Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Ischemic Stroke due to Postmenopausal Hormone Therapy

Jacques E. Rossouw*, Karen C. Johnson, Mary Pettinger, Mary Cushman, Per Morten Sandset, Lewis Kuller, Frits Rosendaal, Jan Rosing, Sylvia Wasserthal-Smoller, Lisa W. Martin, JoAnn E. Manson, Kamakshi Lakshminarayan, Jose G. Merino, John Lynch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background and Purpose-To test whether changes in plasma tissue factor pathway inhibitor (TFPI) levels or activated protein C resistance (normalized activated protein C resistance ratio [nAPCsr]) modify the increased risk of ischemic stroke due to postmenopausal hormone therapy. Methods-Nested case-control study of 455 cases of ischemic stroke and 565 matched control subjects in the Women's Health Initiative trials of postmenopausal hormone therapy. Results-Baseline free TFPI was associated with ischemic stroke risk (OR per SD increase, 1.17; 95% CI, 1.01-1.37; P=0.039), but baseline nAPCsr was not (OR per SD increase, 0.89; 95% CI, 0.75-1.05; P=0.15). Baseline TFPI levels and nAPCsr did not modify the effect of postmenopausal hormone therapy on ischemic stroke. Treatment-induced mean changes of -28% in free TFPI and +65% in nAPCsr did not change the risk of ischemic stroke (interaction P=0.452 and 0.971, respectively). In subgroup analyses, baseline nAPCsr was inversely associated with lacunar strokes (OR per SD increase, 0.74; 95% CI, 0.57-0.96; P=0.025) and baseline free TFPI interacted with treatment to increase large vessel atherosclerotic strokes (P=0.008). Conclusions-Procoagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to postmenopausal hormone therapy.
Original languageEnglish
Pages (from-to)952-957
Issue number4
Publication statusPublished - Apr 2012


  • cerebrovascular accident
  • estrogen
  • hemostasis
  • menopause
  • randomized controlled trials

Cite this