J Thromb Thrombolysis DOI 10.1007/s11239-013-1031-8
Acquired pure red cell aplasia due to treatment with clopidogrel: first case report Gang Li • Zhao-quan Li • Qi-yu Yang Jia-dan Yang
•
Ó Springer Science+Business Media New York 2013
Abstract A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and coronary heart disease started taking clopidogrel, with no addition of any other new drugs. However, with the addition of the drug, the patient was diagnosed as having acquired pure red cell aplasia (PRCA), and no any other inducing factors were detected from the patient. Furthermore, with the withdrawal of clopidogrel from the treatment, the patient recovered from the PRCA and did not recur. Therefore, we report PRCA as a rare side effect of clopidogrel for the first time.
drug reported to date include indigestion, bleeding diathesis, rash, diarrhea, taste disorders and thrombotic thrombocytopenic purpura [1–4]. In addition, clopidogrel in rare instances may be found to be associated with life-threatening side effects, as sever bone marrow suppression manifested as toxic bone marrow failure [5], thrombocytopenia, neutropenia or pancytopenia [6]. Here, we report a case of clopidogrel inducing pure red cell aplasia (PRCA) for the first time.
Case report Keywords Pure red cell aplasia Clopidogrel Adverse reaction
Introduction Clopidogrel has been widely used for treatment of cardiac and extracardiac vascular diseases [1]. Adverse reactions to this
G. Li Department of Pharmacy, Sichuan Provincial People’s Hospital, Chengdu, China Z. Li Laboratory of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China Q. Yang Department of Clinical Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, China J. Yang (&) Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China e-mail: [email protected]
A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and chest pain was admitted to our hospital in February 2010. On admission, the patient complained frequently about chest pain, and the result of electrocardiogram supported myocardial ischemia with the patient. Two days later, the result of coronary arteriongraphy verified the patient was suffering from coronary atherosclerotic heart disease, with anterior descending branch stenosis, circumflex branch stenosis and right coronary artery occlusion. To prevent acute coronary syndrome, the patient started taking clopidogrel at the dose of 75 mg/day from the third day (hemoglobin [Hb] 141 g/L). Combined drugs included isosorbide mononitrate, metoprolol tartrate, perindopril, aspirin, pantoprazole, simvastatin, acarbose and insulin. During the treatment, the patient felt debilitation and dizziness. The level of hemoglobin decreased gradually, with 108, 86 and 77 g/L on the hospital day 7, 9 and 13 (Fig. 1). But the level of white blood cells and platelets was persisted within the normal range (Figs. 2, 3). We suspected that the patient had been attacked by PRCA, which required further diagnosis. At the time of diagnosis of the anemia, the patient was 157 cm in height, 59 kg in weight, 112/63 mmHg in blood
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Fig. 1 Curve of level of hemoglobin
Fig. 5 Bone marrow aspirate smear intact granulocytic and lymphocytic elements (Wright stain, 91,000) Fig. 2 Curve of white blood cell count
Fig. 3 Curve of platelet count
Fig. 6 Bone marrow section (H-G-F stain, 9400) reveals with intact granulocytic and lymphocytic elements. Erythrocytes are virtually absent
Fig. 4 Bone marrow aspirate smear intact granulocytic and megakaryocytic elements (Wright stain, 9100)
pressure, 72/min in heart rate and 36.8 °C in body temperature, with no finding of bleeding and hepatosplenomegaly. The white blood cell count (WBC) and platelet count (PLT) were within normal range(WBC 6,230/lL, neutrophils 4,520/lL, eosinophils 70/lL, basophils 0/lL, monocytes 740/lL, lymphocytes 900/lL, granular
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lymphocytes 0/lL, PLT 146,000/lL). However, there was evidence of normocytic normochromic anemia(red blood cells[RBC] 2.69 9 1,012/L, Hb 77 g/L, hematocrit[Hct] 23.3 %, MCV 86.6 fl, mean corpuscular hemoglobin[MCH] 28.6 pg, mean corpuscular hemoglobin concentration[MCHC] 330 g/L), and the reticulocyte count was low, at 0.47 % (1.4 9 1,010/L). While the level of serum erythropoietin was normal. Biochemically, rise of random blood glucose (9.46 mmol/L) and aspartate aminotransferase (64U/L), reduction of the total protein (6.24 g/dL) and serum albumin (2.79 g/dL) were noted. Renal function was normal. Ham test and Rous test were negative, as was the Coombs test, excluding paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia. Tumor markers and serological test for human parvovirus B19 IgM were also negative. And no evidence
Red cell aplasia with clopidogrel
of abnormal masses, nodules and metabolic overactive tissues was detected by positron emission computed tomography. The bone marrow smear and section showed adequate intact granulocytic, megakaryocytic and lymphocytic elements (Figs. 4, 5, and 6). And erythrocytes are virtually absent (Fig. 6). The findings were thus consistent with PRCA. On the 14th day, clopidogrel which may be the inducing factor of PRCA was withdrawn from the treatment. The condition of anemia improved and the Hb, RBC and reticulocytes were restored gradually (Fig. 1) to the normal range, and PRCA has not recurred since then.
