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

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.