Correspondence

Drug-Induced Immune Thrombocytopenia

N Engl J Med 2007; 357:1869-1871November 1, 2007

Article

To the Editor:

In their review of drug-induced immune thrombocytopenia, Aster and Bougie (Aug. 9 issue)1 do not mention an important aspect of drug-induced thrombocytopenia–thrombosis. Glycoprotein IIb/IIIa inhibitors (both oral and intravenous formulations) and bivalirudin are known to cause both significant thrombocytopenia and thrombosis (myocardial infarction and stroke) and are associated with increased mortality.2-4 Bivalirudin, a direct thrombin inhibitor increasingly used in the United States for percutaneous coronary interventions (PCI), has been found to induce severe thrombocytopenia (<50,000 platelets per cubic millimeter) in 0.3% of patients undergoing PCI, moderate thrombocytopenia (<100,000 platelets per cubic millimeter) in 2.9% of such patients, and mild thrombocytopenia (<150,000 platelets per cubic millimeter) in more than 9.9%.4,5 Glycoprotein IIb/IIIa inhibitors induce drug-dependent antibodies that result in platelet activation, causing thrombotic complications.6 Since the observed thrombosis is predominantly arterial (stroke and myocardial infarction) rather than venous, this adverse effect is often overlooked. It is a paradox that bivalirudin, a drug that is used to treat drug-induced thrombocytopenia (heparin-induced thrombocytopenia and thrombosis), is now a leading cause of drug-induced thrombocytopenia.

Harris V.K. Naina, M.B., B.S.
Samar Harris, M.B., B.S.
Mayo Clinic College of Medicine, Rochester, MN 55905
naina.harris@mayo.edu

6 References

1
Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580-587
Full Text | Web of Science | Medline

2
Scirica BM, Cannon CP, Cooper R, et al. Drug-induced thrombocytopenia and thrombosis: evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes (OPUS-TIMI 16) trial. J Thromb Thrombolysis 2006;22:95-102
CrossRef | Web of Science | Medline

3
McClure MW, Berkowitz SD, Sparapani R, et al. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome: the platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial experience. Circulation 1999;99:2892-2900
Web of Science | Medline

4
Stone GW. Timing of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2007;298:37-38
CrossRef | Web of Science

5
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216
Full Text | Web of Science | Medline

6
Dunkley S, Evans S, Gaudry L, Jepson N. Two distinct subgroups of tirofiban-induced thrombocytopenia exist due to drug dependent antibodies that cause platelet activation and increased ischaemic events. Platelets 2005;16:462-468
CrossRef | Web of Science | Medline

To the Editor:

At our institution, my colleagues and I see many patients with acute and chronic immune thrombocytopenia, and there is always the question of drug-induced thrombocytopenia. Many patients with chronic immune thrombocytopenia are convinced that their disease has been triggered by medications, even when the suspected drug has been stopped long ago. Could the authors comment on which drugs have been reported to cause a clinical picture similar to chronic immune thrombocytopenia? One case of prolonged thrombocytopenia (2 years' duration) after treatment with trimethoprim–sulfamethoxazole has been reported.1 Have chronic thrombocytopenias that persisted after the medication was stopped been reported for any other drugs?

Axel C. Matzdorff, M.D., Ph.D.
Caritasklinik St. Theresia, 66113 Saarbruecken, Germany
a.matzdorff@caritasklinik.de

1 References

1
Aster RH. Can drugs cause autoimmune thrombocytopenic purpura? Semin Hematol 2000;37:229-238
CrossRef | Web of Science | Medline

To the Editor:

The review of drug-induced thrombocytopenia lists new targeted monoclonal antibodies — namely, abciximab and rituximab — among agents associated with the disorder. We report a case of severe thrombocytopenia (3000 platelets per cubic millimeter) 4 days after the first administration of trastuzumab monotherapy.

A 54-year-old woman received a diagnosis of breast cancer metastatic to bone and mediastinal lymph nodes 7 years after the initial diagnosis. Tests for steroid hormone receptors were negative; HER2 was amplified (as determined by fluorescence in situ hybridization analysis). Treatment with trastuzumab alone, at a dose of 8 mg per kilogram of body weight (400 mg), was started as part of a randomized clinical trial, with a planned schedule of administration every 3 weeks. The platelet count was normal at the start of treatment (159,000 per cubic millimeter). Ibandronate was also administered the same day; a single dose of dipyrone for acute low back pain was given on the next day. Four days after the trastuzumab infusion, a prolonged nosebleed occurred and generalized petechiae were observed. The platelet count was 3000 per cubic millimeter, with a normal hemoglobin value and leukocyte count. Coagulation values were normal. A platelet factor 4–antibody test for heparin-induced thrombocytopenia was negative (the patient had been treated with low-molecular-weight heparin until 3 weeks earlier). Treatment with prednisone (50 mg per day for 3 days) was not successful; therefore, high-dose methylprednisolone (1 g given intravenously for 3 days) and immune globulin (0.4 g per kilogram given intravenously for 5 days) were administered.1 The platelet count increased to 113,000 per cubic millimeter within 7 days and was normal thereafter, during and after the tapering of corticosteroids. The patient was reexposed to ibandronate and dipyrone, without a change in the platelet count. Trastuzumab has not been administered since then. A bone marrow biopsy showed normal megakaryocytopoiesis and no sign of cancer. A computed tomographic scan revealed a marked reduction in the size of the lymph nodes after the single dose of trastuzumab and a few weeks of corticosteroid treatment.

