title: Endogenous thrombin potential changes during the first cycle of oral contraceptive use.
abstract: OBJECTIVE
  Venous thromboembolism (VTE) risk increases within months of combination oral contraceptive (COC) initiation. Because elevated endogenous thrombin potential (ETP) has been found in several studies to be a VTE risk factor, we evaluated the extent of ETP changes during the initial cycle of an ethinyl estradiol (EE) and levonorgestrel (LNG) COC. We also assessed the relationship between ETP changes and systemic EE and LNG concentrations.
  
  
  METHODS
  Participants provided multiple blood samples during a first 21-day cycle of a 30-mcg EE/150-mcg LNG COC and after a further 7 days without an active COC. Thrombin generation measured with and without addition of activated protein C (APC) yielded ETP+APCand ETP-APCand the normalized APC sensitivity ratio (nAPCsr). EE and LNG pharmacokinetic analyses were conducted over 24 h after the first COC tablet and again at steady state.
  
  
  RESULTS
  Thrombin generation was determined in 16 of the 17 women who completed the study. Mean ETP-APCincreased steadily to 21% above baseline at 24 h after the 6th COC tablet (COC624; p<.001) and to 28% above baseline at steady state (COC21; p<.001). The percentage increase in mean ETP+APCwas considerably more - 54% at COC624and 79% at steady state. Mean nAPCsr increased by 28% at COC624and by 41% at steady state. Higher concentrations of EE or LNG were not correlated with greater increases in ETP.
  
  
  CONCLUSIONS
  ETP increases during the first COC cycle were substantial.
  
  
  CONCLUSIONS
  The early increases in ETP may provide biological support for the rapid increase in VTE risk during initial COC use. The lack of association between this clotting system perturbation and the systemic EE concentration is surprising and deserves further study.
authors.affiliation: Department of Obstetrics & Gynecology, Columbia University Medical Center, New York, NY 10032, USA; Department of Epidemiology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: clw3@columbia.edu.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Westhoff
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Eisenberger
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
authors.forename: Stella
authors.initials: S
authors.lastname: Thomassen
authors.affiliation: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
mesh_terms: D000328:Adult; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects* / Q000097:blood*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011486:Protein C / Q000032:analysis; D012307:Risk Factors; D013917:Thrombin / Q000032:analysis*; D054556:Venous Thromboembolism / Q000097:blood
chemical_list: D003277:Contraceptives, Oral, Combined; D011486:Protein C; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D013917:Thrombin
keywords: Endogenous thrombin potential; Oral contraceptives; Protein C; Venous thromboembolism