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Severe thrombocytopenia associated with phenytoin and cimetidine therapy
Surg Neurol 1985;23:169-72
169
Severe Thrombocytopenia Associated with Phenytoin and Cimetidine Therapy Yan Yan Wong, Pharm.D., Terry Lichtor, M.D., Ph.D., and Frederick D. Brown, M.D. Department of Pharmaceutical Services, and Section of Neurological Surgery, The University of Chicago, Chicago, Illinois
Wong YY, Lichtor T, Brown FD. Severe thrombocytopenia associated with phenytoin and cimetidine therapy. Surg Neurol 1985;23:169-72.
A 67-year-old man developed a sudden onset of severe isolated thrombocytopenia (platelet count, 1000/mm ~) after 10 days of phenytoin administration as a prophylactic measure prior to craniotomy. The patient had also been taking cimetidine for 2 months prior to admission. No other hematological complications were noted, and an extensive hematologic investigation was otherwise unremarkable. Rapid resolution of the thrombocytopenia upon discontinuation of phenytoin and cimetidine strongly suggests a drug-induced adverse reaction. KEY WORDS: Thrombocytopenia; Phenytoin; Cimetidine
Phenytoin has been widely used as an anticonvulsant for treatment and prophylaxis since its introduction in 1938. Its hematological toxicities such as megaloblastic anemia, aplastic anemia, leukopenia, agranulocytosis, and lymphadenopathy have been reviewed in detail [10]. The phenytoin-associated thrombocytopenia often appears with other hypersensitivity manifestations such as fever, rash, eosinophilia, and lymphadenopathy; it has been considered as an idiosyncratic reaction with an immunological basis. However, thrombocytopenia without concurrent hematological toxicities induced by phenytoin is extremely rare [2,3]. A case o f severe isolated thrombocytopenia apparently related to phenytoin is presented. Case Report A 67-year-old black man with a history o f hypothyroidism and anemia was admitted with the complaint of an excruciating headache for 2 - 3 days. Two months prior to admission, the patient underwent resection of a carAddress reprint requests to: Yan Yan Wong, Pharm.D., Department of Pharmaceutical Services, The University of Chicago Medical Center, 5841 S. Maryland, Chicago, Illinois 60637.
© 1985 by Elsevier Science Publishing Co., Inc.
cinoma of the rectosigmoid colon (Dukes C2) with 1 of 19 lymph nodes positive for tumor. H e had been placed on cimetidine postoperatively and continued taking this medication on an outpatient basis until the time of this admission. Hematological profiles during that time revealed a very minimal microcytic hypochromic anemia but an adequate platelet count ( 1 8 7 - 2 3 7 × 10~/mm~). Upon admission, his blood pressure was 134/84 mmHg, pulse 80/min, respirations 28/min, and he was afebrile. The patient appeared to be lethargic but arousable. H e had bilateral third nerve palsies and a left sixth nerve palsy. His corneal reflexes were also decreased bilaterally. The ptosis of his left eyelid was more severe than the right one. A mild facial palsy was also noted on the right side, and he had a bitemporal hemianopsia. The remainder of his neurological examination was unremarkable. The computed axial tomography scan of his brain demonstrated a large intrasellar mass with a thin rim of hemorrhage around it. On admission the patient's serum sodium was 123 mEq/L and potassium 3.4 mEq/L. T h e remainder of the electrolytes and the renal and liver functions were all normal except for minimal elevation of both S G O T (75 IU/L) and L D H (318 IU/L). The serum thyroxine and free thyroxine index were both 3/zg/ml. Hematological profiles showed a platelet count of 225,000/mm ~, leukocyte count (WBC) of 7 8 0 0 / m m ~, erythrocyte count of 4.47 million/mm ~, hemoglobin (Hgb) content of 11.7 g/dL, hematocrit (Hct) 35%, mean corpuscular volume of 79 /~m ~, mean corpuscular hemoglobin content of 26.3 pg, mean corpuscular hemoglobin concentration 33.4%, prothrombin time (PT) of 11.3 seconds (control 11.5 seconds) and partial thromboplastin time (PTT) of 22.8 seconds (control 23.9 seconds). The patient was placed on dexamethasone medication at 10 mg every 6 hours, cimetidine 300 mg every 6 hours, and levothyroxine 0.1 mg daily. His electrolyte imbalance was corrected. Phenytoin was also initiated as a prophylactic measure prior to a scheduled craniotomy. The patient became more alert and his right third nerve and left sixth nerve palsies resolved, but the left third nerve palsy persisted. A cerebral angiogram re0090-3019/85/$3.30
