Factor XI Deficiency Is Not Associated with Increased Risk of Pneumonia in Adults

Background: Factor XI (FXI) deficiency is a rare bleeding disorder, common in Ashkenazi Jews. Recently, target FXI as antithrombotic therapy became real issue as FXI antisense oligonucleotide appeared safe and efficient for preventing post- operative deep vein thrombosis following knee replacement (Buller et al. NEJM2015). The fact that in two models of Klebsiella pneumonia and Streptococcus pneumonia of FXI knock out (KO) mice there was an increased lethality as a result of enhanced bacterial overgrowth and dissemination along with augmented inflammatory response (Stroo et al. JTH 2017), incited us to explore whether patients with FXI deficiency harbor increased risk of pneumonia or increased pneumonia fatality in comparison to individuals with normal factor XI activity

Methods: This historical cohort study was performed by using the electronic database of the largest health care provider in Israel. All adults tested for FXI activity between 2002 and 2014 were included in the study. FXI activity was classified into three categories; normal (activity >50%), mild-moderate deficiency (activity: 20-50%), and severe deficiency (activity <20%). The cohort was followed until December 31, 2015 for incident overall pneumonia and severe pneumonia defined as pneumonia requiring hospitalization. The association was assessed using Cox proportional regression models with adjustment for age, gender, smoking status , diabetes, chronic obstructive disease ,ischemic heart disease, cirrhosis, previous stroke, malignancy, previous pneumonia, influenza vaccine, as well as pneumococcal vaccine

Results: Of the 10,193 included patients; 8,958 (87.9%) had normal FXI activity, 804 (7.9%) had mild-moderate deficiency and 431 (4.2%) had severe deficiency. A total of 579 individuals had pneumonia and 221 individuals had severe pneumonia during follow up. Compared to individuals with normal FXI activity the adjusted HR for overall pneumonia was 0.81 (95% CI, 0.60-1.10) in those with mild-moderate deficiency, and 0.97 (0.68-1.37) in those with severe factor XI deficiency. The adjusted HR for severe pneumonia was 0.86 (95% CI, 0.56-1.30) in those with mild-moderate deficiency, and 0.86 (0.51-1.40) in those with severe FXI deficiency.Of the 579 patients with pneumonia; 33 (5.7%) and 47 (8.1%) patients died within 30 days and 90 days, respectively. Compared to individuals with normal FXI activity the adjusted HRs for 30 days and 90 days mortality were 0.50 (0.15-1.7) and 0.47 (0.17-1.30), respectivelyin those with mild-moderate deficiency, and 0.81 (0.23-2.9) and 0.47 (0.14-1.60), respectively in those with severe FXI deficiency

Conclusions: FXI deficiency is not associated with increased incidence of pneumonia or with increased mortality among patients with pneumonia and as such it is suggested that FXI target therapy can be applied in adult patients without the fear of exposing them to increased risk of pneumonia