Aplastic anemia and clopidogrel/ Nonfatal aplastic anemia associated with clopidogrel/Aplastik anemi ve klopidogrel/ Klopidogrel ile iliskili ölümcül olmayan aplastik anemi/Author's Reply

To the Editor,

Clopidogrel, is an inhibitor of platelet activation and aggregation via irreversible binding of its metabolite to ADP receptors on platelets. Hematological side effects of clopidogrel has been known for a long time and bone marrow suppression has been reported in case reports.

The patient in your report has been defined as severe pancytopenic but the criteria used for severe aplastic anemia is the presence of two out of following three; neutrophil count less than 200 cells/microliter, platelet count less than 20.000 cells/microliter and corrected reticulocyte count of less than 1%.

Aplastic anemia is not the most common cause of pancytopenia. Differential diagnosis of pancytopenia has to be assessed carefully. The authors have excluded other diseases and performed bone marrow biopsy to diagnose aplastic anemia (1). However, the cellularity percentage and fat content, which are essential for the diagnosis, was not defined in the biopsy specimen. Besides as the biopsy was hypocellular, in order to exclude myelodysplasia FISH analysis could be helpful. The patient in your report has been defined as severe pancytopenic but the criteria used for severe aplastic anemia is the presence of two out of following three; neutrophil count less than 200 cells/microliter, platelet count less than 20.000 cells/microliter and corrected reticulocyte count of less than 1%.

The spontaneous recovery of aplastic anemia is seen extremely rare and disease mostly presents fatal if untreated. So, spontaneous resolution of the patients hematological parameters in a short period as fourteen days, suggests us to revise the diagnosis of the patient as bone marrow suppression instead of aplastic anemia.

Sinem Civriz Bozdag, Muhit Özcan

Department of Hematology, Faculty of Medicine, Ankara University,

Ankara, Turkey

References

1. Uz Ö, Kardesoglu E, Aparci M, Yiginer Ö, Isilak Z, Özmen N. Nonfatal aplastic anemia associated with clopidogrel. Anadolu Kardiyol Derg 2010; 10: 291.

Address for Correspondence/Yazisma Adresi: Dr. Sinem Civriz Bozdag

Department of Hematology, Faculty of Medicine, Ankara University, Ankara, Turkey

Phone: :[phone] E-mail: [email protected]

Available Online Date/Çevrimiçi Yayin Tarihi: 18.04.2011

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doi:10.5152/akd.2011.068

Author's Reply

Dear Editor,

We read with great interest the comments of the authors on our recent paper entitled 'Nonfatal aplastic anemia associated with clopidogrel'. They suggest that "bone marrow depression" should be used instead of "aplastic anemia" to describe our case. Their starting point is spontaneous recovery of the case and the lack of the reporting of the fat content in bone marrow biopsy.

Our case applied to our department for cardiological check up. It is clear from the patient's history that hematological evaluations were made before the patient had applied to our department. In the patient, clopidogrel was thought to cause the hematologic findings and the drug was ceased since he was in the safe period in terms of cardiac. After the drug was stopped, the patients improved in terms of symptoms and hematological findings. To name our case, a literature search was made and it was found that the cases with similar findings were defined as aplastic anemia (1, 2). We do not think that using non-fatal course of the case as an exclusion criterion is correct. Thus, drug-induced aplastic anemia is known since 1930s. The severity of drug- induced aplastic anemia can vary. Drug- induced aplastic anemia can cause mortality in some patients, however some patients heal with a non-severe course. There are also reported cases of non-severe aplastic anemia (nonfatal) in the literature (2). There are two different pathophysiological mechanisms of drug- induced aplastic anemia: a dose-related reversible marrow aplasia and dose-independent idiosyncratic aplasia with a high mortality. These two forms of marrow suppression may be difficult to distinguish (3).

The mechanism of clopidogrel- induced hematologic side effects is not entirely known. However, the mechanisms of aplastic anemias induced by other drugs are blamed. In addition, the authors claim that it is hard to define this case as aplastic anemia since the patient recovered spontaneously. However, the case did not heal spontaneously, the case healed after cessation of the drug. Therefore, it is not possible to know what the patient's clinical course would be if clopidogrel were not stopped. We think that, in the light of literature knowledge, diagnosis of non-severe and non-fatal aplastic anemia in our case is not wrong with regard to the patient's findings and the given message. However, bone marrow depression, as suggested by the authors, can also be used. Whatever its name is; the truth in our patient is that; the patient developed pancytopenia related to clopidogrel and hematologic investigations were made including bone marrow biopsy. Finally, hypocellular bone marrow was detected in bone marrow biopsy.

In conclusion, clopidogrel, although rare, can cause hematologic side effect, which can cause pancytopenia.

Ömer Uz, Ejder Kardesoglu

Department of Cardiology, Haydarpasa Gülhane Military Medical

School, Istanbul, Turkey

References

1. Trivier JM, Caron J, Mahieu M, Cambier N, Rose C. Fatal aplastic anemia associated with clopidogrel. Lancet 2001; 357: 446.

2. Symeonidis A, Kouraklis-Symeonidis A, Seimeni U, Galani A, Giannakoulas N, Fragopanagou E, et al. Ticlopidine-induced aplastic anemia: two new case reports, review, and meta-analysis of 55 additional cases. Am J Hematol 2002; 71: 24-32.

3. Malkin D, Koren G, Saunders EF. Drug-induced aplastic anemia: pathogenesis and clinical aspects. Am J Pediatr Hematol Oncol 1990; 12: 402-10.

Address for Correspondence/Yazisma Adresi: Dr. Ömer Uz

Department of Cardiology, Haydarpasa Gülhane Military Medical School,

Istanbul, Turkey.

Phone: [phone] Fax: [phone] E-mail: [email protected]

Available Online Date/Çevrimiçi Yayin Tarihi: 18.04.2011