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

Abstract

Summary. 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.

Coagulation and the Vessel Wall in Pulmonary Embolism

“…However, a FXII activity rate below 10% does not increase mortality rates, thus resulting in a U-shaped survival curve. 27 Larger epidemiological studies in the Netherlands and Switzerland did not find a correlation between FXII deficiency and increased thrombotic risk. 28,29 Patients with severe deficiency of factor XI, the substrate for activated FXII, have a reduced incidence of DVT.…”

Epidemiologic and clinical data linking factors XI and XII to thrombosis

“…Interestingly, however, the group with fXII:c levels Ͻ10% (n ϭ 58) demonstrated no increased mortality, resulting in a U-shaped survival curve. 15 The reason for the increased mortality in moderate-deficiency patients could not be determined because the relationship held true for noncancer mortality, all-cause vascular mortality, and mortality due to ischemic heart disease.…”

Coagulation Factor XII –A Key Pro-Inflammatory and Pro-Coagulant Protein

“…These questions would require further verification. A clear correlation between FXII and thrombosis and inflammation has not yet been established, and some studies have demonstrated a "U" shaped correlation between plasma FXII concentration and mortality of various reasons [34], suggesting that partial inhibition of FXII may actually increase mortality. Complete or nearly complete inhibition of FXII/FXIIa is difficult to achieve, bringing extra obstacles to development of therapeutic FXII/FXIIa inhibitor.…”