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Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use

Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use Ticlopidine hydrochloride is an antiplatelet agent used for an increasing number of indications, including cerebrovascular disease, unstable angina, coronary artery stenting, and peripheral vascular bypass grafting. It has uncommon but severe hematologic effects, including thrombotic thrombocytopenic purpura. We report 3 new cases of ticlopidine-associated thrombotic thrombocytopenic purpura and review the English-language literature. Of the 13 patients described (10 from published articles), an equal number were women and men. The median age of the women was 50 years, and that of the men was 72 years. Thrombotic thrombocytopenic purpura occurred within 2 to 8 weeks of starting ticlopidine therapy. Survivors received plasma therapy, but of the 4 who died, 3 had received platelet transfusions. With discontinuation of the drug and prompt plasma exchange therapy, mortality was comparable to that seen with idiopathic thrombotic thrombocytopenic purpura, and relapse was uncommon. Physicians and patients should be aware of this potentially fatal but treatable complication of ticlopidine therapy.Ticlopidine hydrochloride is a platelet-aggregation inhibitor that interferes with platelet membrane function by inhibiting adenosine diphosphate–induced platelet activation. It has been available in Europe for more than 15 years and was approved by the US Food and Drug Administration in 1991 for use in persons who have had a completed thrombotic stroke or its precursor symptoms.Ticlopidine therapy may also reduce the risk of death and myocardial infarction in patients with unstable angina.Recent studieshave reported that the use of ticlopidine in combination with aspirin after coronary artery stenting reduced the incidence of cardiac events. As well, the patency of vein bypass grafts for the treatment of peripheral vascular disease was improved with the use of ticlopidine, thus suggesting another indication for its use.The most important adverse effect included in the product labeling when ticlopidine was first introduced was neutropenia. This was noted in 2.4% of stroke patients receiving the drug in premarketing trials, and 0.8% had severe neutropenia, agranulocytosis, or both.Postmarketing surveillance revealed reports of aplastic anemia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP). This prompted an update of the warnings section of the product labeling in 1995 to include these adverse effects.Thrombotic thrombocytopenic purpura is a life-threatening syndrome of thrombocytopenia and microangiopathic hemolytic anemia commonly associated with fluctuating neurologic abnormalities, renal dysfunction, and fever. Although its cause remains unclear, TTP has been linked to a number of medical conditions (eg, infection, malignant neoplasms, and pregnancy) and other drugs (eg, antineoplastics, antibiotics, and cyclosporine).With prompt plasma exchange therapy, most patients survive; otherwise, the disease has high mortality.Because the clinical indications for ticlopidine use are increasing, the incidence of potentially fatal complications of therapy such as TTP is likely to rise. We report 3 cases and review the English-language literature for ticlopidine-associated TTP.REPORT OF CASESCASE 1A 75-year-old woman with recurrent amaurosis fugax despite aspirin therapy (650 mg twice a day) was switched to a regimen of ticlopidine hydrochloride, 250 mg twice a day. This was tolerated poorly because of gastrointestinal tract upset, so the dose was decreased to 250 mg/d. When a surveillance complete blood cell count, with the blood specimen drawn 35 days after ticlopidine therapy was started, revealed a platelet count of 7×109/L, the drug was discontinued. Four days later, the patient developed a headache, left arm paresthesias, and right arm weakness. The next day, when she presented to the hospital, she was afebrile; she had no focal neurologic signs, but she was confused and had word-finding difficulty.Laboratory examination revealed a hemoglobin level of 92 g/L, a white blood cell count of 5.3×109/L, and a platelet count of 19×109/L. The peripheral blood film showed red blood cell fragmentation. A direct antiglobulin test was negative for antibodies. The total bilirubin concentration was 20 µmol/L (1.2 mg/dL); lactate dehydrogenase (LDH), 551 U/L; creatinine, 72 µmol/L (0.8 mg/dL); and serum urea nitrogen, 5.4 mmol/L (15 mg/dL). The prothrombin and activated partial thromboplastin times were normal.The patient was transferred to our center with a diagnosis of TTP. Plasma exchange was initiated with 1.5 plasma volumes for 3 consecutive days using cryoprecipitate-poor plasma as the replacement fluid. During