title: Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Coronary Heart Disease Due To Combined Estrogen Plus Progestin Therapy.
abstract: OBJECTIVE
  To examine whether tissue factor pathway inhibitor or acquired activated protein C (APC) resistance influences the increased risk of coronary heart disease (CHD) due to estrogen plus progestin therapy.
  
  
  RESULTS
  Prospective nested case-control study of 205 cases of CHD and 481 matched controls in the Women's Health Initiative randomized trial of estrogen plus progestin therapy. After multivariable covariate adjustment, both baseline tissue factor pathway activity (P=0.01) and APC resistance (P=0.004) were associated positively with CHD risk. Baseline tissue factor pathway activity and APC resistance singly or jointly did not significantly modify the effect of estrogen plus progestin on CHD risk. Compared with placebo, estrogen plus progestin decreased tissue factor pathway inhibitor activity and increased APC resistance but these changes did not seem to modify or mediate the effect of estrogen plus progestin on CHD risk.
  
  
  CONCLUSIONS
  Tissue factor pathway inhibitor activity and APC resistance are related to CHD risk in women, but may not explain the increased CHD risk due to estrogen plus progestin therapy. The data from this study do not support the clinical use of measuring these hemostatic factors to help stratify risk before hormone therapy.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.). kjohnson@uthsc.edu.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Aragaki
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Alex
authors.initials: A
authors.lastname: Reiner
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Sandset
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Anders E A
authors.initials: AE
authors.lastname: Dahm
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Frits
authors.initials: F
authors.lastname: Rosendaal
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Martin
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Lewis H
authors.initials: LH
authors.lastname: Kuller
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.affiliation: From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (K.C.J.); Fred Hutchinson Cancer Research Center, Seattle, WA (A.K.A., A.R.); Ohio State University Medical Center, Columbus, OH (R.J.); Oslo University Hospital and University of Oslo, Oslo, Norway (P.M.S., A.E.A.D.); Maastrich University, Maastrich, The Netherlands (J.R.); University of Leiden, Leiden, The Netherlands (F.R.); Brigham and Women's Hospital, Harvard University, Boston, MA (J.E.M.); George Washington University, Washington, DC (L.W.M.); Brown University, Providence, RI (S.L.); University of Pittsburgh, PA (L.H.K.); University of Vermont, Burlington, VT (M.C.); and National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.).
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Rossouw
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D017698:Postmenopause; D011372:Progestins / Q000009:adverse effects*; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D004967:Estrogens; D008074:Lipoproteins; D011372:Progestins; C051928:lipoprotein-associated coagulation inhibitor
keywords: activated protein C resistance; coronary disease; estrogens; hemostatics; progestins; tissue factor pathway inhibitor activity