Case ReportAzithromycin-Induced Thrombocytopenia: A Rare Etiology ofDrug-Induced Immune Thrombocytopenia

Muhammad Umer Butt ,1 Ahmad Jabri ,2 and Samy Claude Elayi3

1Cardiology Department, Case Western Reserve University/MetroHealth Medical Center, Cleveland, OH, USA2Internal Medicine Department, Akron General Cleveland Clinic, Akron, OH, USA3Cardiac Electrophysiology Department, University of Florida Jacksonville Medical Center, Jacksonville, FL, USA

Correspondence should be addressed to Ahmad Jabri; ahmad.jabri1@hotmail.com

Received 5 April 2019; Revised 16 May 2019; Accepted 23 June 2019; Published 8 July 2019

Academic Editor: Walter Zidek

Copyright © 2019MuhammadUmer Butt et al.,is is an open access article distributed under the Creative CommonsAttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Drug-induced thrombocytopenia requires a high suspicion for diagnosis and a broad investigation to exclude other etiologies oflow platelets. Cessation of the offending agent often results in recovery of platelet counts. Many medications are known to cause adegree of thrombocytopenia. We present a rare case of severe thrombocytopenia associated with administration of azithromycin.

1. Introduction

Medications that may cause thrombocytopenia continueto be identified in the literature. Drug-induced throm-bocytopenia can result in severe, progressive reductionsin platelet counts with resultant sequelae of bleeding[1–3]. In order to associate thrombocytopenia with amedication, recent exposure to the medication shouldbe documented in addition to an investigation exclud-ing all other causes of thrombocytopenia. Identificationof drug-induced thrombocytopenia is important as thecondition is reversible upon discontinuing the medicine[4, 5]. We present a rare case of azithromycin causingthrombocytopenia.

2. Case Presentation

A 25-year-old African American woman presented to theemergency department with a chief complaint of generalizednonpruritic maculopapular rash. ,e rash was initiallyconfined to the right antecubital fossa but spread diffuselyacross the entire body over the course of 2 days. ,e patienthad no other complaints and was otherwise in her usual stateof health. ,e patient had started taking azithromycin 5 daysprior to admission for a tooth extraction. She was not taking

any other medication. ,ere was no history of any recentillnesses or sick contacts. Vitals were within normal limits.Skin examination was significant for generalized petechiaeand ecchymoses sparing her head and face. ,e patient didnot have signs or symptoms of major bleeding.

Laboratory workup upon admission revealed an iso-lated thrombocytopenia with a platelet level of 2,000/μL(normal range: 150–400 K/µL). Repeat platelet count was3,000/μL, and the same value resulted when using a citratedtube. ,e hemoglobin was within the normal range at12.3mg/dl (normal range: 12.0 to 15.5 g/dL). Prothrombintime was increased with an elevated INR. A positive ANAand elevated ESR were found. Quantitative c-ANCA,p-ANCA, C3 Level, C4 Level, lupus anticoagulant, anddsDNA antibodies were measured and found to be withinnormal limits. Viral serology for hepatitis, HIV, CMV, andEBV was negative. Blood culture was negative for bacterialinfection. A blood smear was performed and ruled outdrug-induced thrombotic microangiopathy. Bone marrowcore biopsy and aspirate smears showed increased mega-karyocytes, myeloid cell hyperplasia, and left-shifted my-eloid maturation. ,ere were no sideroblasts or increase ofblasts, lymphocytes, or plasma cells. Flow cytometry ofbone marrow revealed no significant immunophenotypicabnormalities.

HindawiCase Reports in MedicineVolume 2019, Article ID 6109831, 3 pageshttps://doi.org/10.1155/2019/6109831

Azithromycin was discontinued. Dexamethasone 40mgIV daily and intravenous immunoglobulin (IVIG) therapywere administered. Platelet counts improved to 17,000/μLover the following 10 days. Gradually, over three months,platelet counts returned within the normal range. Drug-dependent anti-platelet antibody testing was not doneduring admission as the patient’s platelet count began toslowly improve after stopping the azithromycin.

3. Discussion

Drug-induced immune thrombocytopenia is attributed todecreased platelet production secondary to myelosup-pression or accelerated platelet destruction secondary to animmune response [1]. Drug-induced thrombocytopenia canpresent with asymptomatic thrombocytopenia, hemolytic-uremic syndrome (HUS), or thrombotic thrombocytopeniapurpura (TTP) in extreme cases [2]. Drug-inducedthrombocytopenia results in severely decreased plateletcounts, often less than 20,000/μL [3]. In most circumstances,a week’s duration is often needed for the offending drug toinduce thrombocytopenia. Discontinuing the medicationcan result in resolution of thrombocytopenia in as little as4–8 days, although less commonly within weeks. [2].