170
Surg Neurol 1985;23:169-72
vealed a large hypovascular mass arising from the sella turcica. The angiogram was repeated 1 week later but was unchanged. After the second angiogram, a fairly large hematoma was noted over the puncture site and the hematocrit at this time was 26.7%. The patient subsequently received 2 U of packed red blood cells and his hematocrit rose to 30%. While the patient was placed on phenytoin, the plasma concentration of phenytoin 6 days after a daily dosage of 400 mg was 10.6/zg/mL. Five days later the platelet count was 1000/ram3; a repeated platelet count was 7000/mm 3. Other laboratory values included WBC 9,900/mm 3 with normal differentials and no eosinophils, RBC 3.77 million/mm3, Hgb 10.5 g/dL, Hct 30.6%, bilirubin 0.3 mg/dL, and the reticulocyte count 2.2%. At this time there were petechiae over his entire body; several hemorrhagic lesions were also found on his buccal mucosa. The patient was afebrile. His spleen was not palpable. Both phenytoin and cimetidine were discontinued immediately and surgical intervention was postponed. However, dexamethasone and levothyroxine were continued throughout his hospitalization. A hematologic investigation was undertaken. A disseminated intravascular coagulation screen showed a slightly hypercoagulable state: PT 12.4 seconds (control 11.4 seconds), PTT 19.8 seconds (control 25.4 seconds), thrombin time 10 seconds (control 9.4 seconds), fibrinogen 195 mg/dL (control 210 mg/dL), fibrin degradation product titer greater than 40 and less than 80 /zg/mL, Factor V 160%, Factor VIII 200%, antithrombin III 66%, and plasminogen 79%. Additional serological studies including haptoglobin 177 mg% and hemopexin 76.1 mg% were within normal limits. The Coombs (direct and indirect) tests were negative. A peripheral smear showed marked thrombocytopenia with mild anisopoikilocytosis. A bone marrow biopsy revealed a normocellular bone marrow with mild erythroid hyperplasia and an adequate number of megakaryocytes. Therefore a drug-induced reaction was the most likely etiology of the thrombocytopenia. After discontinuation of phenytoin and cimetidine, the platelet count began to rise gradually and returned to normal 6 days later (Figure 1). The purpura throughout his body also resolved, and phenobarbital was started for prophylaxis against seizures. The patient underwent a craniotomy where a large thrombosed aneurysm was found and partially debulked. Postoperatively the patient did well but his left third nerve palsy persisted. His platelet count remained within normal limits, and he was discharged 9 days after the operation. The patient was followed periodically in the clinic up to 1 year postoperative, and his platelet counts were within normal limits (164-226/mm~). The phenobarbital was tapered
Wong et al
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F i g u r e 1. Relationship of hematologic profiles and phenytoin and cime-
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gradually and then discontinued completely. The patient's recovery was otherwise uneventful. Discussion Thrombocytopenia is an important adverse reaction to many drugs. This drug-induced syndrome can occur either through immune-related platelet destruction, direct toxicity to platelets, or bone marrow suppression. In most immune-mediated instances, the onset of thrombocytopenia is acute and accompanied with clinical signs of bleeding such as purpuric spots or easy bruising. This idiosyncratic reaction may occur at any time during drug therapy independent of the dose [9]. With discontinuation of the agent, the platelet count normalizes rapidly
Thrombocytopenia
and the bone marrow usually reveals abundance of megakaryocytes. To date only three cases of phenytoin-induced mild thrombocytopenia have been reported to the Registry of Blood Dyscrasia of the American Medical Association [I0]. It is unclear whether these cases of thrombocytopenia were associated with other hematological problems. Although phenytoin-induced thrombocytopenia is a rare phenomenon, it has been recognized since 1962 [12]. Weintraub and his associates reported the acute development of mild thrombocytopenia (platelet count 118-130 × 103/mm 3) associated with high fever, ageneralized maculopapular rash, and severe granulocytopenia in a 39-year-old patient after 4 days of phenytoin therapy [ 12]. A bone marrow aspirate showed minimal megakaryocytes with a normal leukocyte series. Clot retraction studies were positive. The