated at 42.4/22-34 and PT 12/12. The bleeding finally stopped on April 20 and repeated PTT and PT studies remained normal. The patient was discharged from the hospital without levodopa. Case 2. A. N., UVH 67 84 03, a 65-year-old white man with known parkinsonism since 1970, had been on 4 gm. per day levodopa for the previous 6 months. He had a history of prolonged bleeding from cuts and easy bruisability for the previous 6 months; the dose of levodopa was reduced to 2 gm. per day 6 days before hospitalization because of facial and upper extremity dyskinesia. He was hospitalized on June 28, 1972 for symptoms of prostatism. The preoperative PTT was 41.9/22-24 and PT was 14.5/11.5 with normal fibrinogen and bleeding time. The levodopa was stopped and on June 29 the patient underwent suprapubic prostatectomy with a blood loss of
POSTGP.ERATIVE BLEEDIF-..1G
TABLE
2. Laboratory studies in post-prostatectoniy patients Hematologic Studies
Pts.
Hematocrit
DR.* first hospitalization: On levodopa Off levodopa
PTT
:is
[±Q]t
3;3
33.7
DR,second hospitalization: On levodopa Off levodopa
24 31
~t
AN: On levodopa Off levodopa
44 34
[TI]Jt
40-45
Normal
PT
Liver Function Test
Platelets
Fibrinogen
SGOT
470 >500
15 10:lt
13 12
:J04 320
X l()'
1:3 12
:J6) 314
X
10'
X
10'
>500 >500
14.5 13
305 250
X
22. l
10 3 10 3
Not done Not done
22-34 secs.
11-12 secs.
33
> 150
X
X
10'
X l()'
>300 mg.%
Bilirubin
Alkaline Phosphatase
Total Protein
OJi
7:l
0.2
54
8.4 7.6
6.7 5.4
Not done
Not done
35 :J3
0.5 0.6
60 51
<60
< 1.2
< 100
6.5-8.0
* Bleeding times normal.
t Elevated. TABLE
3. Laboratory studies on 20 asymptomatic outpatients
Levodopa dose: 1 to 6 gm. per day Hematologic studies: CBC, PT, PTT, platelets* Liver function tests: Bilirubin, LDH, SGOT, alkaline phosphatase,-1 total protein Cone! usion: 5% (l/20) abnormal prothrombin time 20% ( 4/20) abnormal alkaline phosphatase
* One patient with elevated prothrombin time.
t Four patients with elevated alkaline phosphatase.
TABLE
4. Recommended preoperative evaluation of
patients on levodopa History of bleeding tendency Laboratory screen: CBC Prothrombin time (PT) Partial thromboplastin time (PTT) Liver function tests If bleeding studies are abnormal: Stop levodopa 24-48 hours preoperatively Readminister levodopa only after all bleeding has stopped and catheters have been removed
1,600 cc and brisk the ooeration. The hematocrit decreased from 44 to 34 p~r cent 1 unit of blood. One 22.1/22-34 and the vvas not until the urine cleared and he was I-Ie ,vas gm.
DISCUSSION
Numerous authors have reported abnormal liver function tests, serum gl utamic oxaloacetic transaminase with therapy. 2· ' However, there have been no specific reports of abnormal measurements of PT or PTT in patients given levodopa. Positive Coombs' test, 3
decreased hematocrit of unknown cause and leukopenia 2 are the only hematological abnormalities described. An extensive review of the literature revealed only 2 reports of abnormal bleeding. Ivl.artin's review alluded to 1 patient with a bleeding gastric ulcer. 1 Kruse-Larsen and Garde described 2 women with uterine bleeding and unremarkable dilatation and curettage in whom bleeding after cessation of 5 Table l lists the known ---r----· of Our patients had moderately elevated PTT and only marginally elevated PT with normal liver function tests and other heniatological screening (table 2). The PTT measures the total clotting mechanism (except for platelets and factor VII) and is analogous to coagulation time. The PT indirectly measures the prothrombin the conversion of prothrombin to thrombin. We studied 20 ---~----~- on sured the complete blood count count, phatase and total protein with ratio. 1 of 20 showed an increased PT (table 3), As 4 patients had elevated liver function tests. However, none had abnormal PTT studies_ It is must be studied. before an abnormal PTT is found. In any case, abnormal unusual with The elevated PTT found in our patients may have been D. R. had elevated PTT values after reinstifrom his first of easy bruisability and bleeding on doses of The PTT in this patient became normal after cessation of nP,rPtrnrP the bleeding diathesis may be dose-related. 5 Kruse-Larsen, C. and Garde, K.: Postmenopausal bleeding: another side-effect of levodopa. Lancet, 1: 707, 1971.
576
AGUSTA, GILLENWATER AND MANN
Since the PTT and PT may be elevated in patients with liver disease and it is known that levodopa can cause hepatic dysfunction as seen by elevated liver enzymes, the abnormal bleeding we encountered may be secondary to the effect of levodopa on liver metabolism. It is possible that the bleeding diathesis from levodopa occurs through another mechanism. Although the mechanism of action for levodopa in parkinsonism is not entirely clear, some authors have postulated that it supplies the brain with increased catecholamine precursors. 6 Conversely, other investigators think that it may interfere with the peripheral synthesis of catecholamine stores. 1 • 7 Card and Schiff reported on 5 of 7 patients taking reserpine who had abnormal post-prostatectomy bleeding. 8 They thought that this was related to the depletion of catecholamine stores caused by 6 Axelrod, J. and Weinshilboum, R.: Catecho-lamines. New Engl. J. Med., 287: 237, 1972. 7 Stern, G. M. and Hunter, K. R.: Parkinsonism and the hypotension caused by L-DOPA. Amer. Heart J., 82: 570, 1971.
reserpine. A similar mechanism may be contributing to the bleeding diathesis caused by levodopa in our patients but this has not been previously described. We believe that all patients on levodopa therapy should undergo a careful hematologic investigation, including history, laboratory studies, PT and PTT before undergoing an operation (table 4). If abnormalities are noted levodopa therapy should be discontinued until the patient is well into convalescence. SUMMARY
Two patients on levodopa therapy had abnormal bleeding associated with prostatectomy and had elevated PTT. This is an unusual complication of levodopa therapy. We believe that bleeding studies should be part of the routine preoperative evaluation of any patient on levodopa therapy for parkinsonism. 8 Card, D. J. and Schiff, M., Jr.: Possible role of reserpme in post-prostatectomy hemorrhage. J. Urol., 107: 97, 1972.