Thrombocytopenia induced by quinine

Thrombocytopenia induced by quinine

oral medicine Editor: JAMES W. LITTLE, D.M.D., M.S.D. School of Dentistry University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 5545.5 Th...

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oral medicine Editor: JAMES W. LITTLE, D.M.D., M.S.D.

School of Dentistry University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 5545.5

Thrombocytopenia induced by quinine Anthony P. Barrett, B.D.S., Ph.D.,* Jonathan Tversky, B.D.S..** and Christopher J. Grifiths, B.D.S., D.P.H.(D),*** New South Wales, Australia WESTMEAD

CENTRE

DENTAL

CLINICAL

Occasional cases of quinine-induced of quinine-induced thrombocytopenia, leading to a definitive demonstration described.

SCHOOL

thrombocytopenia have been reported in the dental literature. A case seen first in a dental surgery office, is reported, and the procedure of the role of quinine in the induction of thrombocytopenia is

E

xcessive bleeding following tooth extraction in most casesrepresentsa local disturbance of hemostasis but may be an initial, often subtle, manifestation of an as yet undiagnosed disorder of the hematologic system. Spontaneous widespread oral mucosal bruising and bleeding, in the absence of any apparent predisposing trauma, should automatically alert the dental surgeon to investigate this possibility further. We are reporting a caseof drug-induced thrombocytopenia in which the patient first presented to a dental surgery office. The procedure leading to a definitive diagnosis of quinine-induced thrombocytopenia and the dental surgeon’s role in the early detection and management of this condition are discussed. CASE REPORT

A 71-year-old Anglo-Saxon woman presented to the Department of Assessment and Diagnosis at the Westmead Centre Dental Clinical School complaining of “blood blisters” in her mouth. She stated that she had awakened during the night 4 days earlier with the taste of blood and that she had also noticed progressiveskin bruising over the next 3 days. The skin bruising at the time of presentation was described as “multiplying by the minute.” *Staff Specialist (Oral Diagnosis), Department of Assessment and Diagnosis. **Dental Officer. ***Director, Department of Assessmentand Diagnosis.

The patient’s medical background revealed a 20-year history of asthma and chronic bronchitis and a long, ill-defined history of osteoarthritis. She reported her current medications as salbutamol and beclomethasonedipropionate aerosol inhalations as required and theophylline, 200 mg, betamethasone,0.25 mg., and ibuprofen, 200 mg., three times daily. In addition, the patient reported that she had taken tetracycline hydrochloride, 250 mg. every 6 hours, for 7 days prior to presentation. The past medical history was otherwise unremarkable. The patient had no known allergies. She did not smoke,and she consumedonly occasional modest amounts of alcohol. There was no previous personal or family history of excessiveor spontaneous oral or skin bruising or bleeding. A systemsreview did not reveal chest pain or orthopnea. Dyspnea on exertion was relieved by salbutamol and beclomethasone dipropionate inhalation. There had been no recent hemoptysis, epistaxis, hematuria, visual changes, rigors, excessivefatigue or anorexia, bone pain, or weight loss. She did, however, report minima1 rectal blood loss over the previous 3 days, characterized by “spots of blood” in the feces. There was no history of hemorrhoids. Extraoral examination revealed a 7 l-year-old woman in acute distress. The skin over the trunk, limbs, face, and neck exhibited ecchymotic and petechial hemorrhages (Fig. 1). There was no detectable lymphadenopathy, hepatosplenomegaly, respiratory distress, sternal pain, fundal hemorrhage, raised jugulovenous pressure,heart murmurs, or nail clubbing. The patient was oriented as to time and place and was afebrile; the cranial nerves were grossly intact, the reflexes were normal, and the pulse rate was 70 beats per minute. 351

