Heiko Rühl1, Lars Schröder2, Jens Müller3, Rolf Fimmers4, Shorena Sukhitashvili3, Julia Welz5, Walther C Kuhn2, Johannes Oldenburg3, Christian Rudlowski2, Bernd Pötzsch3. 1. Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany. Electronic address: heiko.ruehl@ukb.uni-bonn.de. 2. Department of Gynecology and Obstetrics, Center for Integrated Oncology (CIO) Köln/Bonn, University Hospital Bonn, 53105 Bonn, Germany. 3. Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, 53105 Bonn, Germany. 4. Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, 53105 Bonn, Germany. 5. 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.
Abstract
INTRODUCTION: 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. MATERIALS AND 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.
INTRODUCTION: 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. MATERIALS AND 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 TAMpatients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.
Authors: Steven P Grover; Yohei M Hisada; Raj S Kasthuri; Brandi N Reeves; Nigel Mackman Journal: Arterioscler Thromb Vasc Biol Date: 2021-02-11 Impact factor: 8.311