Evidence of a U‐shaped association between factor XII activity and overall survival

Introduction: The clinical relevance of decreased coagulation factor XII (FXII) plasma activity as a risk factor for both venous and arterial thrombosis is still discussed controversially. The current study evaluated the predictive value of FXII levels for all‐cause mortality in a large Viennese patient cohort. Patients and methods: Individuals, whose FXII activity levels were determined for suspected coagulation disorders or thrombophilia screening between 1991–2003 were included in this study (n = 8936, 51% male, 49% female, median age 43 years). Death/survival was determined by record linkage with the Austrian Death Registry. The median observation period was 5 years covering a total of 46 400 person years; the death rate was 17.1%. For Cox regression analysis, FXII plasma activity was divided into 11 categories of 10% steps with the category of > 100% FXII serving as a reference category. Results: With decreasing FXII plasma activity, hazard ratios for all‐cause mortality gradually increased linearly from 1.0 in the > 100% category to 1.5 (95% CI: 1.2–1.9) in the 80–90% category to 4.7 (95% CI: 3.4–6.5) in the 10–20% category. Similar results were obtained, when only vascular mortality or death as a result of ischemic heart disease was considered. No significant increase in all‐cause mortality (HR: 1.4, 95%CI 0.7–2.8) was observed in the small group of FXII‐deficient subjects [0–10% category (n = 58)]. Conclusions: This study first demonstrates a strong and almost linear association of FXII plasma activity between 90% and 10% with all‐cause mortality in a large Viennese patient cohort. Interestingly, mortality rates are not increased when FXII activity is below 10%, resulting in a U‐shaped survival curve.