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

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.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.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).Procoagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to postmenopausal hormone therapy. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT 00000611.