the next 10 days, this was followed by an exchange of 1 plasma volume, 2 cryoprecipitate-poor plasma infusions (30 mL/kg), and 2 further exchanges of 1 plasma volume each. Her neurologic symptoms resolved within 24 hours, and her platelet count returned to normal after 3 days. The LDH concentration returned to normal after 2 days. She was discharged on a regimen of enteric-coated aspirin, 325 mg/d, and has been observed for 2 months without relapse.CASE 2A 76-year-old man was placed on a regimen of ticlopidine hydrochloride (250 mg twice a day) following heparin sodium therapy for recurrent brainstem transient ischemic attacks. He presented to the hospital 28 days later with a diffuse petechial rash and abdominal discomfort. He was afebrile with no focal neurologic deficits. His mental status was normal, except for diminished short-term recall.Laboratory testing revealed a hemoglobin level of 132 g/L. The white blood cell count was 6.7×109/L, and the platelet count was 12×109/L. The peripheral blood film showed red blood cell fragmentation. A direct antiglobulin test was negative for antibodies. The total bilirubin concentration was 42 µmol/L (2.5 mg/dL); LDH, 3350 U/L; creatinine, 131 µmol/L (1.5 mg/dL); and serum urea nitrogen, 10.6 mmol/L (30 mg/dL). The prothrombin and activated partial thromboplastin times were normal. A urinalysis revealed blood and protein. Treatment with intravenous immunoglobulin, 30 g; methylprednisolone sodium succinate, 1 g; and 7 U of platelets was begun before the patient was transferred to our center with a diagnosis of TTP.On transfer, the patient's complete blood cell count revealed a hemoglobin level of 120 g/L, a white blood cell count of 4.5×109/L, and a platelet count of 5×109/L. The patient received plasma exchange with 1.5 plasma volumes for 5 consecutive days and 1 plasma volume every 3 days for 4 additional exchanges. The replacement fluid used was cryoprecipitate-poor plasma. Steroid therapy was continued with prednisone, 100 mg/d, in a tapering dose. His abdominal symptoms resolved rapidly, and his platelet count returned to normal after 6 days. The LDH concentration and creatinine level returned to normal after 5 days and 1 day, respectively. His platelet count fell again 19 days and 37 days from the start of plasma exchange. This was treated by increasing the frequency of plasma exchanges. After the second relapse, vincristine sulfate, 2 mg, was administered intravenously. Sustained normalization of his platelet count was achieved after a total of 30 plasma volumes had been exchanged, 51 days after the start of plasma therapy. He was discharged on a regimen of enteric-coated aspirin, 325 mg/d, and has been observed for 6 months without evidence of relapse.CASE 3A 77-year-old man with a history of type 2 diabetes mellitus and coronary artery disease was placed on aspirin therapy for a right-sided stroke with residual left arm weakness. He was able to tolerate only low-dose aspirin (80 mg/d) because of gastrointestinal tract upset, so ticlopidine hydrochloride, 250 mg twice a day, was added. He presented to the hospital 5 weeks later with 3 days of nausea, vomiting, anorexia, and dark red urine. He was afebrile and had no new neurologic deficits, except for word-finding difficulties.Laboratory testing revealed a hemoglobin level of 89 g/L, a white blood cell count of 2.9×109/L, and a platelet count of 14×109/L. Microangiopathic changes were seen on his peripheral blood smear. Direct and indirect antiglobulin tests were negative for antibodies. The total bilirubin concentration was 45 µmol/L (2.6 mg/dL); LDH, 1021 U/L; creatinine, 146 µmol/L (1.6 mg/dL); and serum urea nitrogen, 12.8 mmol/L (36 mg/dL). The results of coagulation studies were normal. The patient's level of consciousness deteriorated during the day, and increasing left-sided weakness was noted.A diagnosis of TTP was made. The patient was transfused with 2 U of packed red blood cells, and plasma exchange was begun. He underwent 12 exchanges during his admission: 8 consecutive sessions of 1.5 plasma volumes, followed by 4 sessions of 1 plasma volume performed on alternate days. The replacement fluid used was cryoprecipitate-poor plasma. His level of consciousness improved, and his weakness returned to baseline after the second plasma exchange. The platelet count and LDH level returned to normal by days 5 and 13, respectively. He was discharged on a regimen of aspirin and has been free of relapse for 1 month.COMMENTWith the addition of these 3 cases, there are now 13 cases of TTP associated with ticlopidine use reported in the English-language literature (Table 1and Table 2). Of the patients described, an equal number were men and women. The median age of the female patients was 50 years, and that of the male patients was 72 years. In