Inherited Factor XI Deficiency Is Associated with Decrease Risk for Cardiovascular Adverse Event and Venous Thromboembolism - Israeli Population Based Study

Introduction

Israel contains within it a unique variety of groups predisposed to autosomal recessive diseases secondary to the history of segregated religious communities. Indicated groups include Ashkenazi Jews and Israeli Arabs. Factor XI deficiency is one of the conditions that can be included in this group of diseases. It is reported to have a prevalence of 8-13.4% within the Ashkenazi Jewish community as compared to a 1 in a million in the general population. Due to the risk for bleeding and delayed coagulation as a result of a deficient Factor XI, it has been postulated that an underlying cardiovascular benefit may protect the Factor XI deficient subjects from developing an adverse cardiovascular event or venous thromboembolism.

Methods

This is an observational, historical cohort study performed using the electronic data base of Clalit Health organization, largest HMO in Israel. The objective of this study is to determine the effects of possessing a Factor XI deficiency on adverse cardiovascular event the venous thromboembolism. The study was approved by a centralized IRB committee. All subjects tested for Factor XI activity were included in the study and divided in 3 groups based on factor XI activity level: Group A - Moderate to Severe deficiency (less than 30% activity), Group B - Mild deficiency (30-50% activity), Group C - Normal (more than 50% activity). Proportional hazard regression analysis was used to assess the association between the time to event and factors XI activity, adjusting for potential confounders.

Distribution of time to the tested event will be presented by Kaplan-Meier curves and compared with the log rank test. Proportional hazard regression analysis will be used to assess the association between time to event and coagulation factors activity, adjusting for potential confounders. The P value for trend will be calculated by including the predefined categories of the coagulation factors as continuous variable in the model. The association will estimated with hazard ratio (HR) with 95% confidence interval (CI), comparing each factor category with the highest category as reference.

Results

Total of 10,193 subjects were tested for Factor XI activity levels between 2002-2015. Moderate to Severe factor XI deficiency (<=30%) was identified in 542 (5.3%) of tested individuals. Mild factor XI deficiency (30-50%) was identified in 693 (6.8%) of tested individuals. Compare to Individuals with factor XI activity >50%, factor XI deficiency was associated with decreased risk of the composite end point of major cardiovascular event (MI, stroke or TIA): For factor XI activity <=30% HR was 0.56 (95% CI, 0.34-0.9); For factor XI activity 30-50% HR was 0.54 (95% CI, 0.33-0.89). Factor XI activity levels of less than 50% were associated with decrease risk for venous thromboembolism (PE or DVT), HR-0.25 (95% CI, 0.08-0.81, p<0.021)

Conclusions

Factor XI deficiency is associated with decrease risk for adverse cardiovascular event and decreased risk for thromboembolic events. Mild factor XI deficiency (activity level of 30-50%) is associated with a similar decrease in risk as moderate to severe deficiency.