Determinants of acquired activated protein C resistance and D-dimer in breast cancer

Mari Tinholt; Per Morten Sandset; Marie-Christine Mowinckel; Øystein Garred; Kristine Kleivi Sahlberg; Vessela N Kristensen; Anne-Lise Børresen-Dale; Anne Flem Jacobsen; Grethe Skretting; Nina Iversen

doi:10.1016/j.thromres.2016.08.003

Determinants of acquired activated protein C resistance and D-dimer in breast cancer

Thromb Res. 2016 Sep:145:78-83. doi: 10.1016/j.thromres.2016.08.003. Epub 2016 Aug 3.

Affiliations

¹ Dept. of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Electronic address: tinholtmari@gmail.com.
² Dept. of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: p.m.sandset@medisin.uio.no.
³ Dept. of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway. Electronic address: UXMAOW@ous-hf.no.
⁴ Department of Pathology, Oslo University Hospital, Oslo, Norway. Electronic address: UXYSGA@ous-hf.no.
⁵ Dept. of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Research, Vestre Viken, Drammen, Norway. Electronic address: kristine.sahlberg@vestreviken.no.
⁶ Dept. of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway. Electronic address: v.n.kristensen@medisin.uio.no.
⁷ Dept. of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. Electronic address: a.l.borresen-dale@medisin.uio.no.
⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Obstetrics and Gynecology, Oslo University Hospital, Oslo, Norway. Electronic address: UXAFJA@ous-hf.no.
⁹ Dept. of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway. Electronic address: grethe.skretting@medisin.uio.no.
¹⁰ Dept. of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Electronic address: nina.iversen@medisin.uio.no.

PMID: 27505249
DOI: 10.1016/j.thromres.2016.08.003

Abstract

Background: We have previously reported acquired activated protein C (APC) resistance and elevated plasma D-dimer levels in breast cancer patients. Here, we aimed to identify phenotypic and genetic determinants that contribute to the acquired APC resistance and increased D-dimer levels in breast cancer. Healthy controls served as reference. We also addressed whether higher APC resistance or D-dimer levels could be potential markers of clinicopathological breast cancer characteristics.

Materials and methods: 358 breast cancer patients and 273 healthy controls were enrolled and hemostatic plasma parameters were determined; factor (F) V, FVIII, FIX, FX, fibrinogen, von Willebrand factor (VWF), normalized APC sensitivity ratio (n-APC-sr), protein C, protein S, antithrombin, tissue factor pathway inhibitor (TFPI), and D-dimer. Common single nucleotide polymorphisms were genotyped in coagulation-related genes in the breast cancer patients.

Results: The phenotypic hemostatic factors explained 25% and 31% of the variability in acquired APC resistance and D-dimer levels, respectively, in the breast cancer patients. Fibrinogen (β=-0.35, P<0.001), protein C (β=0.28, P<0.001), and FIX (β=0.22, P=0.026) were identified as determinants of n-APC-sr (in FV Leiden non-carriers), whereas TFPI (β=0.28, P<0.001), antithrombin (β=-0.25, P<0.001), and FX (β=0.15, P=0.040) were the major determinants of D-dimer. Moreover, borderline higher APC resistance (>75th percentile) was found in patients with triple negative tumors (odds ratio (OR) 1.97, 95% CI 0.99-3.90).

Conclusions: This study reports phenotypic hemostatic parameters that determine acquired APC resistance and D-dimer levels in breast cancer patients. The explanatory power was modest, however, our findings are hypothesis generating and may contribute to further understand the background for cancer associated-coagulopathy and thrombosis.

Keywords: Activated protein C resistance; Breast cancer; Clinicopathological breast cancer characteristics; Coagulation factors; Coagulation inhibitors; D-dimer; Single nucleotide polymorphisms.

MeSH terms

Blood Coagulation Tests / methods*
Breast Neoplasms / blood*
Female
Fibrin Fibrinogen Degradation Products / metabolism*
Humans
Polymorphism, Single Nucleotide / immunology*
Protein C / metabolism*

Substances

Fibrin Fibrinogen Degradation Products
Protein C
fibrin fragment D