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 once therapy biopsy typically reveals absence of granulo begins, and immediately if fever or other evi cytic precursors1,5,14,17 possibly associated with dence of infection or neutropenia develops. aplasia or hypoplasia of platelet and red cell Treatment of ticlopidine-associated agranulo precursors when aplastic anemia is present.17 cytosis consists of discontinuing the drug, Treatment of ticlopidine-associated neutro excluding infection, administering empiric penia entails meticulous general supportive broad-spectrum antibiotics, and, as this case care, aggressive treatment with broad spec demonstrates, possible G-CSF therapy which trum antibiotics in the presence of fever, and may shorten the time to peripheral neutro discontinuation of the drug.1,6,10 Patients with phil recovery. pancytopenia have generally been treated with platelet and red cell transfusions in addition to prednisone and supportive care as men References tioned.10,12,16,20 In the case of drug-induced 1. Young NS. Agranulocytosis. JAMA 1994;271:935-8. agranulocytosis, the average time to neutrophil 2. Keeling RP. Non-neoplastic disorders of granulocytes recovery is approximately 12 days once the and monocytes. In: Thorup OA, ed. Fundamentals of Clinical Hematology. 5th ed. Philadelphia: WB Saun offending drug is discontinued.1 ders, 1987:424-59. Injection of G-CSF was utilized in a patient 3. Hass WK, Easton JD, Adams HP, et al. A randomized with pancytopenia owing to ticlopidine; how trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N ever, the patient died of severe pneumonopa- Engl J Med 1989;321:501-7. thy.14 Another patient with pancytopenia had 4. Schomig A, Neumann FJ, Kastrati A, et al. A random continued neutrophilic hypoplasia despite sev ized comparison of antiplatelet and anticoagulant eral weeks of therapy with G-CSF.5 The therapy after the placement of coronary artery stents. N Engl J Med 1996;334:1084-9. patient in this report had a brisk response in 5. Lesesve JF, Callat MP, Lenormand B, et al. Hemato her neutrophil count four days after commenc logical toxicity of ticlopidine. Am J Hematol 1994;47: ing G-CSF. Whether or not this response was 149-50. due to G-CSF is difficult to prove since ticlo 6 . Gardner FH. Ticlopidine induced neutropenia: rec ognition and management. Intern Med 1991;12:35- pidine was discontinued six days prior. How 41. ever, it is likely she did experience some ben 7. Marinella MA. Reversible hyperkalemia associated efit, since her neutrophil count increased with trimethoprim-sulfamethoxazole. Am J Med Sci significantly to non-neutropenic range after 1995;310:115-7. 8 . Gent M, Easton JD, Hachinski VC, et al. The Cana four days of treatment. It is interesting to note dian American ticlopidine study (CATS) in thrombo that the patient had a monocytosis upon pre embolic stroke. Lancet 1989;i: 1215-20. AGRANULOCYTOSIS AND TICLOPIDINE 421 9. Shear NH, Appel C. Prevention of ischemic stroke. N al., eds. Harrison’s Principles of Internal Medicine. Engl J Med 1995;333:460. 13th ed. New York: McGraw-Hill, 1994:572-83. 10. Gamier G, Taillan B, Pesce A, et al. Ticlopidine and 19. Ono K, Kurohara K, Yoshihara M, et al. Agranulocy severe aplastic anemia. Br J Haematol 1992;81:459- tosis caused by ticlopidine and its mechanism. Am J 60. Hematol 1991;37:239^12. 11. Guerciolini R, Giordano G, Aversa F, et al. Anaemia and agranulocytosis associated with ticlopidine 20. Quaglino D, Salladini G, Ricciotti M. Possible mecha therapy. Acta Haematol 1985;73:232-4. nism of action of ticlopidine on committed granulo 12. Troussard X, Mayo P, Mosquet B, et al. Ticlopidine cyte macrophage precursors. Haematologica 1984;69: and severe aplastic anaemia. Br J Haematol 1992;82: 257-62. 779-80. 21. Oh PI, Lanctot KL, Naranjo CA, et al. Fatal aplas 13. Martin-Nunez G, Fdez-Soria RR, Sanchez-Gil F, et tic anemia associated with ticlopidine therapy- al. Aplastic anaemia and ticlopidine. Br J Haematol approaches to an adverse drug reaction. Can J Clin 1993;85:633. Pharmacol 1995;2:19-22. 14. Khelif A, Assouline D, Ffrench M, et al. Ticlopidine 22. Marinella MA, Moseley RH. Hepatitis C and cancer and aplastic anaemia. Br J Haematol 1993;83:678-9. (letter). Ann Intern Med 1997;126:1002-3. 15. Haushofer A, Halbmayer WM, Pracher H. Neutrope nia with ticlopidine plus aspirin. Lancet 1997;349: 23. Marinella MA, Moseley RH. Chronic lymphocytic 474-5. leukemia complicating chronic hepatitis C infection. J 16. Bedani PL, Fiocchi O, Scapoli PL, et al. Leukopenia Clin Gastroenterol 1996;23:302. due to ticlopidine in a patient with chronic renal fail 24. Lichtman MA. Monocytosis and monocytopenia. ure. Haematologica 1984;69:641-2. In: Williams WJ, Beutler E, Erslev AJ, et al., eds. 17. Mataix R, Ojeda E, Perez MDC, et al. Ticlopidine and Hematology. 4th ed. New York: McGraw-Hill, severe aplastic anaemia. Br J Haematol 1992;80: 1990:882-5. 125-6. 25. Feldman AM, Pepine CJ, Bristow MR, et al. Inci 18. Finberg R. Infections in the immunocompromised dence of vesnarinone-induced neutropenia: the US host. In: Isselbacher KJ, Braunwald E, Wilson JD, et experience. Circulation 1993;88(suppl 2):I-301.
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