2.26 Clopidogrel (Plavix) Induces In Vivo Reduction of Normal B Cells and In Vitro Apoptosis of B-Cell Chronic Lymphocytic Leukemia Cells

Clopidogrel, a drug that is widely used in cardiology, inhibits the ADP receptor on platelets. Very few patients using this drug also have chronic lymphocytic leukemia (CLL). We were able to follow 2 patients with this association and were surprised to observe a 50% reduction in their peripheral lymphocyte count. To search for a possible effect of clopidogrel on lymphocytes, we performed 2 studies. First, we determined B-cell count, defined by expression of CD19 and CD20 on flow cytometry before and after 4 to 6 weeks of use of clopidogrel. Twenty patients were selected at the cardiology unit, and blood was collected after informed consent was obtained. In addition, we evaluated apoptosis of B-CLL cells induced by clopidogrel in vitro in 20 untreated patients with CLL. Blood was collected after informed consent was obtained; lymphocytes were separated on Ficoll, then studied for apoptosis using the Annexin V assay by flow cytometry before and after addition of clopidogrel. The dosage of 20 μg per 4 × 106 cells represents approximately the concentration of in patients treated with the drug. Higher doses of 50 and 100 mg were used for comparison. The results were that B-lymphocyte counts were significantly reduced in patients without CLL who were receiving clopidogrel for cardiac reasons. Mean CD19 was 15.5% before versus 10% after clopidogrel treatment (p = 0.015), and mean CD20 was 15% before versus 9% after 4 to 6 weeks of clopidogrel treatment (p = 0.014). Addition of clopidogrel in vitro induced increased apoptosis: mean of 10% to 20% (p = 0.004) with 20 μg, and a high level of necrosis with the higher doses of 50 and 100 mg. In conclusion, we demonstrated that patients receiving clopidogrel had a significant reduction in B cells after 4 to 6 weeks of treatment. The clinical implication is not yet defined, and further long-term follow-up emphasizing the Ig serum level or frequency of infections will be examined. We also demonstrated that addition of a pharmaceutical dosage of clopidogrel induced a significant increase in in vitro apoptosis, which may explain the reduction in lymphocyte count observed in our 2 patients with B-CLL who were receiving clopidogrel for cardiac reasons. Because the effect of the drug on platelets involves the Akt system, we believe that inhibition of Akt in lymphocytes could explain our findings.