contrast, those affected by idiopathic TTP are twice as likely to be female and younger (mean age, 38 years).Hence, a greater proportion of male patients are affected by ticlopidine-associated TTP than would be expected with idiopathic TTP. This is likely because of the age and sex distribution of ticlopidine users, which is skewed toward older men, who have a higher prevalence of vascular disease.Table 1. Clinical Information at Presentation of 13 Patients With Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use Reported in the English-Language Literature*Ticlopidine UseLaboratory TestsSourcePatient No./Sex/Age, yIndicationDuration, wkHb, g/LPlatelet Count,× 109/LTotal Bilirubin, µmol/L (mg/dL)†LDH, U/LCreatinine, µmol/L (mg/dL)Present study1/F/75TIA; aspirin failed5921920 (1.2)55172 (0.8)2/M/76Recurrent TIA41321242 (2.5)3350131 (1.5)3/M/77Stroke; aspirin-intolerant5891445 (2.6)1021146 (1.6)Page et al,19914/M/75Venous ulcers5941455 (3.2)2961210 (2.4)5/M/72Claudication8701550† (2.9)1490158 (1.8)6/F/47NA36225494† (28.9)6000200 (2.3)7/M/72Stoke4542340 (2.3)NA174 (2.0)Capra et al,19928/F/25Stroke, CAS3.510613NANANAEllie et al,19929/M/69Post MI51142441 (2.4)7450374 (4.2)Kovacs et al,199310/M/68TIA; aspirin-intolerant68021NA955327 (3.7)Ariyoshi et al,199711/F/77TIA31171070 (4.1)3056203 (2.3)Kupfer and Tessler,199712/F/47Coronary stent312787NANANA13/F/42Coronary stent2.5952NANA124 (1.4)*Hb indicates hemoglobin; LDH, lactate dehydrogenase; TIA, transient ischemic attack; NA, not available; CAS, carotid artery stenosis; and post MI, after myocardial infarction.†Indirect total bilirubin concentration.Table 2. Treatment and Outcome of 13 Patients With Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use Reported in the English-Language LiteratureSourcePatient No.Treatment*OutcomePresent study1Plasma exchange, plasma infusionAlive2Plasma exchange, corticosteroid therapy, and vincristine sulfateAlivePage et al,19913Plasma exchangeAlive4Plasma infusion, dipyridamoleAlive5Plasma infusion, aspirin, and dipyridamoleAlive6Plasma exchange, dipyridamole, and aspirinAlive7PlateletsDeadCapra et al,19928Plasma exchange, dipyridamole, IVIG, corticosteroid therapy, and aspirinAliveEllie et al,19929Plasma exchange, dipyridamole, and aspirinDeadKovacs et al,199310Plasma exchange, plasma infusionAliveAriyoshi et al,199711Plasma exchangeAliveKupfer and Tessler,199712Platelets, plasma exchangeDead13PlateletsDead*IVIG indicates intravenous immunoglobulin.The median interval from the initiation of ticlopidine therapy to the onset of symptoms was 4 weeks, ranging from 2.5 to 8 weeks. This is consistent with the duration of ticlopidine therapy before the onset of other adverse hematologic effects such as agranulocytosis.None of the patients we described had coincident neutropenia or agranulocytosis.All patients who recovered from TTP received plasma therapy with cryoprecipitate-poor or fresh-frozen plasma replacement. The survivors had complete resolution of symptoms or mild residual neurologic impairment. Two of the 4 patients who died did not receive plasma exchange or plasma infusion. Three of the 4 patients who died received platelet transfusions. Patient 7 received 3 U of red blood cells and 4 U of platelets and died within 12 hours. Patient 13 received 6 U of platelets and died before the initiation of plasma exchange. Patient 12 died after receiving red blood cell and platelet transfusions despite plasma exchange therapy. Platelet transfusion is relatively contraindicated in patients with TTP because it is thought that circulating platelet aggregators in this disease state would promote further thrombus formation with the transfused platelets.Despite the absence of systematic studies of this issue, based on anecdotal reports of poor outcome following platelet transfusion and the observation that the rapid recovery of platelet counts after plasma exchange therapy has been followed by sudden death, it is common practice to avoid giving platelet transfusions to patients with TTP.Although treatment is successful in most patients with idiopathic TTP, 37% to 68% have at least 1 relapse.Most relapses occur within 30 days of diagnosis, but first relapses have occurred 8 years after the original episode. In this series of 13, only 1 patient (patient 1) relapsed, and this occurred at 14 and 32 days of the illness. With continued plasma exchange, corticosteroid, and vincristine therapy, a sustained resolution of TTP was achieved after 51 days. No patients were readministered ticlopidine. The low relapse rate supports the contention that ticlopidine was the inciting agent for TTP in these patients. Once the offending drug is discontinued and appropriate therapy instituted, recurrent disease should be unlikely.The pathological lesions seen in TTP consist of diffuse platelet microthrombi