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Agranulocytosis Associated with Ticlopidine: a Possible Benefit with Filgastim* MARK A

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Agranulocytosis Associated with Ticlopidine: a Possible Benefit with Filgastim* MARK A ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 27, No. 6 Copyright © 1997, Institute for Clinical Science, Inc. Agranulocytosis Associated with Ticlopidine: A Possible Benefit with Filgastim* MARK A. MARINELLA, M.D. Department of Internal Medicine Wright State University School of Medicine, Dayton, OH 45409 ABSTRACT Ticlopidine is an oral antiplatelet agent frequently utilized in the treatment of cerebrovascular disease and is rarely associated with severe bone marrow suppres­ sion, typically aplastic anemia. Reports in the literature of isolated agranulocytosis are few, although they may be associated with significant morbidity and mortality. A case is reported of an elderly woman who developed febrile agranulocytosis several weeks after commencing ticlopidine but who had a favorable outcome after cessation of that drug and treatment with filgastrim. Introduction isolated agranulocytosis with fever but had normalization of her neutrophil count several Drug-induced neutropenia is a relatively days after cessation of ticlopidine and treat­ uncommon clinical occurrence which typically ment with filgastrim (G-CSF). resolves soon after the implicated drug is dis­ continued. Neutropenia may occur in the con­ Case Report text of aplastic anemia or as an isolated event.1 Agranulocytosis is typically defined as an abso­ An 82-year-old woman with a history of atrial fibrilla­ lute neutrophil count of less than 500 cells/ tion, diabetes mellitus, hypertension, and cerebrovascular disease was admitted to the hospital with a five day history mm3 and represents a true medical emergency of pyrexia, chills, and gingival ulcerations. Five weeks pre­ owing to an increased risk of infection.2 Ticlo­ viously, therapy with ticlopidine 250 mg twice daily was pidine is an anti-platelet drug recently intro­ commenced for drop-attacks presumably owing to poste­ rior circulation ischemia. Serial blood counts were not duced for the treatment of stroke, transient ordered upon discharge. ischemic attacks, and in the setting of intravas- Approximately five days prior to the current admission, cular coronary stents.3,4 Neutropenia occurs in she noted daily pyrexia to 103°F, associated with occa­ sional shaking chills. She complained of painful ulcerations approximately 0.8 to 1.0 percent of patients, over her upper and lower gingiva but denied headache, usually within the first three months of neck stiffness, cough, sputum production, abdominal pain, therapy, and typically resolves once the drug is diarrhea, dysuria, skin rash, or Joint swelling. Other medi­ cations included digoxin, glipizide, and dipyridamole; she discontinued.3,5 Most cases of severe neutro­ denied intake of any non-prescription drugs. There was no penia reported in the literature have occurred prior personal or family history of hematologic or collagen in the setting of aplastic anemia. A case is vascular disorders. She denied alcohol ingestion or previ­ ous blood transfusions. reported of an elderly woman who developed Physical examination revealed a temperature of 102.6°F, pulse 129, respirations 18, and blood pressure 132/76 mm/Hg. Significant physical findings included only * Send reprint requests to: Mark A. Marinella, M.D., 33 diffuse gingival ulcerations and irregular tachycardia. West Rahn Road, #201, Dayton, OH 45429. There was no pharyngeal exudate, cervical adenopathy, 418 0091-7370/97/1100-0418 $01.00 © Institute for Clinical Science, Inc. AGRANULOCYTOSIS AND TICLOPIDINE 419 hepatosplenomegaly, or petechiae. Complete blood count cultures are often sterile in the setting of revealed: leukocyte count 800 cells/mm3 with 0 percent neutrophils, 72 percent lymphocytes, and 28 percent ticlopidine-induced febrile neutropenia, but monocytes; haemoglobin 12.6 g/dl; platelets 393,000 on occasion they are positive, typically yield­ cells/mm3. ing gram-negative organisms.11,13,19 Fever Serum chemistries, liver function tests, coagulation studies, and urinalysis were normal as was a chest radio­ often resolves once the neutrophil count graph. Broad spectrum antimicrobial therapy with piper­ increases, as was noted in the case of the acillin and gentamicin was immediately instituted for patient reported. febrile neutropenia after blood and urine cultures were obtained. Ticlopidine was discontinued. On hospital day 2, As noted previously, ticlopidine-associated severe agranulocytosis persisted, and therapy with G-CSF neutropenia may occur in the setting of aplas­ (filgastrim) 300 meg daily subcutaneously was begun. By tic anemia,14,15 in conJunction with thrombo­ hospital day 7, the absolute neutrophil count was approxi­ mately 5,000 cells/mm3, and G-CSF was