Trastuzumab, the humanized monoclonal antibody against the HER2 receptor, has not been associated with severe thrombocytopenia.2-5 Myelosuppression is rare and generally mild.3,4 The mechanism by which monoclonal antibodies can induce severe thrombocytopenia remains largely unclear. On the basis of our observation, trastuzumab should be added to the list of monoclonal antibodies that potentially induce thrombocytopenia.

Richard Cathomas, M.D.
Kantonsspital Graubünden, CH-7000 Chur, Switzerland
richard.cathomas@ksgr.ch

Aron Goldhirsch, M.D.
European Institute of Oncology, I-20141 Milan, Italy

Roger von Moos, M.D.
Kantonsspital Graubünden, CH-7000 Chur, Switzerland

5 References

1
Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995-1008
Full Text | Web of Science | Medline

2
Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580-587
Full Text | Web of Science | Medline

3
Baselga J, Carbonell X, Castaneda-Soto NJ, et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 2005;23:2162-2171
CrossRef | Web of Science | Medline

4
Hudis CA. Trastuzumab -- mechanism of action and use in clinical practice. N Engl J Med 2007;357:39-51
Full Text | Web of Science | Medline

5
George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 1998;129:886-890
Web of Science | Medline

Author/Editor Response

Naina and Harris state that glycoprotein IIb/IIIa inhibitors and bivalirudin “cause both significant thrombocytopenia and thrombosis” and suggest that we should have mentioned this point in our review. In fact, Table 1 and Table 3 and the Discussion section of our article note that glycoprotein IIb/IIIa inhibitors are an important cause of immune thrombocytopenia. It is true that several reports, including one with which we were associated,1 suggest that treatment with fiban-type glycoprotein IIb/IIIa inhibitors may increase the risk of thrombosis. However, there is as yet no consensus on this point. Naina and Harris cite a report from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) study2 to support their contention that bivalirudin is a common cause of thrombocytopenia. In that study, thrombocytopenia (defined as a platelet count of less than 150,000 per cubic millimeter) developed in about 11% of patients given bivalirudin. However, the incidence of this complication in patients given bivalirudin was not different from that in control patients given alternative antithrombotic agents. We are unaware of any reports claiming a direct cause-and-effect relationship between the administration of bivalirudin and thrombocytopenia.

Matzdorff notes that patients with idiopathic (autoimmune) thrombocytopenia sometimes question whether a drug may have caused their disease and asks that we comment on drugs reported to cause a clinical picture similar to autoimmune thrombocytopenia. In our review, we note that autoimmune thrombocytopenia develops in about 1% of patients treated with injection of gold salts, and we mention procainamide, sulfamethoxazole, and interferons alfa and beta as having been implicated as triggers for autoimmune thrombocytopenia in anecdotal reports. We also note that newly developed therapeutic monoclonal antibodies, such as rituximab, efalizumab, and infliximab, that target the immune response appear to induce a clinical disorder that is similar to autoimmune thrombocytopenia in some patients, usually after at least two exposures. Unfortunately, tools are not available with which to confirm that one of these drugs was the actual cause of autoimmune thrombocytopenia in an individual case.

Cathomas et al. describe a woman treated with the therapeutic monoclonal antibody trastuzumab (anti-HER2) for metastatic breast cancer in whom severe thrombocytopenia and bleeding developed 4 days after the first infusion, with recovery after about 1 week. As noted above, therapeutic monoclonal antibodies that affect the immune response are known to induce a clinical picture similar to autoimmune thrombocytopenia by unknown mechanisms. We are not aware of any reports of this disorder after treatment with trastuzumab and thank the correspondents for bringing this case to our attention.

Richard H. Aster, M.D.
Daniel W. Bougie, Ph.D.
BloodCenter of Wisconsin, Milwaukee, WI 53226-3548
richard.aster@bcw.edu

2 References

1
Scirica BM, Cannon CP, Cooper R, et al. Drug-induced thrombocytopenia and thrombosis: evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes (OPUS-TIMI 16) trial. J Thromb Thrombolysis 2006;22:95-102
CrossRef | Web of Science | Medline

2
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-2216
Full Text | Web of Science | Medline

Citing Articles (1)