Sex-specific Effect and Disconnect Between Plasma Levels of FXII and FXIIa-C1-esterase Inhibitor Complexes in Pneumonia

Abstract Background: Sex-dependent differences in immunity and coagulation play an active role in 28 the outcome of community-acquired pneumonia (CAP). Factor XII acts at the crossroads 29 between inflammation and coagulation thus representing a point of convergence in host 30 defense against infection. Here, we evaluated FXII/FXIIa levels in plasma of CAP patients 31 and correlated them to clinical disease severity.Methods and Results: FXII was activated in CAP plasma as evident by the presence of 33 FXIIa-C1-esterase inhibitor (C1INH) complexes. The levels of FXIIa-C1INH complexes 34 were elevated in plasma of CAP patients (n=140) as compared to age- and sex-matched 35 healthy controls (n=58; p<0.001). No simultaneous decrease in FXII levels, indicating its 36 consumption, was observed. Stratification by sex revealed augmented levels of FXII in 37 plasma of CAP women as compared to healthy females (p=0.008) yet no apparent differences 38 in men (p=0.619). This sex-specific difference was, however, attributable to the lower levels 39 of FXII in healthy females relative to healthy men (p=0.011). Upon contact with CAP plasma, 40 isolated blood neutrophils released FXII and female blood neutrophils were able to re-induce 41 FXII mRNA synthesis (p=0.031). Despite this sex-specific effect, exposure of female blood 42 neutrophils to estradiol did not induce FXII mRNA expression. Finally, although we observed 43 accumulation of FXIIa-C1INH complexes in plasma of severe CAP patients, the relationship 44 between the levels of FXIIa-C1INH complexes and CAP severity, as assessed by CRB65 45 score, did not reach statistical significance (p=0.057). 46Conclusions: Our study identifies age- and sex-dependent differences in FXII expression that 47 may contribute to specific clinical outcomes in CAP in different patient subgroups.