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mas, metastatic disease, leukemia, or lymphomatous deposits was not observed. Serum chemistry revealed only a marginal elevation of blood urea; testing for rheumatoid factor was negative; blood was not detected in the urine or feces; and viral and bacteriologic analyses of urine, feces, and oropharyngeal washings were unremarkable. On admission the patient received 10 units of platelets and was started on 60 mg. of prednisone daily. After 48 hours the platelet count had risen to 24,000 per cubic millimeter, and extraoral and intraoral examination revealed no evidence of continued formation of ecchymoses,hemorrhagic bullae, or petechiae. Early resolution of the oral lesions was apparent. Evidence of quinineinduced antiplatelet antibody in the patient’s serum was obtained by an in vitro platelet suspensionimmunofluorescence assay,’ thus establishing a definitive diagnosis of quinine-induced thrombocytopenia. By the fifth day after admission the platelet count had risen to 314,000 per cubic millimeter with no evidence of new extraoral or intraoral purpura. The intraoral lesions had virtually resolved. The patient was discharged on the sixth day and was reviewed as an outpatient with tapering dosesof prednisone. Six months after the first presentation there had been no evidence of renewed thrombocytopenia after cessation of quinine. DISCUSSION Fig.

1. A large ecchymosis on the right arm of the

patient. Intraoral examination revealed multiple intact, as well as ruptured, hemorrhagic bullae and petechiae involving the lip, tongue, and buccal and palatal mucosae (Fig. 2). There was also evidence of spontaneousgingival bleeding. Blood was obtained for a complete blood examination, but at this stage skin bleeding time was not determined and blood pressure was not recorded becauseof the apparent tendency toward excessive hemorrhage. The patient was referred without delay to a hematologist, with a provisional diagnosis of thrombocytopenia secondary to drug ingestion or acute leukemia. She was admitted immediately to the hospital and all medication was ceased. Repeated questioning revealed that the patient had previously omitted to include quinine bisulfate, 300 mg. three times daily, in her list of current medications, despite having taken it intermittently over a 15year period for muscle cramps. She had stopped taking this drug 1 month before and had recommenced 7 days prior to presentation. The complete blood examination revealed a peripheral white blood cell count of 2,800 per cubic millimeter, with a normal distribution of cell types and no blast cells present. Platelets were not observed on the stained blood film examined. The hemoglobin level was 13.2 Cm. per deciliter and the platelet count was 9,000 per cubic millimeter. Bone marrow biopsy revealed a relatively hypocellular marrow, although erythroid, granulocyte, and megakaryocyte cell types were all represented. Evidence of granulo-

Drugs may induce thrombocytopenia at two levels: (1) by reducing platelet production becauseof direct marrow toxicity and (2) by increased platelet destruction in the peripheral blood. Destruction of platelets in the peripheral blood is the most commonly observed mechanism of druginduced thrombocytopenia, in the absenceof accompanying depression of the erythroid and leukocyte cell series. Selective megakaryocyte toxicity is rare, although it may occur with certain drugs and in persons with systemic lupus erythematosus.* When thrombocytopenia results from drug-induced marrow toxicity, it is usually part of a pancytopenia, as seen in chemotherapeutic protocols employed in the management of leukemias. The dental surgeon should be aware of the possibility that a patient may exhibit evidence of a probable drug-induced thrombocytopenia having an underlying hematopoietic pancytopenia with its potential for greater morbidity and mortality. The need for close liaison with the hematologist and for prompt referral of such patients to him is emphasized.Bottiger and Westerholm3reported only two deaths directly attributable to thrombocytopenia alone in their analysis of 126 casesof drug-induced thrombocytopenia. However, this does not condone a delay in referring such patients to the hematologist, as immediate cessation of the suspected causative agent and early initiation of supportive measures,