Discussion PRCA, a syndrome characterized by severe normochromic normocytic anemia, reticulocytopenia, and an erythroblastopenia in the bone marrow, is a primary hematologic disorder but can also occur secondary to various infections, hematologic malignancies, chronic hemolytic anemia, autoimmune diseases, thymoma, severe malnutrition, and exposure to a variety of drugs and toxins [7]. Drugs which have been reported to be associated with PRCA include micafungin [8], azathioprine [7], ticlopidine [9], diphenylhydantoin [10], isoniazid [11], erythropoietin [12], and zidovudine [13]. There were no any above factors associated with the patient. However, it’s worth noting that clopidogrel, in chemical strcture, is similar to ticlopidine which is an inducing factor of PRCA [9]. Therefore, we speculated that clopidogrel was also associated with PRCA. In addition, clopidogrel was the only new drug that the patient had been started on before the onset of the PRCA. Furthermore, it was also the only drug which was withdrawn from the treatment, then the patient recovered from the PRCA gradually. Therefore, we diagnosed PRCA as a rare side effect of clopidogrel. As clopidogrel has been expanded for primary prevention of cardiovascular events in patients with peripheral vascular diseases [14], it is likely that more patients will have clopidogrel initiated and managed in primary care. As
a potentially life-threatening side effect, PRCA induced by clopidogrel should attract more attention from the prescribers. Nevertheless, there remains a limitation to this report. Because of the safety of the patient, she was not re-exposed with clopidogrel and therefore the causality is still assumed.
References 1. Ksouda K, Affes H, Hammami B et al (2011) Ageusia as a side effect of clopidogrel treatment. Indian J Pharmacol 43:350–351 2. Golka K, Roth E, Huber J et al (2000) Reversible ageusia as an effect of Clopidogrel treatment. Lancet 355:465–466 3. Cave AJ, Cox DW, Vicaruddin O (2008) Loss of taste with clopidogrel. Can Fam Physician 54:195–196 4. Bennett CL, Connors JM, Carwile JM et al (2000) Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342:1773–1777 5. Chemnitz J, Sohngen D, Schulz A et al (2003) Fatal toxic bone marrow failure associated with clopidogrel. Eur J Haematol 71: 473–474 6. Andres E, Perrin AE, Alt M et al (2001) Febrile pancytopenia associated with clopidogrel. Arch Intern Med 161:125 7. Agrawal A, Parrott NR, Riad HN et al (2004) Azathioprineinduced pure red cell aplasia: case report and review. Transpl Proc 36:2689–2691 8. Yoshida-Hiroi M, Koizumi M, Oka R et al (2011) First case report of acquired pure red cell aplasia associated with micafungin. Intern Med 50:1051–1054 9. Lee JY, Park EB, Ahn JH et al (2008) A case of ticlopidine induced acute cholestatic hepatitis and pure red cell aplasia. Korean J Hepatol 14:102–107 10. Rusia U, Malhotra P, Joshi PJ (2006) Diphenylhydantoin-induced pure red cell aplasia. J Indian Med Assoc 104:34–36 11. Loulergue P, Mir O, Dhote R (2007) Pure red blood cell aplasia and isoniazid use. Emerg Infect Dis 13:1427–1428 12. Boven K, Knight J, Bader F et al (2005) Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Transpl 20S:33–40 13. Balakrishnan A, Valsalan R, Sheshadri S et al (2010) Zidovudineinduced reversible pure red cell aplasia. Indian J Pharmacol 42:189–191 14. Cave AJ, Cox DW, Vicaruddin O (2008) Loss of taste with clopidogrel. Can Fam Physician 54:195–196
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Acquired pure red cell aplasia due to treatment with clopidogrel: first case report Gang Li • Zhao-quan Li • Qi-yu Yang Jia-dan Yang
•
Ó Springer Science+Business Media New York 2013
Abstract A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and coronary heart disease started taking clopidogrel, with no addition of any other new drugs. However, with the addition of the drug, the patient was diagnosed as having acquired pure red cell aplasia (PRCA), and no any other inducing factors were detected from the patient. Furthermore, with the withdrawal of clopidogrel from the treatment, the patient recovered from the PRCA and did not recur. Therefore, we report PRCA as a rare side effect of clopidogrel for the first time.
