DRUG-INDUCED THROMBOCYTOPENIA

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DRUG-INDUCED THROMBOCYTOPENIA

• James N. George, M.D.
• EHA Working Group on Thrombocytopenias
• June 10, 2004

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Drug-Induced Thrombocytopenia

• Frequency is uncertain
• Frequency of medication use increases with age
• Frequency of alternative medicine use is
  increasing at all ages

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Drug-Induced Thrombocytopenia

• Often initially diagnosed as ITP
• Correct diagnosis is essential to
• avoid inappropriate treatment
• prevent recurrence

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Frequency of Drug-Induced Thrombocytopenia

• Sweden (1966-1970) 1.0/100,000/year
• Denmark (1968-1991) 1.0/100,000/year
• U.S. (1972-1991) 0.6/100,000/year
• U.S. (1983-1991) 1.8/100,000/year

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Frequency of Drug Use in Adults Ages 65 Years or
Older

• 1 medication/week 90
• 5 or more different medications/week 40
• 10 or more different medications/week 12
• JAMA 2002 287337

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Frequency of Complementary and Alternative
Medicine Use in the U.S.

• 199712.1 of U.S. adults had used an herbal
  medicine in the previous 12 months, compared to
  2.5 in 1990 (JAMA 1998 2801569)
• 2001 in U.S. 4.2 billion spent on herbs and
  botanical remedies (NEJM 2002 3472073)
• 443 Web sites market herbal products (JAMA 2003
  2901505)

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Drug-Induced Thrombocytopenia Initial Diagnosis
as ITP

• 343 patients registered as ITP, 1993-1999
• 28 (8) excluded because of subsequent diagnosis
  of drug-induced thrombocytopenia
• Quinine most common cause (13 of 28, 46)
• Neylon, Br J Haem 2003 122966

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Recurrent Acute ITP

• 68 yo man, ITP diagnosed in 1992, required
  splenectomy, complete response.
• January 1999 MI, CABG.
• 12-20-99 extensive purpura, severe epistaxis,
  plt 2000. DC all meds glucotrol, clonidine,
  HCTZ, aspirin, cayenne pepper pills, arthrx,
  quinine. Treat with IV steriod, IVIG.
• Plt ? 44,000 on 12-23 379,000 on 12-27.
• Home on prednisone, insulin
• J Okla State Med Assoc 2000 93519
• Calvins story. http//moon.ouhsc.edu/jgeorge

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Recurrent Acute ITP

• 12-28-99 recurrent severe bleeding, plt 5000,
  IVIG. Plt ? 302,000 on 1-3.
• 1-6-00 recurrent severe bleeding, plt 2000,
  IVIG, cytoxan. Plt ? 278 on 1-13.
• 1-15-00 recurrent severe bleeding, no platelet
  count. Bleeding resolved in 2 days.
• J Okla State Med Assoc 2000 93519
• Calvins story. http//moon.ouhsc.edu/jgeorge

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Quinine-Induced Thrombocytopenia
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Quinine-Induced Thrombocytopenia

• Report of 4 patients. Lancet July 8, 1865, p. 37
• Case 1. Mrs. C____, about 50 yo, suffering from
  neuralgia of the heart. Quinine disulphate, 2-3
  grains every 6 hours. On day 3, the body was
  covered with purple spots. Quinine discontinued.
  Several months later, again prescribed quinine
  for neuralgia of a dental nerve purpura
  appeared after several doses.

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Drug-Induced Thrombocytopenia Pathogenesis

• Drug-dependent antibodies to epitopes formed by
  drug binding to platelet surface GP
• Drug binding is weak, reversible
• Epitopes may be on GP, or drug GP
• Epitopes may be on multiple GPs
• Some epitopes common for multiple drugs

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Mechanism of Drug-Dependent Antibody Formation
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Epitopes for Drug-Dependent Platelet Antibodies

• GP Ib? (aa 283-293 Quinine
• GP IX (Arg110 , GIn115) Quinine,
  Ranitidine, Rifampin
• GP IIIa (aa 50-66) Quinine

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Drug-Induced Thrombocytopenia Platelet GP
IIb-IIIa Inhibitors

• May cause sudden severe thrombocytopenia with
  first exposure
• Sudden severe thrombocytopenia occurred in 1 of
  patients receiving abciximab in one recent study
  (10/1079 patients, NEJM 2004 350232)
• In studies of oral GP IIb-IIIa inhibitors,
  thrombocytopenia occurred in 5-13

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Development of Naturally Occurring Antibodies to
Platelet GP IIb-IIIa
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Prediction of Thrombocytopenia Caused by GP
IIb-IIIa Inhibitor, Roxifiban

