title: Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study.
abstract: BACKGROUND
  The increased thrombotic risk of oral contraceptives (OC) has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC). To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use.
  
  
  METHODS
  Blood samples were collected prospectively from healthy women (n = 21) before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA) technology. Thrombin generation markers and other hemostasis parameters were measured additionally.
  
  
  RESULTS
  All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003). Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur.
  
  
  CONCLUSIONS
  In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk.
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Rühl
authors.affiliation: Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Schröder
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: Shorena
authors.initials: S
authors.lastname: Sukhitashvili
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany; Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Welz
authors.affiliation: Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, Bonn, Germany.
authors.forename: Walther C
authors.initials: WC
authors.lastname: Kuhn
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rudlowski
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Pötzsch
mesh_terms: D020016:Activated Protein C Resistance / Q000139:chemically induced*; D000293:Adolescent; D000328:Adult; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects*; D006801:Humans; D008297:Male; D011446:Prospective Studies; D013927:Thrombosis / Q000139:chemically induced*; D055815:Young Adult
chemical_list: D003278:Contraceptives, Oral, Hormonal