小児期心疾患に対する抗血小板薬 ticlopidine の有用性と安全性についての検討

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1 原 著 PEDIATRIC CARDIOLOGY and CARDIAC SURGERY VOL.26 NO.5 ( ) 小児期心疾患に対する抗血小板薬 ticlopidine の有用性と安全性についての検討 Key words: ticlopidine, antithrombotic therapy, antiplatelet drug, Fontan procedure, systemic to pulmonary artery shunt Safety and Efficacy of Ticlopidine in Pediatric Patients with Heart Disease Kiyoshi Ogawa, Masatoshi Iijima, Reiji Ito, Sadataka Kawachi, Kenji Sugamoto, Takashi Hishitani, and Kenji Hoshino Division of Pediatric Cardiology, Saitama Children s Medical Center, Saitama, Japan Background: Although prolonged antiplatelet therapy with aspirin is widely recommended for children with heart disease, aspirin alone may not be sufficient to prevent thrombotic events. The safety and efficacy of thienopyridine derivatives such as ticlopidine and clopidogrel have been established in adult patients with coronary artery disease. However, very limited information has been published on the use of ticlopidine in a pediatric population. Methods: A retrospective study of all children treated with ticlopidine was performed. 87 patients with congenital or acquired heart disease were identified. Those patients were divided into three different groups by age and procedures at ticlopidine use. Results: The total daily dose of ticlopidine ranged from 1.0 to 7.4 mg/kg/day. The relationship between the degree of ADPinduced platelet aggregation inhibition and the dose of ticlopidine was not linear in any of the three groups. Two patients developed thrombotic events after systemic to pulmonary artery shunting. There were no serious bleeding events or adverse gastrointestinal effects attributed to the ticlopidine. Hematological abnormalities were documented in 7 patients. Isolated thrombocytopenia was identified in 6 patients 2 to 13 years after the initiation of ticlopidine. Platelet counts gradually decreased in all patients. Conclusions: Ticlopidine was well tolerated in our pediatric patients with heart disease, and adverse events were minimal. The doses of ticlopidine were considerably lower than those for adult use. Patients should be monitored for thrombocytopenia during ticlopidine administration. 要旨 aspirin aspirin clopidogrel ticlopidine ticlopidine 87 3 ADP mg/kg/day 2 6 Ticlopidine

2 401 Table 1 Clinical characteristics Infant Young child Child Total Number Age 14 day 2 y 2 y 7 y 7 y 15 y 14 day 15 y Male/female 18/12 20/11 16/10 54/33 Heart disease SP shunt SP shunt-fontan Fontan Coronary lesion SP shunt: systemic to pulmonary artery shunt 背景 Fontan 1 5 clopidogrel Plavix 6 clopidogrel Ticlopidine Panaldine clopidogrel adenosine diphosphate ADP P2Y12 7 ticlopidine TTP 8 9 clopidogrel Clopidogrel 1 6 mg/kg/day mg/kg/ day ticlopidine 13 Ticlopidine 500 mg/ 3 4 ticlopidine 方法 Fontan ticlopidine Fontan Glenn 3 Fontan Table1 ADP Ticlopidine ticlopidine 2 4 Ticlopidine 5 mg/kg/ 3 ADP PICOLO trial 結果 Ticlopidine ADP Fig mg/kg/day Fig. 2 Fontan Fig. 3 Ticlopidine Fig. 4 ADP

3 402 Fig. 1 Effect of ticlopidine on ADP-induced platelet aggregation. No linear relationship between the degree of ADPinduced platelet aggregation inhibition and the dosage of ticlopidine was detected in pediatric patients with heart disease. Fig. 2 Effect of ticlopidine on ADP-induced platelet aggregation in three different age groups. No linear relationship between the degree of ADP-induced platelet aggregation inhibition and the dosage of ticlopidine was detected in three different age groups. Fig. 3 Effect of ticlopidine on ADP-induced platelet aggregation in children with two different procedure groups. No linear relationship between the degree of ADP-induced platelet aggregation inhibition and the dosage of ticlopidine was detected in children with two different procedure groups

4 403 Fig. 4 Effect of ticlopidine on ADP-induced platelet aggregation in three different age groups. Fig. 5 Time course of ticlopidine dose and % inhibition of platelet aggregation in a child. 1 ticlopidine ADP Fig. 5 Ticlopidine 5 mg/kg 19 Ticlopidine Ticlopidine 1 aspirin 1 γgtp 3 15 /μl

5 404 Fig. 6 Time course of platelet count in cases with thrombocytepenia. The numbers of platelet decreased slowly in all patients and became lower than /mm 3 in 2 patients. Table 2 Clinical characteristics of patients with abnormal platelet count Age at No. Heart disease Operation ticlopidine initiation Ticlopidine dose (mg/kg) # Duration of ticlopidine Hb (g/dl) ## Complication treatment 1 TA, PA Fontan procedure 2m y 15.8 thrombocytopenia 2 PA, VSD, hypo PA pali. RV-PA cond. 1m 4.3 5y2m 12.6 thrombocytopenia 3 SRV Fontan procedure 8y4m 3.1 2y 14.1 thrombocytopenia 4 TGA(III), s-mv Fontan procedure 1m y7m 14.6 thrombocytopenia 5 DORV, hypo LV, PS Fontan procedure 11y2m 2.3 4y6m 16.8 thrombocytopenia 6 HLHS Fontan procedure 1m 2 9y11m 16.0 thrombocytopenia 7 C-TGA, PA, VSD Fontan procedure 2m 3 7y10m 13.6 thrombocytosis # Ticlopidine dose at onset of abnormal platelet count, ## Hemoglobin at onset of abnormal platelet count TA: tricuspid atresia, PA: pulmonary atresia, VSD: ventricular septal defect, hypo PA: hypoplastic pulmonary artery. SRV: single right ventricle, TGA: transposition of the great arteries, s-mv: straddling mitral valve, DORV: double outlet right ventricle, hypo LV: hypoplastic left ventricle, PS: pulmonary stenosis, HLHS: hypoplastic left heart syndrome, C-TGA: corrected trasposition of the great arteries, pali. RV-PA cond.: palliative right ventricle-pulmonary artery couduit 6 40 /μl 1 7 Table 2 6 Fontan 1 palliative RV-PA conduit 1 ticlopidine 2 ticlopidine Fig /μl 1 3 platelet associated IgG PA-IgG 5 aspirin /μl aspirin /μl JAK2 V617F 考案

6 405 6 aspirin dipyridamole warfarin heparin aspirin 14 ticlopidine clopidogrel aspirin 1 5 ticlopidine clopidogrel Page 15 ticlopidine TTP 8 9 ticlopidine clopidogrel ticlopidine TTP ticlopidine aspirin 18 warfarin ticlopidine ticlopidine Ticlopidine aspirin 1990 Ticlopidine 5 mg/kg/day mg/kg/day 21 1 mg/kg/day clopidogrel PICOLO trial mg/ mg/kg/ 5 mg/kg/day ADP 1 mg/kg/day ADP clopidogrel 75 mg/day ADP PICOLO trial ticlopidine ADP PICOLO trial aspirin hyporesponder hyper-responder hypo-responder Ticlopidine BT shunt aspirin aspirin ticlopidine 3 ticlopidine 9 ticlopidine Ticlopidine PA-IgG /μl 1 ticlopidine 3 2 predonisolone 6 PA-IgG 2 ticlopidine 1 Fontan

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