hematological toxicities resolved within 2 weeks after withdrawal of phenytoin. Cimo and his colleagues [2] described another case involving a 46-year-old patient who was treated with phenytoin and diazepam after a sudden grand mal seizure. He also received pentazocin for his back pain. Subsequently, he presented with facial petechiae, a hemorrhagic glossal bullous lesion, and severe thrombocytopenia (platelet count 3000/mm 3) within 1 week of drug therapy. A bone marrow biopsy revealed an increased number of megakaryocytes. A phenytoindependent antibody in the serum of the patient was identified with the lysis test of platelet labeled with chromium (51Cr). The platelet count returned to normal 4 days after discontinuation of the medications. Fincham and his associates [3] reported a patient on phenytoin therapy alone for 8 years because of postencephalitic seizures who suddenly developed severe thrombocytopenic purpura without other hematological manifestations. The platelet count was 5000/mm~; liver-spleen scan, peripheral blood smear, bone marrow study, viral titer screen, and platelet-bound immunoglobulin were normal. Laboratory studies for an immunological basis of phenytoin-induced thrombocytopenia including platelet aggregation, inhibition of clot retraction, and the 5~Cr platelet lysis test were negative. The thrombocytopenia resolved in 1 week after withdrawal of phenytoin. Despite extensive serological testing, a specific phenytoin-induced antibody was not identified. A severe isolated thrombocytopenia developed in our patient after 2 weeks of phenytoin therapy, although he had been receiving cimetidine more than 2 months. His hematological investigation was negative and his platelet count rose rapidly after discontinuation of both phenytoin and cimetidine. The absence of signs and symptoms of infection, negative Coombs test, as well as un-
Surg Neurol 1985;23:169-72
171
remarkable disseminated intravascular coagulation screen, excluded other disorders such as disseminated intravascular coagulation, hemolytic anemia, or a transfusion reaction as the cause of thrombocytopenia. Adequate numbers of megakaryocytes were seen in the bone marrow biopsy, which suggested peripheral destruction of platelets instead of bone marrow suppression. The decline in hematocrit due to blood loss after the second angiographic study might be attributed to the development of thrombocytopenia. Drug-induced immunemediated thrombocytopenia is difficult to confirm with laboratory tests [1,8,9]. Most of the in vitro tests to detect drug antibodies are either insensitive, nonspecific, or not readily available for routine clinical use. The rapid recovery after withdrawal of phenytoin and cimetidine in our patient is strongly suggestive of a druginduced thrombocytopenia. It is uncertain whether the thrombocytopenia was secondary to both phenytoin and cimetidine or either one alone. Uncomplicated thrombocytopenia associated with cimetidine therapy has been described in the literature [4-7]. In most cases the thrombocytopenia developed within 1 week after cimetidine therapy and resolved promptly after withdrawal of cimetidine [4,6,7]. In one instance the thrombocytopenia occurred after 49 days of cimetidine treatment, although this might be partly attributed to the sarcoidosis of the patient. Because severe isolated thrombocytopenia is a very unusual complication of phenytoin therapy alone, cimetidine may have synergistic effects on phenytoininduced thrombocytopenia in our patient. Granulocytopenia secondary to concomitant therapy of phenytoin and cimetidine has been reported [ 11 ]. Our patient had been on cimetidine over 2 months prior to admission. The possibility of a late-onset thrombocytopenia induced by cimetidine alone could not be excluded. Therefore, the thrombocytopenia in our patient may likely be due to both phenytoin and cimetidine. Rechallenge with either phenytoin or cimetidine was not recommended because of the unacceptable risk. Phenobarbital and antacids were then prescribed to this patient as alternative measures. In summary, the combination of phenytoin and cimetidine may be responsible for the severe thrombocytopenia in our patient. Clinicians should be alerted to the unpredictability of this idiosyncratic reaction. Management should include discontinuation of the suspected medication, evaluation of other possible etiologies of thrombocytopenia, and provision of alternative drug treatment. We thank Dr. J. LanceLichtorfor his technicalassistance.
