Pre‐diagnostic plasma concentrations of Fibrinogen, sGPIIb/IIIa, sP‐selectin, sThrombomodulin, Thrombopoietin in relation to cancer risk: Findings from a large prospective study

Abstract

While enhanced platelet activation may drive cancer progression and metastases, less is known about its role in early cancer development. Thus, we evaluated whether pre-diagnostic biomarkers of platelet activation and coagulation are related to the risks of common cancers in the prospective EPIC-Heidelberg Study using a case-cohort design. Levels of fibrinogen, soluble glycoprotein (sGP) IIb/IIIa, soluble P-selectin (sP-selectin), soluble thrombomodulin (sTM), and thrombopoietin (TPO) were measured in baseline plasma samples of a random subcohort (n = 2,480) and incident cases of breast (n = 605), prostate (n = 543), and colorectal cancer (n = 249). Multivariable Cox regression models revealed no statistically significant associations between biomarker concentrations and any of the cancer endpoints. Subgroup analyses showed a significant inverse relationship between TPO and colorectal cancer among men, with a hazard ratio (HR, highest vs. lowest quartile) of 0.60 (95% confidence interval: 0.37,0.95), whereas no significant association was observed among women. With regard to fibrinogen levels and breast cancer risk, there was a significant positive association among nulliparous women (HR: 2.53 [95% CI: 1.21, 5.30]), but not among parous women. Overall, our data suggest that enhanced platelet activation and a pro-coagulative state may not be related to increased risks of common cancers, although studies on other potential biomarkers of platelet activation and further cancer types are needed. Findings from our subgroup analyses require further investigation, as potential underlying mechanisms are not known.

Plasma Fibrinogen and sP-Selectin are Associated with the Risk of Lung Cancer in a Prospective Study

“…These results are in line with well-known detrimental effects of cigarette smoke on the endothelium, and especially with evidence that smoking increases platelet activation and coagulation (40)(41)(42), which in turn may drive carcinogenesis (43). They are indirectly supported by our previous observation that neither fibrinogen nor sP-Selectin were associated with the risks of breast, prostate, or colorectal cancer, that is, cancers with a much lower fraction of cases attributable to smoking compared with lung cancer (30).…”

“…After exclusion of the prevalent cases, the subcohort consisted of 2,386 participants. As intended by design, participants in the subcohort showed highly similar characteristics compared with the full cohort (30).…”

Biomarkers of Vascular Injury and Type 2 Diabetes: A Prospective Study, Systematic Review and Meta-Analysis

“…Enzyme-linked immunosorbent assays (ELISA) was used to measure GP IIb/IIIa and fibrinogen levels, using the essay kits "ab108851" from Abcam (Cambridge, UK) and "KA0475" from Abnova (Heidelberg, Germany). Within-and between-batch coefficients of variation were as follows (within-batch CV (between-batch CV)): P-Selectin 3.3% (9.1%), E-Selectin 3.6% (10.6%), thrombomodulin 3.8% (10.1%), thrombopoietin 4.6% (19.5%), GP IIb/IIIa 5.5% (46.9%) and ICAM3 7.5% (10.2%) ( Supplementary Table S4) [33]. All biomarkers showed good biological reproducibility in a pilot study carried out prior to the present analyses including 78 participants from the EPIC-Heidelberg subcohort, with Spearman's coefficients (ρ) for intra-individual correlations over one year of 0.88 (E-Selectin), 0.80 (P-Selectin), 0.69 (ICAM3), 0.63 (thrombomodulin), 0.73 (thrombopoietin), and 0.51 (GP IIb/IIIa) ( Supplementary Table S4) [23,36].…”

“…The present analyses on plasma biomarkers and T2D risk were conducted using a randomly selected subcohort of approximately 10% of the original cohort. This subcohort was initially drawn for case-cohort analyses on biomarkers in relation to risks of common cancers and cardiovascular diseases [33,34] and included 2224 EPIC-Heidelberg participants free of diabetes at baseline (n = 194 prevalent cases excluded). Follow-up was conducted through 31st December 2012.…”

Thrombomodulin and Thrombopoietin, Two Biomarkers of Hemostasis, Are Positively Associated with Adherence to the World Cancer Research Fund/American Institute for Cancer Research Recommendations for Cancer Prevention in a Population-Based Cross-Sectional Study

“…In order to assess whether adherence to these lifestyle recommendations has an impact on parameters of coagulation and platelet activation beyond known determinants, as particularly smoking, we investigated associations between hemostatic biomarkers and adherence to the WCRF/AICR recommendations using a questionnaire-based score [8] among a random subcohort ( n = 2267) of the prospective European Investigation into Cancer and Nutrition (EPIC)-Heidelberg. The score and its individual components were analyzed in relation to five biomarkers of hemostasis, glycoprotein (GP) IIb/IIIa, P-Selectin, thrombopoietin (TPO), thrombomodulin (TM), and fibrinogen, which were selected based on literature review [1,9]. In short, GPIIb/IIIa and P-Selectin are both platelet integral membrane proteins, which are expressed on the platelet surface upon platelet activation [10], and play a crucial role in platelet aggregation and adhesion.…”