• Thrombocytopenia occurred in 2 (8/386 patients)
  DDAb demonstrated in 5 of 6 patients
• Screen and exclude patients who had
  roxifiban-dependent antiplatelet antibodies
  before treatment with roxifiban (3.9)
• With screening, only 0.2 (2 of 1044) patients
  developed thrombocytopenia

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Criteria for Documentation of a Drug as the
Etiology of Thrombocytopenia

• Clinical criteria
• individual case reports
• randomized controlled clinical trials
• epidemiology
• Laboratory criteria
• demonstration of drug-dependent
• anti-platelet antibodies

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Flow Cytometry Detection of Drug-Dependent
Antibodies
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Limitations of Laboratory Detection of
Drug-Dependent Antibodies

• Different methods have different sensitivities
  for different drugs
• Distinction of positive and negative is
  empirical
• Drug may not be water soluble
• Etiology may be a metabolite

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Documentation of a Drug as the Cause of
Thrombocytopenia

• Randomized controlled clinical trials (GP
  IIb-IIIa blocking agents)
• Case control study (aspirin, dipyridamole)

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Documentation of a Drug as the Cause of
Thrombocytopenia

• Defined literature search strategy to identify
  individual case reports
• Rules for evaluable articles, patients
• Data extraction form
• Multiple independent reviewers
• Construct database for analysis
• Construct evidence table for publication
• Ann Int Med 1997 126376

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Drug-Induced Thrombocytopenia

• Case reports excluded
• age lt15 years
• not a licensed drug
• inappropriate use
• chemotherapy
• drug-induced systemic disease

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Clinical Criteria for Diagnosis of Drug-Induced
Thrombocytopenia
1. Drug preceded thrombocytopenia,

recovery complete and sustained 2. Drug
was only drug used or other
drugs continued/restarted 3. Other causes
excluded 4. Re-exposure resulted in recurrent
thrombocytopenia Level I (1-4)
II (1-3) III (1) IV (none)
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Evaluation of Drug-Induced Thrombocytopenia
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Drug-Induced Thrombocytopenia

• Results of literature searches
• 846 articles
• 1232 patient case reports
• 438 reports excluded
• 794 reports reviewed (187 drugs)

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Drug-Induced Thrombocytopenia

• Definite evidence (level I) 60 drugs
• 2 or more reports with probable evidence (level
  II) 25 additional drugs

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Drug-Induced Thrombocytopenia

• Full bibliography
• Complete database of drugs
• Regular updating
• Ann Int Med
• 129886, 1998
• 134346, 2001
• 138239, 2003
• http//moon.ouhsc.edu/jgeorge

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Jui (Chinese Herbal Remedy)-Induced
Thrombocytopenia

• 51 yo Japanese woman with minor purpura and
  platelet count 16,000/?L at a routine annual
  exam. Diagnosis, ITP
• Spontaneous recovery to 492,000/?L after 7 days.
  Additional history had taken Jui for several
  days before each annual exam for past 3 years
• Informed consent for re-challenge Jui supplied
  as a teabag, infused in 600 mL water. Platelet
  count 305,000?2000/?L in 3 hours with
  appearance of petechiae. Treated platelet
  transfusion, IVIG, prednisone
• Lancet 1999 354304

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Chinese Herb (Jui)-Induced Thrombocytopenia
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Tahini-Induced Thrombocytopenia

• 27 yo woman, diffuse petechiae, platelet count
  37,000/?L. Diagnosis, ITP. Recovered
  spontaneously, but fluctuated between
  30,000-180,000/?L over 3 mo.
• Platelet count 18,000/?L with purpura, begin
  prednisone. Platelets decreased to 6000/?L while
  on prednisone. Patient reported relation between
  eating tahini and thrombocytopenia.
• Abstain from tahini, platelet count ?161,000/?L.
  Challenge with tahini, platelet count ?34,000/?L
• Lancet 1998 352618

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Tahini-Induced Thrombocytopenia
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Oxaliplatin-Induced Thrombocytopenia

• 40 yo woman with metastatic colon cancer
  developed severe thrombocytopenia (platelets
  lt10,000/?L) following oxaliplatin, 5-FU,
  leukovorin. Recovery to normal platelet count in
  1 week.
• Oxaliplatin-dependent antibodies to platelet
  GP IIb-IIIa documented by flow cytometry and
  ELISA
• Blood 2003 102538a

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CONCLUSIONS

• Drug-induced thrombocytopenia may be more common
  than we think
• The frequency of drug-induced thrombocytopenia
  may be increasing
• Herbal remedies and foods may cause acute, severe
  thrombocytopenia