172
Surg Neurol 1985;23:169-72
References 1. Cimo PL. Documenting suspected drug-induced thrombocytopenia. Arch Intern Med 1983;143:1117-8. 2. Cimo PL, Pisciotta AV, Desai RG, PinoJL, Aster RH. Detection of drug-dependent antibodies by the 51Crplatelet lysis test: Documentation of immune thrombocytopenia induced by diphenylhydantoin, diazepam and sulfisoxazole. Am J Hematol 1977; 2:65-72. 3. Fincham RW, Hamilton HE, Schottelius DD. Late onset thrombocytopenia with phenytoin therapy. Ann Neurol 1979;6:370. 4. Idvall J. Cimetidine-associated thrombocytopenia. Lancet 1979; 2:159. 5. Isaacs AJ. Cimetidine and thrombocytopenia. Br Med J 1980;280:294.
Wong et al
6. Mann HJ, Schneider JR, Miller JB, Delaney JP. Cimetidineassociated thrombocytopenia. Drug Intell Clin Pharm 1983; 17:126-8. 7. McDaniel JL, Stein JJ. Thrombocytopenia with cimetidine therapy. N Engl J Med 1979;300:864. 8. Miescher PA, GrafJ. Drug-induced thrombocytopenia. Clin Haematol 1980;9:505-19. 9. Moss RA. Drug-induced immune thrombocytopenia. Am J Hematol 1980;9:439-46. 10. Pisciotta AV. Phenytoin: Hematological toxicity. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs. 2nd ed. New York: Raven Press, 1982:257-68. 11. Sazie E, Jaffe JP. Severe granulocytopenia with cimetidine and phenytoin. Ann Intern Med 1980;93:151-2. 12. Weintraub RM, Pechet L, Alexander B. Rapid diagnosis of druginduced thrombocytopenic purpura. JAMA 1962;180:130-4.
169
Severe Thrombocytopenia Associated with Phenytoin and Cimetidine Therapy Yan Yan Wong, Pharm.D., Terry Lichtor, M.D., Ph.D., and Frederick D. Brown, M.D. Department of Pharmaceutical Services, and Section of Neurological Surgery, The University of Chicago, Chicago, Illinois
Wong YY, Lichtor T, Brown FD. Severe thrombocytopenia associated with phenytoin and cimetidine therapy. Surg Neurol 1985;23:169-72.
A 67-year-old man developed a sudden onset of severe isolated thrombocytopenia (platelet count, 1000/mm ~) after 10 days of phenytoin administration as a prophylactic measure prior to craniotomy. The patient had also been taking cimetidine for 2 months prior to admission. No other hematological complications were noted, and an extensive hematologic investigation was otherwise unremarkable. Rapid resolution of the thrombocytopenia upon discontinuation of phenytoin and cimetidine strongly suggests a drug-induced adverse reaction. KEY WORDS: Thrombocytopenia; Phenytoin; Cimetidine
Phenytoin has been widely used as an anticonvulsant for treatment and prophylaxis since its introduction in 1938. Its hematological toxicities such as megaloblastic anemia, aplastic anemia, leukopenia, agranulocytosis, and lymphadenopathy have been reviewed in detail [10]. The phenytoin-associated thrombocytopenia often appears with other hypersensitivity manifestations such as fever, rash, eosinophilia, and lymphadenopathy; it has been considered as an idiosyncratic reaction with an immunological basis. However, thrombocytopenia without concurrent hematological toxicities induced by phenytoin is extremely rare [2,3]. A case o f severe isolated thrombocytopenia apparently related to phenytoin is presented. Case Report A 67-year-old black man with a history o f hypothyroidism and anemia was admitted with the complaint of an excruciating headache for 2 - 3 days. Two months prior to admission, the patient underwent resection of a carAddress reprint requests to: Yan Yan Wong, Pharm.D., Department of Pharmaceutical Services, The University of Chicago Medical Center, 5841 S. Maryland, Chicago, Illinois 60637.
