Inherited genetic predispositions in F13A1 and F13B genes predict abdominal adhesion formation: identification of gender prognostic indicators

Abstract

Abdominal adhesions (AA) account for the most common complication of peritoneal surgery with bowel obstruction being the severest problem in the absence of effective predicting biomarkers. Anti-AA-barriers or adhesiolysis did not completely prevent bowel obstruction, although there is evidence they might reduce related complications requiring reoperation. In addition, gender-related predispositions have not been adequately investigated. We explored the role of coagulation Factor XIII (F13A1 and F13B subunit-genes) in patients following laparotomy, mostly median/lower median incision line. Globally, 426 patients (54%,♀), were PCR-SNP-genotyped for FXIIIA V34L (rs5985), FXIIIA P564L (rs5982), FXIIIA Y204F (rs3024477) and FXIIIB H95R (rs6003). Patients' clinical phenotypes were: Group-A (n = 212), those who developed AA, and 55.2% of them developed bowel obstruction (subgroup-A1), the remaining were subgroup-A2; Group B (n = 214) were those who did not develop AA (subgroup-B1; 53.3%) or symptoms/complications (subgroup-B2). Among different laparotomy, colon surgery associated with AA at a major extent (OR = 5.1; 3.24-7.8; P < 0.0001) with different gender scores (♀OR = 5.33; 2.32-12.23; P < 0.0001 and ♂OR = 3.44; 1.58-7.49; P < 0.0001). Among SNPs, P564L (OR = 4.42; 1.45-13.4; P = 0.008) and Y204F (OR = 7.78; 1.62-37.3; P = 0.01) significantly predicted bowel obstruction and survival-analyses yielded interesting gender distinctions (♀HR = 5.28; 2.36-11.8; P = 0.00005; ♂HR = 2.22; 1.31-3.85; P = 0.0034). Active compounds preventing AA belong to the anticoagulant/fibrinolysis areas, suggesting them candidate investigation targets. We identified novel prognostic markers to predict AA/bowel obstruction giving insights to design novel therapeutic and gender prevention programs.

Figure 1

Schematic representation of the cross-talk between blood coagulation and inflammation involved in the normal Fibrin matrix resolution or development of abdominal adhesions. CKs, Cytokines; PLTs, Platelets; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator; PAI-1 and PAI-2, plasminogen activator inhibitors 1 and 2; FXIII, Factor XIII (A2B2); α2-AP, Alpha 2-antiplasmin; MMPs, Matrix Metalloproteinases; TIMPs, Tissue Metalloproteinase Inhibitors.

Figure 2

Flowchart of the study. The picture shows the whole group of enrolled patients who underwent to a previous LAP surgical procedure and sub-group stratification according to the clinical phenotype.

Figure 3

(A,B) Event Free Survival (EFS) at 10-years survey for the different type of original LAP. In (A) bowel obstruction occurrence was analyzed according to the different LAP in the whole cohort of patients. Colon surgery (red line) differs in survival compared to the remaining LAPs that show similar trend and frequency. In (B) bowel obstruction occurrence after colon surgery was compared to that obtained from the remaining LAPs taken together (i.e. appendectomy, splenectomy, cholecystectomy and hysterectomy).

Figure 4

(A,B) Gender sub-analysis for bowel obstruction occurrence by different LAP. In (A), Event Free Survival (EFS) at 10-years survey for the different type of original LAP in males. In (B) Event Free Survival (EFS) at 10-years survey for the different type of original LAP in females.

Figure 5

(A,B) Gender sub-analysis for bowel obstruction occurrence of colon surgery vs the other LAP taken together. Event Free Survival (EFS) at 10-year survey after colon surgery compared to that of the remaining LAPs taken together (i.e. appendectomy, splenectomy, cholecystectomy) in males (A) and females (B).

Figure 6

(A–F) Overall Event Free Survival (EFS) for bowel obstruction occurrence at 10-years survey according to different FXIII SNPs considered. F13A1 V34L (VV vs VL vs LL) (A); F13A1 P564L (PP vs PL vs LL) (B); F13A1 V34L (VV + VL vs LL) (C); F13A1 P564L (PP vs PL + LL) (D); F13A1 Y204F (YY vs YF) (E); F13B H95R (HH vs HR + RR) (F).

Figure 7

Overall Event Free Survival (EFS) for bowel obstruction occurrence at 10-years survey for FXIII SNPs (any) in male and females. EFS in patients carrying any of the considered SNPs vs patients carrying no-SNPs (i.e. wild type for all SNPs considered). (*) Interestingly, females carrying any SNPs (dashed pink line) and males wild types for all the SNPs considered (solid blue line) show completely overlapping survival curves.