Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

J Thromb Haemost. 2008 Dec;6(12):2168-74. doi: 10.1111/j.1538-7836.2008.03196.x. Epub 2008 Oct 18.

Abstract

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 > or =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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Coagulation / drug effects
  • Blood Platelets / chemistry
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Paroxetine / administration & dosage
  • Paroxetine / pharmacology*
  • Pharmacogenetics
  • Platelet Function Tests
  • Polymorphism, Genetic
  • Serotonin
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / pharmacology*
  • beta-Thromboglobulin

Substances

  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • beta-Thromboglobulin
  • Serotonin
  • Paroxetine