© 1985 by Elsevier Science Publishing Co., Inc.
cinoma of the rectosigmoid colon (Dukes C2) with 1 of 19 lymph nodes positive for tumor. H e had been placed on cimetidine postoperatively and continued taking this medication on an outpatient basis until the time of this admission. Hematological profiles during that time revealed a very minimal microcytic hypochromic anemia but an adequate platelet count ( 1 8 7 - 2 3 7 × 10~/mm~). Upon admission, his blood pressure was 134/84 mmHg, pulse 80/min, respirations 28/min, and he was afebrile. The patient appeared to be lethargic but arousable. H e had bilateral third nerve palsies and a left sixth nerve palsy. His corneal reflexes were also decreased bilaterally. The ptosis of his left eyelid was more severe than the right one. A mild facial palsy was also noted on the right side, and he had a bitemporal hemianopsia. The remainder of his neurological examination was unremarkable. The computed axial tomography scan of his brain demonstrated a large intrasellar mass with a thin rim of hemorrhage around it. On admission the patient's serum sodium was 123 mEq/L and potassium 3.4 mEq/L. T h e remainder of the electrolytes and the renal and liver functions were all normal except for minimal elevation of both S G O T (75 IU/L) and L D H (318 IU/L). The serum thyroxine and free thyroxine index were both 3/zg/ml. Hematological profiles showed a platelet count of 225,000/mm ~, leukocyte count (WBC) of 7 8 0 0 / m m ~, erythrocyte count of 4.47 million/mm ~, hemoglobin (Hgb) content of 11.7 g/dL, hematocrit (Hct) 35%, mean corpuscular volume of 79 /~m ~, mean corpuscular hemoglobin content of 26.3 pg, mean corpuscular hemoglobin concentration 33.4%, prothrombin time (PT) of 11.3 seconds (control 11.5 seconds) and partial thromboplastin time (PTT) of 22.8 seconds (control 23.9 seconds). The patient was placed on dexamethasone medication at 10 mg every 6 hours, cimetidine 300 mg every 6 hours, and levothyroxine 0.1 mg daily. His electrolyte imbalance was corrected. Phenytoin was also initiated as a prophylactic measure prior to a scheduled craniotomy. The patient became more alert and his right third nerve and left sixth nerve palsies resolved, but the left third nerve palsy persisted. A cerebral angiogram re0090-3019/85/$3.30
170
Surg Neurol 1985;23:169-72
vealed a large hypovascular mass arising from the sella turcica. The angiogram was repeated 1 week later but was unchanged. After the second angiogram, a fairly large hematoma was noted over the puncture site and the hematocrit at this time was 26.7%. The patient subsequently received 2 U of packed red blood cells and his hematocrit rose to 30%. While the patient was placed on phenytoin, the plasma concentration of phenytoin 6 days after a daily dosage of 400 mg was 10.6/zg/mL. Five days later the platelet count was 1000/ram3; a repeated platelet count was 7000/mm 3. Other laboratory values included WBC 9,900/mm 3 with normal differentials and no eosinophils, RBC 3.77 million/mm3, Hgb 10.5 g/dL, Hct 30.6%, bilirubin 0.3 mg/dL, and the reticulocyte count 2.2%. At this time there were petechiae over his entire body; several hemorrhagic lesions were also found on his buccal mucosa. The patient was afebrile. His spleen was not palpable. Both phenytoin and cimetidine were discontinued immediately and surgical intervention was postponed. However, dexamethasone and levothyroxine were continued throughout his hospitalization. A hematologic investigation was undertaken. A disseminated intravascular coagulation screen showed a slightly hypercoagulable state: PT 12.4 seconds (control 11.4 seconds), PTT 19.8 seconds (control 25.4 seconds), thrombin time 10 seconds (control 9.4 seconds), fibrinogen 195 mg/dL (control 210 mg/dL), fibrin degradation product titer greater than 40 and less than 80 /zg/mL, Factor V 160%, Factor VIII 200%, antithrombin III 66%, and plasminogen 79%. Additional serological studies including haptoglobin 177 mg% and hemopexin 76.1 mg% were within normal limits. The Coombs (direct and indirect) tests were negative. A peripheral smear showed marked thrombocytopenia with mild anisopoikilocytosis. A bone marrow biopsy revealed a normocellular bone marrow with mild erythroid hyperplasia and an adequate number of megakaryocytes. Therefore a drug-induced reaction was the most likely etiology of the thrombocytopenia. After discontinuation of phenytoin and cimetidine, the platelet count began to rise gradually and returned to normal 6 days later (Figure 1). The purpura throughout his body also resolved, and phenobarbital was started for prophylaxis against seizures. The patient underwent a craniotomy where a large thrombosed aneurysm was found and partially debulked. Postoperatively the patient did well but his left third nerve palsy persisted. His platelet count remained within normal limits, and he was discharged 9 days after the operation. The patient was followed periodically in the clinic up to 1 year postoperative, and his platelet counts were within normal limits (164-226/mm~). The phenobarbital was tapered
Wong et al
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F i g u r e 1. Relationship of hematologic profiles and phenytoin and cime-
tidine therapy.
