Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two rando...

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Bibliographic Details
Published in:	Blood coagulation & fibrinolysis Vol. 15; no. 8; pp. 649 - 655
Main Authors:	Duschek, Erik JJ, Neele, Simone J, Thomassen, M Christella LGD, Rosing, Jan, Netelenbos, Coen
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA Lippincott Williams & Wilkins, Inc 01-10-2004 The Scientist
Subjects:	Activated Protein C Resistance - chemically induced Aged Biological and medical sciences Blood coagulation. Blood cells Double-Blind Method Estrogen Replacement Therapy Estrogens, Conjugated (USP) - administration & dosage Factor V Female Fundamental and applied biological sciences. Psychology Hematologic and hematopoietic diseases Homocysteine - blood Humans Male Medical sciences Medroxyprogesterone Acetate - administration & dosage Middle Aged Molecular and cellular biology Placebos Platelet diseases and coagulopathies Postmenopause - blood Raloxifene Hydrochloride - administration & dosage Raloxifene Hydrochloride - adverse effects Antineoplastic agent Estrogen receptor Replacement therapy Antiestrogen Cardiovascular disease Antihormone Vascular disease Randomization Homocystein Blood vessel men Postmenopause Adult Female Thromboembolism Vein Non steroid compound hormonal replacement therapy Protein C (activated) Human homocysteine Thiol Serine endopeptidases Enzyme Thrombosis Embolism Sulfur containing aminoacid Resistance Peptidases Sensitivity venous thromboembolism Placebo normalized activated protein C sensitivity ratio Hydrolases Raloxifene Hormone replacement therapy Circulatory system Agonist antagonist Elderly
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Summary:	Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 ± 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n = 17), 60 mg raloxifene (n = 23), 150 mg raloxifene (n = 20) or placebo (n = 23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 ± 2.4 years) randomly received 120 mg raloxifene (n = 15) or placebo (n = 15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 ± 0.82 to 2.87 ± 0.86 at 24 months (P < 0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.
ISSN:	0957-5235 1473-5733
DOI:	10.1097/00001721-200412000-00004