partially occluding the vascular lumen of arterioles and capillaries with overlying proliferative endothelium. Ultralarge multimers of von Willebrand factor (vWF) are released into the circulation by damage to endothelial cells. These ultralarge vWF multimers increase platelet adhesiveness in vitro and may be one of the platelet-aggregating agents responsible for the platelet microthrombi that characterize TTP in vivo.It is thought that ultralarge vWF multimers are normally proteolytically converted to the smaller forms usually found in the circulation. Deficiency in the activity of a specific protease that cleaves purified vWF has been reported in 4 patients with chronic relapsing TTP.In addition, 1 patient described in the literaturehad TTP associated with deficient activity of the vWF-cleaving protease due to the presence of an IgG inhibitor in plasma. These observations suggest that a deficiency of the vWF-cleaving protease due to autoimmune or other mechanisms may predispose to TTP. Neither ultralarge vWF multimers nor vWF-cleaving protease activity has been measured in patients with ticlopidine-associated TTP. However, presuming that TTP is an end result of varied insults to the vascular endothelium, ticlopidine may directly or indirectly damage endothelial cells, leading to the release into the circulation of ultralarge vWF multimers that, in susceptible persons (eg, those with a deficiency of vWF-cleaving protease activity), are processed abnormally and so initiate intravascular platelet clumping. In vitro, ticlopidine has been shown to retard the adherence and growth of human endothelial cells and to alter endothelial cell structure.In addition, it inhibits fibronectin synthesis in endothelial cells, which impairs cell-to-cell adhesion and compromises cell-to-subendothelium interaction. This may also expose elements in vivo that promote platelet aggregation and thrombus formation. The mechanism for TTP associated with ticlopidine use is thought to be different from that of agranulocytosis associated with ticlopidine. In the latter instance, ticlopidine has a direct toxic effect on marrow cells in susceptible persons.Case reports of ticlopidine use associated with antinuclear antibody positivity, vasculitis, serum sickness, and immune thrombocytopenia also raise the possibility that ticlopidine use may predispose to vWF-cleaving protease deficiency by autoimmune mechanisms.The clinical indications for ticlopidine use are expanding, and thus, serious adverse effects such as TTP are being encountered more frequently. With discontinuation of the drug and prompt plasma exchange therapy, mortality is comparable to that seen with idiopathic TTP, and relapse is uncommon. Physicians and patients should be aware of this potentially fatal but treatable complication of ticlopidine therapy.MGentJABlakelyJDEastonThe Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.Lancet.1989;1:1215-1220.WKHassJDEastonHPAdams JrA randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients.N Engl J Med.1989;321:501-507.FBalsanoPRizzonFVioliAntiplatelet treatment with ticlopidine in unstable angina.Circulation.1990;82:17-26.ASchomigFJNeumannAKastratiA randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.N Engl J Med.1996;334:1084-1089.JPBecqueminEffect of ticlopidine on the long-term patency of saphenous vein bypass grafts in the legs.N Engl J Med.1997;337:1726-1731.Not AvailableDrug Facts and Comparisons.51st ed. St Louis, Mo: Facts and Comparisons; 1997:300-304.DKWysowksiJBacsanyiBlood dyscrasias and hematologic reactions in ticlopidine users [letter].JAMA.1996;276:952.JNGeorgeMEl-HorakeThrombocytopenia due to enhanced platelet destruction by nonimmunologic mechanisms.In: Beutler E, Lichtman MA, Coller BS, et al, eds. William's Hematology.5th ed. New York, NY: McGraw-Hill Book Co; 1995:1315-1355.WRBellHGBrainePMNessTSKicklerImproved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.N Engl J Med.1991;325:398-403.YPageBTardyFZeniCComtetRTerranaJCBertrandThrombotic thrombocytopenic purpura related to ticlopidine.Lancet.1991;337:774-776.RCapraNMarcianoFFieniMCapucciPFerremiAOrlandiniCerebral hemorrhage and thrombotic thrombocytopenic purpura during ticlopidine treatment: case report.Acta Neurol Belg.1992;92:83-87.EEllieCDurrieuPBesseJJulienGGbipki-BenissanThrombotic thrombocytopenic purpura associated with ticlopidine [letter].Stroke.1992;23:922-923.MJKovacsPYSoongIHChin-YeeThrombotic thrombocytopenic purpura associated with ticlopidine.Ann Pharmacother.1993;27:1060-1061.KAriyoshiKShinoharaXRuirongThrombotic thrombocytopenic purpura caused by ticlopidine, successfully treated by plasmapheresis [letter].Am J Hematol.1997;54:175-176.YKupferSTesslerTiclopidine and thrombotic thrombocytopenic purpura [letter].N Engl J Med.1997;337:1245.WRBellThrombotic thrombocytopenic