gradually and then discontinued completely. The patient's recovery was otherwise uneventful. Discussion Thrombocytopenia is an important adverse reaction to many drugs. This drug-induced syndrome can occur either through immune-related platelet destruction, direct toxicity to platelets, or bone marrow suppression. In most immune-mediated instances, the onset of thrombocytopenia is acute and accompanied with clinical signs of bleeding such as purpuric spots or easy bruising. This idiosyncratic reaction may occur at any time during drug therapy independent of the dose [9]. With discontinuation of the agent, the platelet count normalizes rapidly
Thrombocytopenia
and the bone marrow usually reveals abundance of megakaryocytes. To date only three cases of phenytoin-induced mild thrombocytopenia have been reported to the Registry of Blood Dyscrasia of the American Medical Association [I0]. It is unclear whether these cases of thrombocytopenia were associated with other hematological problems. Although phenytoin-induced thrombocytopenia is a rare phenomenon, it has been recognized since 1962 [12]. Weintraub and his associates reported the acute development of mild thrombocytopenia (platelet count 118-130 × 103/mm 3) associated with high fever, ageneralized maculopapular rash, and severe granulocytopenia in a 39-year-old patient after 4 days of phenytoin therapy [ 12]. A bone marrow aspirate showed minimal megakaryocytes with a normal leukocyte series. Clot retraction studies were positive. The hematological toxicities resolved within 2 weeks after withdrawal of phenytoin. Cimo and his colleagues [2] described another case involving a 46-year-old patient who was treated with phenytoin and diazepam after a sudden grand mal seizure. He also received pentazocin for his back pain. Subsequently, he presented with facial petechiae, a hemorrhagic glossal bullous lesion, and severe thrombocytopenia (platelet count 3000/mm 3) within 1 week of drug therapy. A bone marrow biopsy revealed an increased number of megakaryocytes. A phenytoindependent antibody in the serum of the patient was identified with the lysis test of platelet labeled with chromium (51Cr). The platelet count returned to normal 4 days after discontinuation of the medications. Fincham and his associates [3] reported a patient on phenytoin therapy alone for 8 years because of postencephalitic seizures who suddenly developed severe thrombocytopenic purpura without other hematological manifestations. The platelet count was 5000/mm~; liver-spleen scan, peripheral blood smear, bone marrow study, viral titer screen, and platelet-bound immunoglobulin were normal. Laboratory studies for an immunological basis of phenytoin-induced thrombocytopenia including platelet aggregation, inhibition of clot retraction, and the 5~Cr platelet lysis test were negative. The thrombocytopenia resolved in 1 week after withdrawal of phenytoin. Despite extensive serological testing, a specific phenytoin-induced antibody was not identified. A severe isolated thrombocytopenia developed in our patient after 2 weeks of phenytoin therapy, although he had been receiving cimetidine more than 2 months. His hematological investigation was negative and his platelet count rose rapidly after discontinuation of both phenytoin and cimetidine. The absence of signs and symptoms of infection, negative Coombs test, as well as un-
Surg Neurol 1985;23:169-72
171
