Tamoxifen induces resistance to activated protein C

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• 作者：Heiko R&uuml ; hl^a ; ¹ ; ^{heiko.ruehl@ukb.uni-bonn.de" class="auth_mail} ; Lars Schrö ; der^b ; ¹ ; Jens M&uuml ; ller^a ; Rolf Fimmers^c ; Shorena Sukhitashvili^a ; Julia Welz^a ; ^b ; Walther C. Kuhn^b ; Johannes Oldenburg^a ; Christian Rudlowski^b ; Bernd Pö ; tzsch^a
• 关键词：APC ; activated protein C ; aPTT ; activated partial thromboplastin time ; BSA ; bovine serum albumin ; AT ; antithrombin ; CAT ; calibrated automated thrombography ; EC ; epirubicin ; cyclophosphamide ; EC-D ; epirubicin ; cyclophosphamide ; docetaxel ; ETP ; endogenous thrombin generation potential ; F1+2 ; prothrombin fragment 1+2 ; FII ; factor II ; FV ; factor V ; FVII ; factor VII ; FVIII ; factor VIII ; FIX ; factor IX ; FX ; factor X ; FXI ; factor XI ; FXIII ; factor XIII ; FEC ; fluorouracil ; epirubicin ; cyclophosphamide
• 刊名：Thrombosis Research
• 出版年：May, 2014
• 年：2014
• 卷：133
• 期：5
• 页码：886-891
• 全文大小：404 K

文摘

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.