purpura/hemolytic uremic syndrome relapse.Semin Hematol.1997;34:134-139.GARockKHShumakNABuskardComparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura.N Engl J Med.1991;325:393-397.HCKwaanGASoffManagement of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.Semin Hematol.1997;34:159-166.LIGordonHCKwaanECRossiDeleterious effects of platelet transfusions and recovery thrombocytosis in patients with thrombotic microangiopathy.Semin Hematol.1987;24:194-201.MRoseAEldorHigh incidence of relapses in thrombotic thrombocytopenic purpura: clinical study of 38 patients.Am J Med.1987;83:437-444.KHShumakGARockRCNairLate relapses in patients successfully treated for thrombotic thrombocytopenic purpura: Canadian Apheresis Group.Ann Intern Med.1995;122:569-572.JMoakeStudies on the pathophysiology of thrombotic thrombocytopenic purpura.Semin Hematol.1997;34:83-89.MFurlanRRoblesMSolenthalerMWassmerPSandozBLammleDeficient activity of von Willebrand factor–cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura.Blood.1997;89:3097-3103.MFurlanRRoblesMSolenthalerBLammleAcquired deficiency of von Willebrand factor–cleaving protease in a patient with thrombotic thrombocytopenic purpura.Blood.1998;91:2839-2846.FPiovellaMMRicettiPAlmasioASamadenGSeminoEAscariThe effect of ticlopidine on human endothelial cells in culture.Thromb Res.1984;33:323-332.KOnoKKuroharaMYoshiharaYShimamatoMYamaguchiAgranulocytosis caused by ticlopidine and its mechanism.Am J Hematol.1991;37:239-242.Accepted for publication August 15, 1998.Reprints: David M. C. Sutton, MD, FRCPC, Princess Margaret Hospital, 610 University Ave, Fifth Floor, Room 207, Toronto, Ontario, Canada M5G 2M9. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use

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Publisher
American Medical Association
Copyright
Copyright 1999 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/archinte.159.3.311
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Abstract

Ticlopidine hydrochloride is an antiplatelet agent used for an increasing number of indications, including cerebrovascular disease, unstable angina, coronary artery stenting, and peripheral vascular bypass grafting. It has uncommon but severe hematologic effects, including thrombotic thrombocytopenic purpura. We report 3 new cases of ticlopidine-associated thrombotic thrombocytopenic purpura and review the English-language literature. Of the 13 patients described (10 from published articles), an equal number were women and men. The median age of the women was 50 years, and that of the men was 72 years. Thrombotic thrombocytopenic purpura occurred within 2 to 8 weeks of starting ticlopidine therapy. Survivors received plasma therapy, but of the 4 who died, 3 had received platelet transfusions. With discontinuation of the drug and prompt plasma exchange therapy, mortality was comparable to that seen with idiopathic thrombotic thrombocytopenic purpura, and relapse was uncommon. Physicians and patients should be aware of this potentially fatal but treatable complication of ticlopidine therapy.Ticlopidine hydrochloride is a platelet-aggregation inhibitor that interferes with platelet membrane function by inhibiting adenosine diphosphate–induced platelet activation. It has been available in Europe for more than 15 years and was approved by the US Food and Drug Administration in 1991 for use in persons who have had a completed thrombotic stroke or its precursor symptoms.Ticlopidine therapy may also reduce the risk of death and myocardial infarction in patients with unstable angina.Recent studieshave reported that the use of ticlopidine in combination with aspirin after coronary artery stenting reduced the incidence of cardiac events. As well, the patency of vein bypass grafts for the treatment of peripheral vascular disease was improved with the use of ticlopidine, thus suggesting another indication for its use.The most important adverse effect included in the product labeling when ticlopidine was first introduced was neutropenia. This was noted in 2.4% of stroke patients receiving the drug in premarketing trials, and 0.8% had severe neutropenia, agranulocytosis, or both.Postmarketing surveillance revealed reports of aplastic anemia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP). This prompted an update of the warnings section of the product labeling in 1995 to include these adverse effects.Thrombotic thrombocytopenic purpura is a life-threatening syndrome of thrombocytopenia and microangiopathic hemolytic anemia commonly associated with fluctuating neurologic abnormalities, renal dysfunction, and fever. Although its cause remains unclear, TTP has been linked to a number of medical conditions (eg, infection, malignant neoplasms, and pregnancy) and other drugs (eg, antineoplastics, antibiotics, and