title: Tamoxifen induces resistance to activated protein C.
abstract: BACKGROUND
  The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.
  
  
  METHODS
  Blood samples were collected prospectively from women with breast cancer before (n=25) and monthly after start of adjuvant TAM treatment (n=75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.
  
  
  RESULTS
  APC sensitivity decreased by 41% (p=0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p=0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.
  
  
  CONCLUSIONS
  This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany. Electronic address: heiko.ruehl@ukb.uni-bonn.de.
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, 53105 Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Schröder
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Shorena
authors.initials: S
authors.lastname: Sukhitashvili
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany; Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, 53105 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, 53105 Bonn, Germany.
authors.forename: Walther C
authors.initials: WC
authors.lastname: Kuhn
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 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, 53105 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rudlowski
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Pötzsch
mesh_terms: D020016:Activated Protein C Resistance / Q000139:chemically induced*; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D011446:Prospective Studies; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011486:Protein C; D011994:Recombinant Proteins; D013629:Tamoxifen
keywords: Activated Protein C Resistance; Tamoxifen; Thrombophilia