Levels of the anti-coagulant and anti-inflammatory protein S (PROS1) in patients with inflammatory bowel disease (IBD) relationship with disease activity, IBD disease patterns, and C4-binding protein (C4BP)

Inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) show an increased risk of thrombosis. PROS1 is a well-established anticoagulant. Plasma PROS1 circulates in a free form that can function as an anticoagulant or in complex with the complement C4b-binding protein (C4BP). Interestingly, PROS1 has also emerged as a potent anti-inflammatory mediator due to its function as agonist of the TAM receptor tyrosine kinases (Rothlin 2015). Here, we aimed to test if IBD or subsets of IBD are associated with reduced amounts of the anticoagulant and anti-inflammatory protein, PROS1. AIMS: to measure and compare free PROS1 and total C4BP levels in CD, UC and healthy controls and their relationship with activity status (Determined for indexes: CDAI, Mayo) and disease patterns (Montreal). Free PROS1 and C4BP (immunoturburbimetry, Liatest, Stago, France) were determined in 103 IBD patients (45 M, 58 F, UC: n = 66, CD n = 37) and 30 healthy controls (18 M, 12 F), mean ages: 37.5 ± 15.6, 41.4 ± 14.6, 38.2 ± 12.2, respectively. Mean PROS1 levels in CD (89.9. ± 28.0) were significantly lower compared with controls (109.6 ± 23.9, p = 0.0019) and UC (104.4 ± 27.0, p = 0.0076). Within the CD group, a statistical difference vs. controls was observed in patients with active disease (n = 25, levels 84.9 ± 24.1, p = 0.0004), but not in patients in remission (n = 12: 100.2 ± 33.5). Moreover, the moderate–severe subset (n = 21), presented the lowest levels (84.0 ± 25.9) vs. controls p = 0.0006. In UC, PROS1 levels did not show differences between subsets (42 active, 24 remission: 101.1 ± 26.3 and 110.0 ± 27, respectively) or with controls. CD patterns (behaviour, location) and UC extent (12 proctitis, 54 more extensive) did not show significant differences. C4BP levels were also found to be decreased in CD (global sample, active patients, severe-moderate subsets: 98.6 ± 14.4, 98.8 ± 12.0, 98.4 ± 12.6, 109.9 ± 8.8, p = 0.0004, p = 0.0008, p = 0.0014 vs. controls, respectively). Unlike PROS1, C4BP in UC (102.8 ± 9.9) was lower than in controls (p = 0.0010) mainly in severe–moderate activity (p = 0.0322), and besides, no statistical differences were observed between UC and CD. (1) Free PROS1 levels were significantly lower in active CD vs. controls (especially in the severe–moderate activity subsets), but in the case of UC the levels were indistinguishable from controls. On contrary, C4BP levels were reduced in both diseases, particularly in patients with higher disease activity. (2) Decrease of Free PROS1 in CD, was not secondary to a potential C4BP-bound PROS1 for C4BP increase. (3) Future studies will aim to test if reduced levels of PROS1 in circulation might not only contribute to the increased risk of thrombosis but also to the enhanced inflammation in CD.