cyclosporine).With prompt plasma exchange therapy, most patients survive; otherwise, the disease has high mortality.Because the clinical indications for ticlopidine use are increasing, the incidence of potentially fatal complications of therapy such as TTP is likely to rise. We report 3 cases and review the English-language literature for ticlopidine-associated TTP.REPORT OF CASESCASE 1A 75-year-old woman with recurrent amaurosis fugax despite aspirin therapy (650 mg twice a day) was switched to a regimen of ticlopidine hydrochloride, 250 mg twice a day. This was tolerated poorly because of gastrointestinal tract upset, so the dose was decreased to 250 mg/d. When a surveillance complete blood cell count, with the blood specimen drawn 35 days after ticlopidine therapy was started, revealed a platelet count of 7×109/L, the drug was discontinued. Four days later, the patient developed a headache, left arm paresthesias, and right arm weakness. The next day, when she presented to the hospital, she was afebrile; she had no focal neurologic signs, but she was confused and had word-finding difficulty.Laboratory examination revealed a hemoglobin level of 92 g/L, a white blood cell count of 5.3×109/L, and a platelet count of 19×109/L. The peripheral blood film showed red blood cell fragmentation. A direct antiglobulin test was negative for antibodies. The total bilirubin concentration was 20 µmol/L (1.2 mg/dL); lactate dehydrogenase (LDH), 551 U/L; creatinine, 72 µmol/L (0.8 mg/dL); and serum urea nitrogen, 5.4 mmol/L (15 mg/dL). The prothrombin and activated partial thromboplastin times were normal.The patient was transferred to our center with a diagnosis of TTP. Plasma exchange was initiated with 1.5 plasma volumes for 3 consecutive days using cryoprecipitate-poor plasma as the replacement fluid. During the next 10 days, this was followed by an exchange of 1 plasma volume, 2 cryoprecipitate-poor plasma infusions (30 mL/kg), and 2 further exchanges of 1 plasma volume each. Her neurologic symptoms resolved within 24 hours, and her platelet count returned to normal after 3 days. The LDH concentration returned to normal after 2 days. She was discharged on a regimen of enteric-coated aspirin, 325 mg/d, and has been observed for 2 months without relapse.CASE 2A 76-year-old man was placed on a regimen of ticlopidine hydrochloride (250 mg twice a day) following heparin sodium therapy for recurrent brainstem transient ischemic attacks. He presented to the hospital 28 days later with a diffuse petechial rash and abdominal discomfort. He was afebrile with no focal neurologic deficits. His mental status was normal, except for diminished short-term recall.Laboratory testing revealed a hemoglobin level of 132 g/L. The white blood cell count was 6.7×109/L, and the platelet count was 12×109/L. The peripheral blood film showed red blood cell fragmentation. A direct antiglobulin test was negative for antibodies. The total bilirubin concentration was 42 µmol/L (2.5 mg/dL); LDH, 3350 U/L; creatinine, 131 µmol/L (1.5 mg/dL); and serum urea nitrogen, 10.6 mmol/L (30 mg/dL). The prothrombin and activated partial thromboplastin times were normal. A urinalysis revealed blood and protein. Treatment with intravenous immunoglobulin, 30 g; methylprednisolone sodium succinate, 1 g; and 7 U of platelets was begun before the patient was transferred to our center with a diagnosis of TTP.On transfer, the patient's complete blood cell count revealed a hemoglobin level of 120 g/L, a white blood cell count of 4.5×109/L, and a platelet count of 5×109/L. The patient received plasma exchange with 1.5 plasma volumes for 5 consecutive days and 1 plasma volume every 3 days for 4 additional exchanges. The replacement fluid used was cryoprecipitate-poor plasma. Steroid therapy was continued with prednisone, 100 mg/d, in a tapering dose. His abdominal symptoms resolved rapidly, and his platelet count returned to normal after 6 days. The LDH concentration and creatinine level returned to normal after 5 days and 1 day, respectively. His platelet count fell again 19 days and 37 days from the start of plasma exchange. This was treated by increasing the frequency of plasma exchanges. After the second relapse, vincristine sulfate, 2 mg, was administered intravenously. Sustained normalization of his platelet count was achieved after a total of 30 plasma volumes had been exchanged, 51 days after the start of plasma therapy. He was discharged on a regimen of enteric-coated aspirin, 325 mg/d, and has been observed for 6 months without evidence of relapse.CASE 3A 77-year-old man with a history of type 2 diabetes mellitus and coronary artery disease was placed on aspirin therapy for a right-sided stroke with residual left arm weakness. He was able to tolerate only low-dose aspirin (80 mg/d) because of gastrointestinal tract