It is quite challenging to establish the temporal asso-ciation of thrombocytopenia and administration ofmedication especially when a patient is taking multiplemedications. Clinical criteria were developed by Hackettet al. for the diagnosis of drug-induced thrombocytopeniawhich includes (1) thrombocytopenia occurring after drugusage and discontinuing the drug results in resolution ofthrombocytopenia, (2) all possible causes of thrombocy-topenia were excluded, (3) no other drug was started priorto the thrombocytopenia or other medications except forthe offending drug were continued with no effect on theplatelet count, and (4) reexposure of the offending drugresults in recurrence of thrombocytopenia [4]. Meeting allfour criteria makes the diagnosis of drug-inducedthrombocytopenia definite. When criteria 1, 2, and 3 aremet, as in our case, drug-induced thrombocytopenia isconsidered probable. Meeting criteria 1 suggests possiblediagnosis of drug-induced thrombocytopenia [4]. ,ediagnosis is clinical and usually based upon thoroughtesting that rules out other causes of thrombocytopeniaincluding hypersplenism, lymphoproliferative disorders,infections, mononucleosis, and autoimmune disorders anddocumenting resolution of symptoms after discontinua-tion of the suspected medication. Recurrent thrombocy-topenia after reexposure to medication further supportsthe diagnosis [4, 5]. Platelet-reactive antibody testing canbe used to assist in diagnosis; however, this testing islimited by availability and an uncertain sensitivity [2]. ,emanagement of drug-induced thrombocytopenia relies onfirst stopping the offending agent and then managingsymptoms of bleeding. Platelet transfusions are initiated inpresence of apparent hemorrhage [2, 6]. Since idiopathicthrombocytopenic purpura (ITP) is often hard to exclude,corticosteroids and/or IVIG are often initiated [3].However, no benefit has been associated with immune

suppression using corticosteroids in drug-inducedthrombocytopenia [2].

We presented a rare case of azithromycin-inducedthrombocytopenia. While macrolide-induced thrombocyto-penia has been reported with clarithromycin [7, 8], it has beenrarely reported with azithromycin. [9] In the reported case byAzharuddin et al., the azithromycin-induced thrombocyto-penia resolved within three days despite the 48–72 hour half-life of azithromycin [9]. Our case has a prolonged course ofthrombocytopenia that is not explained by the half-life ofazithromycin. It was previously postulated that patientsproduce drug-dependent and drug-independent antibodiesafter exposure to an offending medication [10, 11]. Drug-independent antibodies, also known as autoantibodies, aremost often transient; however, they can persist for a longperiod of time. ,is may have contributed to the prolongedrecovery phase for our patient [12]. Since the risk of drug-induced thrombocytopenia is low when starting new medi-cation, excluding other causes of thrombocytopenia is nec-essary [2]. However, given the extensive list of drugsimplicated, physicians should have high suspicion when apatient presents with severe, isolated thrombocytopeniawithin two weeks of a new drug exposure [13].

4. Conclusion

Drug-induced thrombocytopenia is a clinical diagnosis afterexclusion of other etiologies of thrombocytopenia. Azi-thromycin is a rare cause of severe thrombocytopenia thathas been highlighted in our case. Our patient experiencedresolution of thrombocytopenia after stopping azi-thromycin, although she had a delayed recovery time.

Conflicts of Interest

,e authors declare that there are no conflicts of interestregarding the publication of this paper.

References

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[3] J. N. George and R. H. Aster, “Drug-induced thrombocyto-penia: pathogenesis, evaluation, and management,” Hema-tology, vol. 2009, no. 1, pp. 153–158, 2009.

[4] J. N. George, G. E. Raskob, S. R. Shah et al., “Drug-inducedthrombocytopenia: a systematic review of published casereports,” Annals of internal medicine, vol. 129, no. 11,pp. 886–890, 1998.

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[6] T. J. Coker, “Drug-induced immune thrombocytopenia due tomoxifloxacin,” BMJ Case Reports, vol. 2013, Article IDbcr2012007501, 2013.

2 Case Reports in Medicine

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[8] J. A. Oteo, R. A. Gomez-Cadinanos, L. Rosel, and J. M. Casas,“Clarithromycin-induced thrombocytopenic purpura,” Clin-ical Infectious Diseases, vol. 19, no. 6, pp. 1170-1171, 1994.

[9] M. Azharuddin, L. B. Munshi, R. Raj, and P. C. Lee, “Azi-thromycin-induced severe thrombocytopenia: a rare entity,”Open Journal of Clinical and Medical Case Reports, vol. 3,no. 20, 2017.

[10] W. Lerner, R. Caruso, D. Faig, and S. Karpatkin, “Drug-de-pendent and non-drug-dependent antiplatelet antibody indrug-induced immunologic thrombocytopenic purpura,”Blood, vol. 66, no. 2, pp. 306–311, 1985.

[11] R. H. Aster, “Can drugs cause autoimmune thrombocytopenicpurpura?,” Seminars in Hematology, vol. 37, no. 3, pp. 229–238, 2000.

[12] R. H. Aster, “Drug-induced immune cytopenias,” Toxicology,vol. 209, no. 2, pp. 149–153, 2005.

[13] J. A. Reese, X. Li, M. Hauben et al., “Identifying drugs thatcause acute thrombocytopenia: an analysis using 3 distinctmethods,” Blood, vol. 116, no. 12, pp. 2127–2133, 2010.

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