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Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Background/Aims: The newly adapted generic KINDL-A(dult)B(rief) questionnaire showed satisfactory cross-sectional psychometric properties in adults with bleeding disorders or thrombophilia. This investigation aimed to evaluate its cross-sectional and longitudinal construct validity. Methods: After ethical committee approval and written informed consent, 335 patients (mean age 51.8 ± 16.6 years, 60% women) with either predominant thrombophilia (n = 260) or predominant bleeding disorders (n = 75) participated. At baseline, patients answered the KINDL-AB, the MOS 36-item Short-Form Health Survey (SF-36), and the EQ-5D-3L. A subgroup of 117 patients repeated the questionnaire after a median follow-up of 2.6 years (range: 0.4–3.5). A priori hypotheses were evaluated regarding convergent correlations between KINDL-AB overall well-being and specific subscales, EQ-5D-3L index values (EQ-IV), EQ-5D visual analog scale (EQ-VAS), and SF-36 subscales. Results: Contrary to hypothesis, baseline correlations between the KINDL-AB and EQ-IV/EQ-VAS were all moderate while, as hypothesized, several KINDL-AB subscales and SF-36 subscales correlated strongly. At follow-up, no significant changes in all three instruments occurred. Correlations between instruments over the follow-up were mostly moderate and partially strong. Contrary to hypothesis but consistent with no significant changes in health-related quality of life, convergent correlations between changes in KINDL-AB overall well-being, physical and psychological well-being, and EQ-IV/EQ-VAS were all weak. Conclusions: While repeated measures of KINDL-AB showed moderate to strong correlations, changes in KINDL-AB overall well-being and subscales correlated more weakly than expected with changes involving two established instruments of generic health status.

Background Bleeding is a common but possibly underreported side effect of Extracorporeal Membrane Oxygenation (ECMO). Impairment of primary hemostasis by acquired von Willebrand syndrome (aVWS) and platelet dysfunction as well as activation and consumption of plasmatic coagulation factors contribute to hemorrhage. The aim of the present cohort study of consecutively enrolled patients admitted to our ECMO center was to collect demographic, medical and laboratory data possibly associated with i) development of clinically relevant bleeding and/or ii) death during a 12-months follow-up. Results Within a 3-year period 338 white patients aged 18–89 years (median: 60; male 64.5%) were enrolled. 78 of 338 patients (23%) presented with clinical relevant bleeding symptoms. The overall death rate was 74.6% within a median time of 9 days (1–229) post intervention. Logistic-regression analysis adjusted for age and gender revealed that i) the presence of blood group O versus non-O (Odds ratio (OR)/95%CI: 1.9/1.007–3.41), ECMO duration per day (1.1/1.06–1.14), veno-venous versus veno-arterial ECMO cannulation (2.33/1.2–4.5) and the overall need for blood product administered per unit (1.02/1.016–1.028) was independenly associated with bleeding in patients suffering from aVWS. ii) Older age (increase per year) at ECMO start (1.015/1.012–1.029) and an increasing amount of blood product units were significantly related with death (1.007/1.001–1.013). Patients with veno-venous versus veno-arterial cannulation survived longer (0.48/0.24–0.94). Conclusion In the present cohort study we found a clinical relevant bleeding rate of 23% in subjects with aVWS associated with blood group O, a longer ECMO duration and veno-venous cannulation.

Background The objective of the present study was to evaluate safety and efficacy of Rivaroxaban (RIVA) being administered as a routine medication for patients with venous thromboembolism (VTE) in a multicenter outpatient cohort. Methods 212 consecutively admitted outpatients (14– Findings Patients were followed over a median period of 16months. The bleeding incidence rate per 100 patient-years was 17.8% in fertile/premenopausal women and 4.0% in men with an annualized re-VTE rate of 0.48% (women only). The median daily RIVA dose of 0.25mg/kg in females was significantly higher compared to males with 0.21mg/kg ( p p =0.008). Multivariate analysis adjusted for gender, body mass index, RIVA dose and FVIII revealed an increased hazard of 3.4% in women to develop RIVA-induced bleeding. Additionally, a gradual decrease of FVIII per IU/ml was significantly associated with clinical relevant bleeding. Interpretation Our data demonstrated a high incidence of mucosal type bleeding in women on standard RIVA. This has clinical implications suggesting a need for RIVA monitoring in selected individuals that are at an increased bleeding risk. Funding The study was supported by grants from the pediatric/adolescent stroke foundation "Schlaganfall und Thrombosen im Kindesalter e.V." and Interdisziplinares Zentrum fur Klinische Forschung (IZKF: CRA01-09), University of Munster. The explorative study part, e.g. the HrQoL assessment, was sponsored by an unrestricted grant donated by Biotest Ag (Langen, Germany).