upset, so ticlopidine hydrochloride, 250 mg twice a day, was added. He presented to the hospital 5 weeks later with 3 days of nausea, vomiting, anorexia, and dark red urine. He was afebrile and had no new neurologic deficits, except for word-finding difficulties.Laboratory testing revealed a hemoglobin level of 89 g/L, a white blood cell count of 2.9×109/L, and a platelet count of 14×109/L. Microangiopathic changes were seen on his peripheral blood smear. Direct and indirect antiglobulin tests were negative for antibodies. The total bilirubin concentration was 45 µmol/L (2.6 mg/dL); LDH, 1021 U/L; creatinine, 146 µmol/L (1.6 mg/dL); and serum urea nitrogen, 12.8 mmol/L (36 mg/dL). The results of coagulation studies were normal. The patient's level of consciousness deteriorated during the day, and increasing left-sided weakness was noted.A diagnosis of TTP was made. The patient was transfused with 2 U of packed red blood cells, and plasma exchange was begun. He underwent 12 exchanges during his admission: 8 consecutive sessions of 1.5 plasma volumes, followed by 4 sessions of 1 plasma volume performed on alternate days. The replacement fluid used was cryoprecipitate-poor plasma. His level of consciousness improved, and his weakness returned to baseline after the second plasma exchange. The platelet count and LDH level returned to normal by days 5 and 13, respectively. He was discharged on a regimen of aspirin and has been free of relapse for 1 month.COMMENTWith the addition of these 3 cases, there are now 13 cases of TTP associated with ticlopidine use reported in the English-language literature (Table 1and Table 2). Of the patients described, an equal number were men and women. The median age of the female patients was 50 years, and that of the male patients was 72 years. In contrast, those affected by idiopathic TTP are twice as likely to be female and younger (mean age, 38 years).Hence, a greater proportion of male patients are affected by ticlopidine-associated TTP than would be expected with idiopathic TTP. This is likely because of the age and sex distribution of ticlopidine users, which is skewed toward older men, who have a higher prevalence of vascular disease.Table 1. Clinical Information at Presentation of 13 Patients With Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use Reported in the English-Language Literature*Ticlopidine UseLaboratory TestsSourcePatient No./Sex/Age, yIndicationDuration, wkHb, g/LPlatelet Count,× 109/LTotal Bilirubin, µmol/L (mg/dL)†LDH, U/LCreatinine, µmol/L (mg/dL)Present study1/F/75TIA; aspirin failed5921920 (1.2)55172 (0.8)2/M/76Recurrent TIA41321242 (2.5)3350131 (1.5)3/M/77Stroke; aspirin-intolerant5891445 (2.6)1021146 (1.6)Page et al,19914/M/75Venous ulcers5941455 (3.2)2961210 (2.4)5/M/72Claudication8701550† (2.9)1490158 (1.8)6/F/47NA36225494† (28.9)6000200 (2.3)7/M/72Stoke4542340 (2.3)NA174 (2.0)Capra et al,19928/F/25Stroke, CAS3.510613NANANAEllie et al,19929/M/69Post MI51142441 (2.4)7450374 (4.2)Kovacs et al,199310/M/68TIA; aspirin-intolerant68021NA955327 (3.7)Ariyoshi et al,199711/F/77TIA31171070 (4.1)3056203 (2.3)Kupfer and Tessler,199712/F/47Coronary stent312787NANANA13/F/42Coronary stent2.5952NANA124 (1.4)*Hb indicates hemoglobin; LDH, lactate dehydrogenase; TIA, transient ischemic attack; NA, not available; CAS, carotid artery stenosis; and post MI, after myocardial infarction.†Indirect total bilirubin concentration.Table 2. Treatment and Outcome of 13 Patients With Thrombotic Thrombocytopenic Purpura Associated With Ticlopidine Use Reported in the English-Language LiteratureSourcePatient No.Treatment*OutcomePresent study1Plasma exchange, plasma infusionAlive2Plasma exchange, corticosteroid therapy, and vincristine sulfateAlivePage et al,19913Plasma exchangeAlive4Plasma infusion, dipyridamoleAlive5Plasma infusion, aspirin, and dipyridamoleAlive6Plasma exchange, dipyridamole, and aspirinAlive7PlateletsDeadCapra et al,19928Plasma exchange, dipyridamole, IVIG, corticosteroid therapy, and aspirinAliveEllie et al,19929Plasma exchange, dipyridamole, and aspirinDeadKovacs et al,199310Plasma exchange, plasma infusionAliveAriyoshi et al,199711Plasma exchangeAliveKupfer and Tessler,199712Platelets, plasma exchangeDead13PlateletsDead*IVIG indicates intravenous immunoglobulin.The median interval from the initiation of ticlopidine therapy to the onset of symptoms was 4 weeks, ranging from 2.5 to 8 weeks. This is consistent with the duration of ticlopidine therapy before the onset of other adverse hematologic effects such as agranulocytosis.None of the patients we described had coincident neutropenia or agranulocytosis.All patients who recovered from TTP received plasma therapy with cryoprecipitate-poor or fresh-frozen plasma replacement. The survivors had complete resolution of symptoms or mild residual neurologic