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including platelet transfusions as required, are essential. In addition to this, peripheral blood examination and bone marrow biopsy are important in eliminating the possibility of the thrombocytopenia being part of an accompanying hematopoietic pancytopenia or part of a previously undeclared malignancy involving the bone marrow. Recovery of normal platelet levels is characteristically rapid in uncomplicated drug-induced thrombocytopenia, as this case illustrates, after cessation of the offending drug; however, it may persist in some cases.3’4 Quinine has long been recognized as capable of inducing thrombocytopenia.s Both quinine and its dextrorotatory stereo-isomer quinidine have received ongoing attention in the medical and dental literature as causes of thrombocytopenia,6-” and many drugs have since been identified as capable of inducing this condition.3*5”Z”3 The clinician should be aware of the diversity of these drugs and the possibility of detecting thrombocytopenia induced by drugs not previously suspected of being capable of initiating this response. The immune mechanisms involved in druginduced thrombocytopenia have been the subject of much research. Two hypotheses have predominated. One proposes that antibody is produced in response to an antigen, made up of the drug and its binding site on the platelets, and that platelet destruction occurs as a direct result of antibody binding to this antigenic site.I2 Another proposesthat the drug acts as a hapten and, by binding to a plasma protein, induces antibody formation which binds to the drug and the complex is passively absorbed onto the platelet, the destruction of which is facilitated by reticulohistiocytic phagocytosis.‘4*I5 The latter is the so-called “innocent bystander” theory. Until recent times the latter theory was held by many.5 However, recent experience has given considerable support to the former.‘6-‘8The development of a number of in vitro techniques has made it possible not only to study the mechanisms of drug-induced thrombocytopenia but also to provide definitive evidence of a drug’s role in promoting clinically detectable immune reactions and its specificity for one or more cell lines, without the need to risk rechallenging the patient with the drug. It is of considerable importance to the clinician that these techniques have been employed, as seen in the present case, to demonstrate that drugs, such as quinidine, may induce thrombocytopenia by activity at both the marrow and the peripheral blood levels and may at the same time involve the erythroid and/or granulocytic cell lines.4*I9 It is the experience of one of us (A.P.B.), in the

Thrombocytopenia induced by quinine

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Fig. 2. Multiple hemorrhagic bullae and petechiae on the left buccal mucosa and dorsal surface of the tongue.

management of leukemic patients, that oral purpuras-intra-oral petechiae followed by hemorrhagic bullae-are accurate indicators of an impending thrombocytopenic crisis and may herald the appearance of skin purpura and hemorrhage from other sites by several days, if the progressive decline in platelet numbers is gradual. In the present case the progression of the thrombocytopenia was rapid, although the patient did report the appearance of oral hemorrhagic bullae immediately prior to skin bruising. The dental surgeon may therefore detect such an impending crisis by its pattern of intraoral manifestations and facilitate the early diagnosis and management of the condition, This case also illustrates the need to question patients carefully, often repeatedly, concerning their drug intake if thrombocytopenia is suspected. Patients may fail to mention drugs used intermittently, as quinine may be in the management of episodes of muscle cramping, particularly if their lists of current medications are extensive. This can lead to a delay in recognizing the agent responsible. Finally, quinine-induced thrombocytopenia may be overlooked if the clinician is unaware of its inclusion in other substancesapart from its recognized medicinal form. Casesof thrombocytopenia have been reported in which quinine was the causative factor but was not immediately identified because of the vehicle in which it was contained; examples reported include beverages,such as tonic water and gin20 and “streetsold” heroin.*’ The authors wish to thank Dr. T. Robertson, consultant physician to the Westmead Centre, for his permission to report this patient.