discontinued. cytopenia or anemia (bicytopenia),11,19 or as an Three sets of blood cultures and the urine culture isolated event;5,15,16 however, case reports are remained sterile. Antinuclear antibody was negative, and few. The etiology of ticlopidine-associated thyroid function studies were normal. Serology was nega­ tive for hepatitis B and parvovirus. There was evidence of neutropenia may be due to a direct toxic effect previous exposure to cytomegalovirus, Epstein-Barr virus, on myeloid precursors. Inhibition of bone and hepatitis C virus, although liver transaminases were marrow colony forming units in culture normal. The patient defervesced and felt symptomatically improved as well. She was discharged on all of her pre­ (CFU-C) has been demonstrated when ticlo­ hospital medications, with the exception of ticlopidine, pidine in concentrations similar to therapeutic with a normal white blood cell count. plasma levels is added to bone marrow cul­ tures.19,20 This toxicity may be due to local Discussion increases in prostaglandin El levels that occur with ticlopidine.17 Some patients may have Drug-induced neutropenia occurs in approxi­ an inborn sensitivity of marrow precursors mately 10 cases per 100 million persons annu­ to ticlopidine, perhaps predisposing them ally and has been associated with a myriad of to myelosuppression.20 agents, of which include captopril, cimetidine, Immunologic mechanisms have also been trimethoprim-sulfamethoxazole, phenothi- suggested.11,16,20 The formation of the reactive azines, and penicillins.6,7 Ticlopidine, a novel metabolites thiopene-S-oxides has been pro­ anti-platelet agent that inhibits adenosine posed as another mechanism of ticlopidine diphosphate induced platelet aggregation, has myelotoxicity, and patients with inability been associated with neutropenia in approxi­ to detoxify these metabolites may be at mately 1 percent of patients and typically an increased risk.21 Patients with renal fail­ occurs during the first three months of ure may be at increased risk for hematologic therapy.3,4,8,9 Neutropenia usually resolves toxicity since 30 percent of the drug is within several days upon cessation of the renally eliminated.16 drug,3,4 but it may take up to six weeks, usu­ Coexistent causes for neutropenia, such as ally in the setting of pancytopenia.5,10,11,12 overwhelming sepsis, viral infections, autoim­ Deaths owing to ticlopidine-induced bone mune disease, hematologic malignancy, and marrow suppression have been reported and other drugs, need to be excluded in all have usually occurred in the setting of aplas­ patients.1 This patient had no clinical evidence tic anemia.14,15 of infection other than pyrexia, had negative Fever is a common manifestation of ticlopi- cultures, and was continued on all of her other dine-induced neutropenia,5,10,13,14,15,16,17 and drugs with the exception of ticlopidine, with patients taking ticlopidine who develop fever resolution of neutropenia. However, antibod­ should have a complete blood count obtained ies to the hepatitis C virus were present to exclude myelosuppression. Febrile neutro­ (HCV), but there was no clinical or laboratory penia is a medical emergency, and patients evidence of active hepatitis. should receive empiric antimicrobial therapy A patient with antibodies to HCV without for coverage of skin and bowel flora.18 Blood apparent active infection, who developed 420 MARINELLA agranulocytosis with ticlopidine was previously sentation (28 percent). Monocytosis in the set­ reported,5 as was a patient with active HCV ting of agranulocytosis is felt to be a favorable infection and cirrhosis who died of complica­ indicator of impending neutrophil recovery.24 tions owing to aplastic anemia.13 The HCV has Hematopoietic growth factors such as G-CSF been associated with many extrahepatic mani­ and GM-CSF exert their effect directly on festations, including autoimmune phenomena bone marrow progenitor cells and are widely as well as abnormal lymphoid tissue prolifera­ used in patients undergoing chemotherapy tion.22,23 However, it is unclear whether or not and bone marrow transplantation.1 Some infection with HCV predisposes patients to series have shown a potential decrease in the neutropenia when taking ticlopidine. duration of drug-induced neutropenia with A bone marrow biopsy was not obtained in G-CSF by approximately three days, but this this patient owing to the temporal association remains to be established.1,25 of neutropenia with commencement of the In conclusion, agranulocytosis is a rare drug, no strong clinical evidence to implicate adverse effect of ticlopidine therapy, although an underlying infection or other disease pro­ it may be life-threatening if not aggressively cess, and rapid recovery of the neutrophil treated. All patients should have regular moni­ count after cessation of the drug. Bone marrow toring of their blood counts
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