impairment. Two of the 4 patients who died did not receive plasma exchange or plasma infusion. Three of the 4 patients who died received platelet transfusions. Patient 7 received 3 U of red blood cells and 4 U of platelets and died within 12 hours. Patient 13 received 6 U of platelets and died before the initiation of plasma exchange. Patient 12 died after receiving red blood cell and platelet transfusions despite plasma exchange therapy. Platelet transfusion is relatively contraindicated in patients with TTP because it is thought that circulating platelet aggregators in this disease state would promote further thrombus formation with the transfused platelets.Despite the absence of systematic studies of this issue, based on anecdotal reports of poor outcome following platelet transfusion and the observation that the rapid recovery of platelet counts after plasma exchange therapy has been followed by sudden death, it is common practice to avoid giving platelet transfusions to patients with TTP.Although treatment is successful in most patients with idiopathic TTP, 37% to 68% have at least 1 relapse.Most relapses occur within 30 days of diagnosis, but first relapses have occurred 8 years after the original episode. In this series of 13, only 1 patient (patient 1) relapsed, and this occurred at 14 and 32 days of the illness. With continued plasma exchange, corticosteroid, and vincristine therapy, a sustained resolution of TTP was achieved after 51 days. No patients were readministered ticlopidine. The low relapse rate supports the contention that ticlopidine was the inciting agent for TTP in these patients. Once the offending drug is discontinued and appropriate therapy instituted, recurrent disease should be unlikely.The pathological lesions seen in TTP consist of diffuse platelet microthrombi partially occluding the vascular lumen of arterioles and capillaries with overlying proliferative endothelium. Ultralarge multimers of von Willebrand factor (vWF) are released into the circulation by damage to endothelial cells. These ultralarge vWF multimers increase platelet adhesiveness in vitro and may be one of the platelet-aggregating agents responsible for the platelet microthrombi that characterize TTP in vivo.It is thought that ultralarge vWF multimers are normally proteolytically converted to the smaller forms usually found in the circulation. Deficiency in the activity of a specific protease that cleaves purified vWF has been reported in 4 patients with chronic relapsing TTP.In addition, 1 patient described in the literaturehad TTP associated with deficient activity of the vWF-cleaving protease due to the presence of an IgG inhibitor in plasma. These observations suggest that a deficiency of the vWF-cleaving protease due to autoimmune or other mechanisms may predispose to TTP. Neither ultralarge vWF multimers nor vWF-cleaving protease activity has been measured in patients with ticlopidine-associated TTP. However, presuming that TTP is an end result of varied insults to the vascular endothelium, ticlopidine may directly or indirectly damage endothelial cells, leading to the release into the circulation of ultralarge vWF multimers that, in susceptible persons (eg, those with a deficiency of vWF-cleaving protease activity), are processed abnormally and so initiate intravascular platelet clumping. In vitro, ticlopidine has been shown to retard the adherence and growth of human endothelial cells and to alter endothelial cell structure.In addition, it inhibits fibronectin synthesis in endothelial cells, which impairs cell-to-cell adhesion and compromises cell-to-subendothelium interaction. This may also expose elements in vivo that promote platelet aggregation and thrombus formation. The mechanism for TTP associated with ticlopidine use is thought to be different from that of agranulocytosis associated with ticlopidine. In the latter instance, ticlopidine has a direct toxic effect on marrow cells in susceptible persons.Case reports of ticlopidine use associated with antinuclear antibody positivity, vasculitis, serum sickness, and immune thrombocytopenia also raise the possibility that ticlopidine use may predispose to vWF-cleaving protease deficiency by autoimmune mechanisms.The clinical indications for ticlopidine use are expanding, and thus, serious adverse effects such as TTP are being encountered more frequently. With discontinuation of the drug and prompt plasma exchange therapy, mortality is comparable to that seen with idiopathic TTP, and relapse is uncommon. 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C. Sutton, MD, FRCPC, Princess Margaret Hospital, 610 University Ave, Fifth Floor, Room 207, Toronto, Ontario, Canada M5G 2M9.

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 8, 1999

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