drug reported to date include indigestion, bleeding diathesis, rash, diarrhea, taste disorders and thrombotic thrombocytopenic purpura [1–4]. In addition, clopidogrel in rare instances may be found to be associated with life-threatening side effects, as sever bone marrow suppression manifested as toxic bone marrow failure [5], thrombocytopenia, neutropenia or pancytopenia [6]. Here, we report a case of clopidogrel inducing pure red cell aplasia (PRCA) for the first time.
Case report Keywords Pure red cell aplasia Clopidogrel Adverse reaction
Introduction Clopidogrel has been widely used for treatment of cardiac and extracardiac vascular diseases [1]. Adverse reactions to this
G. Li Department of Pharmacy, Sichuan Provincial People’s Hospital, Chengdu, China Z. Li Laboratory of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China Q. Yang Department of Clinical Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, China J. Yang (&) Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China e-mail: [email protected]
A 62-year-old woman with hypertension, type 2 diabetes mellitus, hyperlipemia and chest pain was admitted to our hospital in February 2010. On admission, the patient complained frequently about chest pain, and the result of electrocardiogram supported myocardial ischemia with the patient. Two days later, the result of coronary arteriongraphy verified the patient was suffering from coronary atherosclerotic heart disease, with anterior descending branch stenosis, circumflex branch stenosis and right coronary artery occlusion. To prevent acute coronary syndrome, the patient started taking clopidogrel at the dose of 75 mg/day from the third day (hemoglobin [Hb] 141 g/L). Combined drugs included isosorbide mononitrate, metoprolol tartrate, perindopril, aspirin, pantoprazole, simvastatin, acarbose and insulin. During the treatment, the patient felt debilitation and dizziness. The level of hemoglobin decreased gradually, with 108, 86 and 77 g/L on the hospital day 7, 9 and 13 (Fig. 1). But the level of white blood cells and platelets was persisted within the normal range (Figs. 2, 3). We suspected that the patient had been attacked by PRCA, which required further diagnosis. At the time of diagnosis of the anemia, the patient was 157 cm in height, 59 kg in weight, 112/63 mmHg in blood
123
G. Li et al.
Fig. 1 Curve of level of hemoglobin
Fig. 5 Bone marrow aspirate smear intact granulocytic and lymphocytic elements (Wright stain, 91,000) Fig. 2 Curve of white blood cell count
Fig. 3 Curve of platelet count
Fig. 6 Bone marrow section (H-G-F stain, 9400) reveals with intact granulocytic and lymphocytic elements. Erythrocytes are virtually absent
Fig. 4 Bone marrow aspirate smear intact granulocytic and megakaryocytic elements (Wright stain, 9100)
pressure, 72/min in heart rate and 36.8 °C in body temperature, with no finding of bleeding and hepatosplenomegaly. The white blood cell count (WBC) and platelet count (PLT) were within normal range(WBC 6,230/lL, neutrophils 4,520/lL, eosinophils 70/lL, basophils 0/lL, monocytes 740/lL, lymphocytes 900/lL, granular
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lymphocytes 0/lL, PLT 146,000/lL). However, there was evidence of normocytic normochromic anemia(red blood cells[RBC] 2.69 9 1,012/L, Hb 77 g/L, hematocrit[Hct] 23.3 %, MCV 86.6 fl, mean corpuscular hemoglobin[MCH] 28.6 pg, mean corpuscular hemoglobin concentration[MCHC] 330 g/L), and the reticulocyte count was low, at 0.47 % (1.4 9 1,010/L). While the level of serum erythropoietin was normal. Biochemically, rise of random blood glucose (9.46 mmol/L) and aspartate aminotransferase (64U/L), reduction of the total protein (6.24 g/dL) and serum albumin (2.79 g/dL) were noted. Renal function was normal. Ham test and Rous test were negative, as was the Coombs test, excluding paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia. Tumor markers and serological test for human parvovirus B19 IgM were also negative. And no evidence
Red cell aplasia with clopidogrel
of abnormal masses, nodules and metabolic overactive tissues was detected by positron emission computed tomography. The bone marrow smear and section showed adequate intact granulocytic, megakaryocytic and lymphocytic elements (Figs. 4, 5, and 6). And erythrocytes are virtually absent (Fig. 6). The findings were thus consistent with PRCA. On the 14th day, clopidogrel which may be the inducing factor of PRCA was withdrawn from the treatment. The condition of anemia improved and the Hb, RBC and reticulocytes were restored gradually (Fig. 1) to the normal range, and PRCA has not recurred since then.