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REFERENCES I. Von dem Borne, A. E. G. Jr., Verheught, F. W. A., Oosterhof, F., van Riesz. E., de la Riviere, A. B., and Engelfriet, C. P.: A Simple lmmunofluorescence Test for the De&ion of Platelet Antibodies, Br. J. Haematol. 39: 195-206, 1978. 2. Griner, P. F., and Hoyer, L. W.: Amegakaryocytic Thrombocytopenia in Systemic Lupus Erythematosus, Arch. Intern. Med. 125: 328-332, 1970. 3. Bottiger, L. E., and Westerholm, B.: Thrombocytopenia. II. Drug-Induced Thrombocytopenia, Acta Med. Stand. 191: 541-548, 1972. 4. Kelton, J. G., Huang, A. T., Mold, N., Logue, G., and Rosse, W. F.: The Use of In Vitro Technics to Study Drug-Induced Pancytopenia, N. Engl. J. Med. 301: 621-624, 1979. 5. Moss, R. A.: Drug-Induced Immune Thrombocytopcnia, Am. J. Hematol. 9: 439-446, 1980. 6. Kissmeyer-Nielson, F.: Thrombocytopenic Purpura Following Quinine Medication: An Immunological Study, Acta Med. Stand. 154: 289-298, 1956. 7. Levine, S.: Thrombocytopenic Purpura Due to Quinine With Oral Symptoms, ORAL SURG 12: 692-695, 1959. 8. Helmly, R. B., Bergin, J. J., and Shulman, N. R.: QuinineInduced Thrombocytopenia: Observation on Antibody Titers, Arch. Intern. Med. 120: 59-62, 1967. 9. Rennie, T.. Freilich, R., Kotkis, S. J., and Catania, A.: Sequelae of Dental Extraction During Quinine-Induced Thrombocytopenia, J. Oral Surg. 34: 272-275, 1976. IO. Cohen, 1. S., Jick, H., and Cohen, S. I.: Adverse Reactions to Quinidine in Hospitalized Patients: Findings Based on Data From the Boston Collaborative Drug Surveillance Program, Prog. Cardiovasc. Dis., 20: I5 I - 163, 1977. 1 I. Clark, M. J., Redford, D. S., Baddour, H. M., and Tilson, H. B.: Quinidine-Induced Thrombocytopenia, ORAL SURG 51: 478-480, I98 I. 12. Ackroyd, J. F.: Allergic Purpura, Including Purpura Due to Foods. Drugs and Infections, Am. J. Med. 14: 605-632, 1953. 13. de Gruchy, G. C.: Drug-Induced Blood Disorders, Melbourne, 1975, Blackwell Scientific Publications, p. 124.

Oral Surg. April. I983 14. Miescher, P. A.: Drug-Induced Thrombocytopenia, Semin. Hematol. 10: 31 l-325, 1973. 15. Shulman, N. R.: Immunoreactions Involving Platelets, 1. A. Steric and Kinetic Model for Formation of a Complex From a Human Antibody, Quinidine as a Haptene, and Platelets, and for Fixation of Complement by the Complex, J. Exp. Med. 107: 665-690, 1958. 16. Kunicki, T. J., Johnson, M. M., and Aster, R. H.: Absence of the Platelet Receptor for Drug-Dependent Antibodies in the Bernard-Soulier Syndrome, J. Clin. Invest. 62: 716-719, 1978. 17. Hosseinzadeh, P. K., Firkin, B. G., and Pfueller, S. L.: Study of the Factors That Cause Specific Transformation in Cultures of Lymphocytes From Patients With Quinine- and Quinidine-Induced Immune Thrombocytopenia, J, Clin. Invest. 66: 638-645, 1980. 18. Pfueller, S. L., Hosseinzadeh, P. K., and Firkin, B. G.: Quinine- and Quinidine-Dependent Antiplatelet Antibodies, J. Clin. Invest. 67: 907-910, 1981. 19. Zeigler, Z., Shadduck, R. K., Winkelstein, A., and Stroupe, T. K.: Immune Hemolytic Anemia and Thrombocytopenia Secondarv to Ouinidine: In Vitro Studies of the OuinidineDependent Red Cell and Platelet Antibodies, Blood 53: 396-402, 1979. 20. Belkin, G. A.: Cocktail Purpura: An Unusual Case of Quinine Sensitivity, Ann. Intern. Med. 66: 583-586, 1967. 21. Kraut, R. A., and Buhler, J. E.: Heroin-Induced Thrombocytopenic Purpura, ORAL SURC. 46: 637-640, 1978.

Reprint requests to. Dr. Anthony P. Barrett Department of Assessment and Diagnosis Westmead Centre Dental Clinical School Westmead, New South Wales 2145, Australia