International Journal of Hematology

, Volume 109, Issue 6, pp 641–649 | Cite as

Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study

  • Takekazu MiyoshiEmail author
  • Hisato Oku
  • Saiko Asahara
  • Akira Okamoto
  • Koichi Kokame
  • Michikazu Nakai
  • Kunihiro Nishimura
  • Fumiyuki Otsuka
  • Aya Higashiyama
  • Jun Yoshimatsu
  • Toshiyuki Miyata
Original Article


The association between low-dose combined oral contraceptives (COCs) and anticoagulation factors in Japanese women has been rarely studied. A total of 394 Japanese women with a new beginning cycle of COC use were enrolled, of whom 335 women visited the clinic within 4 weeks after starting the first cycle of COC. Visits occurred in the active phase (272 women) and the placebo phase (63 women). Free protein S (PS) antigen and activity levels and antithrombin activity levels decreased significantly in both the active and placebo phase groups. Protein C (PC) activity levels increased significantly in both groups. Larger reductions in free PS antigen and activity levels occurred with COC comprising either 30 µg ethinylestradiol/desogestrel or 20 µg ethinylestradiol/drospirenone than that comprising 35 µg ethinylestradiol/norethisterone. In four women with the Japanese-specific PS K196E mutation, mean PS activity was 65% before COC use and 57% during COC use, indicating further decrease with COC use. In conclusion, decreased antigen and activity levels of PS and antithrombin and increased activity levels of PC were observed even during the first cycle of low-dose COC use. The effects on PS and PC activities were also observed in the hormone-free interval.


Anticoagulation factor Combined oral contraceptive Protein S Thrombophilia Venous thromboembolism 



We thank Dr. Kazuhisa Ideta and the medical staff of Chayamachi Ladies Clinic for their contribution to particpants’ recruitment and sample collection. We thank Dr. Mana Mitsuguro and Ms. Yumiko Uchida at NCVC for measuring anticoagulation factors and genotyping. We thank Dr. Reiko Neki at NCVC and Dr. Shota Nii at Mie University for their expert advice on this manuscript. This research was performed using the NCVC Biobank resource (for NCVC Biobank see


This work was supported by the Takeda Science Foundation, Bayer Scholarship for Cardiovascular Research Foundation, and Kanzawa Medical Research Foundation. These funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.


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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Takekazu Miyoshi
    • 1
    Email author
  • Hisato Oku
    • 2
  • Saiko Asahara
    • 2
  • Akira Okamoto
    • 3
  • Koichi Kokame
    • 4
  • Michikazu Nakai
    • 5
  • Kunihiro Nishimura
    • 5
  • Fumiyuki Otsuka
    • 6
  • Aya Higashiyama
    • 7
  • Jun Yoshimatsu
    • 1
  • Toshiyuki Miyata
    • 8
  1. 1.Department of Perinatology and GynecologyNational Cerebral and Cardiovascular CenterSuitaJapan
  2. 2.Chayamachi Ladies ClinicOsakaJapan
  3. 3.Laboratory of Clinical ChemistryNational Cerebral and Cardiovascular CenterSuitaJapan
  4. 4.Department of Molecular PathogenesisNational Cerebral and Cardiovascular CenterSuitaJapan
  5. 5.Department of Statistics and Data Analysis, Center for Cerebral and Cardiovascular Disease InformationNational Cerebral and Cardiovascular CenterSuitaJapan
  6. 6.Department of Cardiovascular MedicineNational Cerebral and Cardiovascular CenterSuitaJapan
  7. 7.Department of Preventive CardiologyNational Cerebral and Cardiovascular CenterSuitaJapan
  8. 8.Department of Cerebrovascular MedicineNational Cerebral and Cardiovascular CenterSuitaJapan

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