remarkable disseminated intravascular coagulation screen, excluded other disorders such as disseminated intravascular coagulation, hemolytic anemia, or a transfusion reaction as the cause of thrombocytopenia. Adequate numbers of megakaryocytes were seen in the bone marrow biopsy, which suggested peripheral destruction of platelets instead of bone marrow suppression. The decline in hematocrit due to blood loss after the second angiographic study might be attributed to the development of thrombocytopenia. Drug-induced immunemediated thrombocytopenia is difficult to confirm with laboratory tests [1,8,9]. Most of the in vitro tests to detect drug antibodies are either insensitive, nonspecific, or not readily available for routine clinical use. The rapid recovery after withdrawal of phenytoin and cimetidine in our patient is strongly suggestive of a druginduced thrombocytopenia. It is uncertain whether the thrombocytopenia was secondary to both phenytoin and cimetidine or either one alone. Uncomplicated thrombocytopenia associated with cimetidine therapy has been described in the literature [4-7]. In most cases the thrombocytopenia developed within 1 week after cimetidine therapy and resolved promptly after withdrawal of cimetidine [4,6,7]. In one instance the thrombocytopenia occurred after 49 days of cimetidine treatment, although this might be partly attributed to the sarcoidosis of the patient. Because severe isolated thrombocytopenia is a very unusual complication of phenytoin therapy alone, cimetidine may have synergistic effects on phenytoininduced thrombocytopenia in our patient. Granulocytopenia secondary to concomitant therapy of phenytoin and cimetidine has been reported [ 11 ]. Our patient had been on cimetidine over 2 months prior to admission. The possibility of a late-onset thrombocytopenia induced by cimetidine alone could not be excluded. Therefore, the thrombocytopenia in our patient may likely be due to both phenytoin and cimetidine. Rechallenge with either phenytoin or cimetidine was not recommended because of the unacceptable risk. Phenobarbital and antacids were then prescribed to this patient as alternative measures. In summary, the combination of phenytoin and cimetidine may be responsible for the severe thrombocytopenia in our patient. Clinicians should be alerted to the unpredictability of this idiosyncratic reaction. Management should include discontinuation of the suspected medication, evaluation of other possible etiologies of thrombocytopenia, and provision of alternative drug treatment. We thank Dr. J. LanceLichtorfor his technicalassistance.
172
Surg Neurol 1985;23:169-72
References 1. Cimo PL. Documenting suspected drug-induced thrombocytopenia. Arch Intern Med 1983;143:1117-8. 2. Cimo PL, Pisciotta AV, Desai RG, PinoJL, Aster RH. Detection of drug-dependent antibodies by the 51Crplatelet lysis test: Documentation of immune thrombocytopenia induced by diphenylhydantoin, diazepam and sulfisoxazole. Am J Hematol 1977; 2:65-72. 3. Fincham RW, Hamilton HE, Schottelius DD. Late onset thrombocytopenia with phenytoin therapy. Ann Neurol 1979;6:370. 4. Idvall J. Cimetidine-associated thrombocytopenia. Lancet 1979; 2:159. 5. Isaacs AJ. Cimetidine and thrombocytopenia. Br Med J 1980;280:294.
Wong et al
6. Mann HJ, Schneider JR, Miller JB, Delaney JP. Cimetidineassociated thrombocytopenia. Drug Intell Clin Pharm 1983; 17:126-8. 7. McDaniel JL, Stein JJ. Thrombocytopenia with cimetidine therapy. N Engl J Med 1979;300:864. 8. Miescher PA, GrafJ. Drug-induced thrombocytopenia. Clin Haematol 1980;9:505-19. 9. Moss RA. Drug-induced immune thrombocytopenia. Am J Hematol 1980;9:439-46. 10. Pisciotta AV. Phenytoin: Hematological toxicity. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs. 2nd ed. New York: Raven Press, 1982:257-68. 11. Sazie E, Jaffe JP. Severe granulocytopenia with cimetidine and phenytoin. Ann Intern Med 1980;93:151-2. 12. Weintraub RM, Pechet L, Alexander B. Rapid diagnosis of druginduced thrombocytopenic purpura. JAMA 1962;180:130-4.