Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism
Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism
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DOI：
10.1111/j.1538-7836.2008.03196.x
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发表时间：
2008-12-01
影响因子：
10.4
通讯作者：
Kamphuisen, P. W.
中科院分区：
文献类型：
--
作者：
Abdelmalik, N.;Ruhe, H. G.;Kamphuisen, P. W.
背景：选择性血清素再摄取抑制剂（SSRIs）与出血倾向增加有关。目的：前瞻性量化帕罗西汀的量效效应及血清素转运基因（SLC6A4）启动子多态性（5-HTTLPR）对血小板功能的影响。方法：对19例无药物精神科门诊患者（44.5±10.8岁）进行帕罗西汀治疗（20mg天（-1））前后6周的检测。根据临床症状，11例患者帕罗西汀剂量增加（40-50 mg /天），持续6周以上。通过出血时间、血小板功能分析仪（PFA）、血小板5 -羟色胺、血小板因子4 （PF4）、β -血小板球蛋白（β - tg）和聚集试验评估血小板功能相关参数。结果：帕罗西汀20 mg天（-1）使平均出血时间增加1.2分钟（95%可信区间(95% CI) -0.2-2.7），血小板血清素中位数水平降低(463 ng 10（-9）个血小板；四分位数范围（IQR） 361-666)，血小板ss-TG浓度(3.1 IU 10（-6）血小板；差0.3 - -6.0)。其他血小板参数无明显变化。系列血小板聚集试验未出现异常。帕罗西汀剂量增加不进一步影响血小板功能。然而，5-HTTLPR多态性改变了这些效应：在L(A)/L(A)等位基因携带者中，出血时间没有改变（-0.2 min; 95% CI -0.6 ~ 0.9），而在< 2L(A)等位基因携带者中，出血时间显著增加（2.3 min; 95% CI 0.5 ~ 4.07; P = 0.032）。无L(A)-等位基因的患者血小板血清素下降幅度较大(868 ng 10（-9）个血小板；IQR 585 ~ 1213)比>= 1 L(A)等位基因携带者(457 ng 10（-9）个血小板；IQR 392至598；P = 0.035)。无L(A)-等位基因的患者PFA关闭时间和PF4显著增加。结论：帕罗西汀20mg天（-1）不增加总出血时间，但通过降低血小板血清素和血小板ss-TG水平损害血小板功能。这些帕罗西汀效应似乎是由5-HTTLPR介导的，在没有L(A)-等位基因的患者中效果最明显。
Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose-response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) on platelet function. Methods: Nineteen drug-free psychiatric outpatients (44.5 +/- 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day(-1)). Based on clinical symptoms, paroxetine dosages were increased (40-50 mg day(-1)) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), and aggregation tests. Results: Paroxetine 20 mg day(-1) increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) -0.2-2.7) and reduced median platelet serotonin level (463 ng 10(-9) platelets; inter quartile range (IQR) 361-666), and platelet ss-TG concentration (3.1 IU 10(-6) platelets; IQR 0.3-6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose-escalation did not further influence platelet function. However, 5-HTTLPR polymorphisms modified these effects: in L(A)/L(A)-carriers, bleeding times did not change (-0.2 min; 95% CI -0.6 to 0.9), while bleeding times significantly increased in < 2L(A)-allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L(A)-alleles (868 ng 10(-9) platelets; IQR 585 to 1213) than in >= 1 L(A)-allele carriers (457 ng 10(-9) platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L(A)-alleles. Conclusions: Paroxetine 20 mg day(-1) does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ss-TG. These paroxetine effects appear to be mediated by 5-HTTLPR, with most pronounced effects in patients without L(A)-alleles.