Discussion PRCA, a syndrome characterized by severe normochromic normocytic anemia, reticulocytopenia, and an erythroblastopenia in the bone marrow, is a primary hematologic disorder but can also occur secondary to various infections, hematologic malignancies, chronic hemolytic anemia, autoimmune diseases, thymoma, severe malnutrition, and exposure to a variety of drugs and toxins [7]. Drugs which have been reported to be associated with PRCA include micafungin [8], azathioprine [7], ticlopidine [9], diphenylhydantoin [10], isoniazid [11], erythropoietin [12], and zidovudine [13]. There were no any above factors associated with the patient. However, it’s worth noting that clopidogrel, in chemical strcture, is similar to ticlopidine which is an inducing factor of PRCA [9]. Therefore, we speculated that clopidogrel was also associated with PRCA. In addition, clopidogrel was the only new drug that the patient had been started on before the onset of the PRCA. Furthermore, it was also the only drug which was withdrawn from the treatment, then the patient recovered from the PRCA gradually. Therefore, we diagnosed PRCA as a rare side effect of clopidogrel. As clopidogrel has been expanded for primary prevention of cardiovascular events in patients with peripheral vascular diseases [14], it is likely that more patients will have clopidogrel initiated and managed in primary care. As
a potentially life-threatening side effect, PRCA induced by clopidogrel should attract more attention from the prescribers. Nevertheless, there remains a limitation to this report. Because of the safety of the patient, she was not re-exposed with clopidogrel and therefore the causality is still assumed.
References 1. Ksouda K, Affes H, Hammami B et al (2011) Ageusia as a side effect of clopidogrel treatment. Indian J Pharmacol 43:350–351 2. Golka K, Roth E, Huber J et al (2000) Reversible ageusia as an effect of Clopidogrel treatment. Lancet 355:465–466 3. Cave AJ, Cox DW, Vicaruddin O (2008) Loss of taste with clopidogrel. Can Fam Physician 54:195–196 4. Bennett CL, Connors JM, Carwile JM et al (2000) Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342:1773–1777 5. Chemnitz J, Sohngen D, Schulz A et al (2003) Fatal toxic bone marrow failure associated with clopidogrel. Eur J Haematol 71: 473–474 6. Andres E, Perrin AE, Alt M et al (2001) Febrile pancytopenia associated with clopidogrel. Arch Intern Med 161:125 7. Agrawal A, Parrott NR, Riad HN et al (2004) Azathioprineinduced pure red cell aplasia: case report and review. Transpl Proc 36:2689–2691 8. Yoshida-Hiroi M, Koizumi M, Oka R et al (2011) First case report of acquired pure red cell aplasia associated with micafungin. Intern Med 50:1051–1054 9. Lee JY, Park EB, Ahn JH et al (2008) A case of ticlopidine induced acute cholestatic hepatitis and pure red cell aplasia. Korean J Hepatol 14:102–107 10. Rusia U, Malhotra P, Joshi PJ (2006) Diphenylhydantoin-induced pure red cell aplasia. J Indian Med Assoc 104:34–36 11. Loulergue P, Mir O, Dhote R (2007) Pure red blood cell aplasia and isoniazid use. Emerg Infect Dis 13:1427–1428 12. Boven K, Knight J, Bader F et al (2005) Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Transpl 20S:33–40 13. Balakrishnan A, Valsalan R, Sheshadri S et al (2010) Zidovudineinduced reversible pure red cell aplasia. Indian J Pharmacol 42:189–191 14. Cave AJ, Cox DW, Vicaruddin O (2008) Loss of taste with clopidogrel. Can Fam Physician 54:195–196
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