Background/Aims: The generic quality of life KINDL-R ­questionnaire is validated for use in children/adolescents ≤16 years. The aim of this cross-sectional investigation was to modify the KINDL-R questionnaire for use in adults and to validate its psychometric properties. Methods: Five items of the KINDL-R questionnaire were adapted and the newly developed KINDL-A(dult) questionnaire administered to 255 patients with hereditary and acquired bleeding disorders (mean age 53 years). Its internal consistency and convergent and divergent construct validity were investigated and confirmatory factor analysis was used to evaluate the latent factor structure. Results: The KINDL-A questionnaire showed satisfactory reliability, varying construct validity, but inconclusive factor structure. The KINDL-AB(rief) was developed by removing half of the items and combining 2 sub-axes. This led to factor loadings between 0.62 and 0.91 and increased overall fit (Goodness of fit > 0.8 and Root Mean Square Error of Approximation, RMSEA, < 0.08). Results were validated in 966 healthy blood donors (mean age 38 years). In this group, the KINDL-AB questionnaire showed factor loadings between 0.43 and 0.77, Goodness of fit > 0.95 and RMSEA < 0.05. Conclusions: The new KINDL-AB suggests sufficient to good psychometric properties in adult patients with hereditary and acquired bleeding disorders.

Absolute values of reference ranges for coagulation assays in humans vary within the entire lifespan and confirm the concept of developmental hemostasis. It is known that physiologic concentrations of coagulation factors (F) gradually increase over age: they are lower in premature infants as compared to full-term babies, healthy children or adults. Here we demonstrate in a cohort of 1011 blood donors and in a group of 193 healthy pregnant women, that the process of developmental hemostasis proceeds in adults. During the course of pregnancy F and activation markers steadily increase until delivery with a parallel decrease noticed for protein S. From adolescents, young adults to the elderly there is a further increase of F, reaching significance starting between 35 and 50years of age compared to younger subjects. Covering the entire lifespan FVIII and von-Willebrand-factor showed the lowest values in carriers of blood group "O". Apart from pregnancy differences related to gender, pill users, smoking habits or the presence of thrombophilic variants were reported. Laboratory test results should be compared to age-related reference intervals when hemostatic defects are suspected to avoid misclassifications as being "healthy", prone to "bleeding" or vice versa to "thrombosis".

Background To better understand self-reported health-related quality-of-life (HrQoL) in children and adults with chronic hemostatic conditions compared with healthy controls. Methods/patients/results Group 1 consisted of 74 children/adolescents aged 8–18 years with hereditary bleeding disorders (H-BD), 12 siblings and 34 peers. Group 2 consisted of 82 adult patients with hereditary/acquired bleeding disorders (H/A-BD), and group 3 of 198 patients with deep venous thrombosis (DVT) on anticoagulant therapy. Adult patients were compared to 1011 healthy blood donors. HrQoL was assessed with a ‘revised KINDer Lebensqualitaetsfragebogen’ (KINDL-R)-questionnaire adapted to adolescents and adults. No differences were found in multivariate analyses of self-reported HrQoL in children with H-BD. In contrast, apart from family and school-/work-related wellbeing in female patients with DVT the adult patients showed significantly lower HrQoL sub-dimensions compared to heathy control subjects. Furthermore, adults with H/A-BD disorders reported better friend-related HrQoL compared to patients with DVT, mainly due to a decreased HrQoL subscale in women on anticoagulation. Conclusion In children with H-BD, HrQoL was comparable to siblings and peers. In adults with H/A-BD HrQoL was comparable to patients with DVT while healthy blood donors showed better HrQoL. The friend-related HrQoL subscale was significantly reduced in female compared to male patients.

Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombotic therapy with Rivaroxaban [RIVA] is increasingly being administered for TE treatment in adults. Aim: The objective of the present study was to evaluate efficacy and safety of standard RIVA administered as routine medication in an outpatient cohort of patients with TE. Methods: In 212 consecutively admitted outpatients (14- Results: Patients were followed over a median of 12 months. The median daily RIVA dose of 0.25 mg (0.1-0.52) in females was significantly higher compared to males with 0.21 mg (0.09-0.4; p Conclusion: Along with good efficacy results our data demonstrate a high bleeding rate of 36.9% in women on standard RIVA. Lower RISTO activities in fertile/premenopausal women contributed significantly to B. Disclosures Kenet: Bayer, LFB, NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Nowak-Gottl:Bayer, LFB: Membership on an entity's Board of Directors or advisory committees.

Background: Antithrombotic therapy with Rivaroxaban [RIVA] is increasingly being administered for secondary TE prophylaxis in adults. The objective of the present study was to evaluate efficacy and safety of standard RIVA administered as routine medication in an outpatient cohort of pts with TE. Furthermore, on an explorative basis we investigated the influence of RIVA on coagulation factors and biomarkers, and the impact of RIVA monitoring during routine administration. Methods: In 140 consecutively admitted whiteoutpts (15-82 yrs; male 56%) with TE and standard RIVA medication (2x 15 mg followed by 20 mg absolute) recruited between January 2013 and January 2014, a comprehensive monitoring of RIVA through (24h) and peak levels (2h, 4h; Xa-based chromogenic substrate S-2732; Haemochrom Diagnostica) alongwith anti-factor-Xa-activities [Xa; Xa-based assay, Haemochrom Diagnostica], selected coagulation factors and biomarkers (factors II, V, VIII, von-Willebrand-Ristocetin-cofactor [RICO], antithrombin [AT], protein C [PC], D-Dimer, prothrombin fragment F1+2 [F1+2], dRVVT-ratio) was performed during routine follow-up. Efficacy endpoints were defined as any TE or thrombus progression during treatment, safety endpoints were defined as significant bleeding requiring any medical intervention, such as dose reduction, withdrawal of RIVA or death related to therapy. Blood samples were taken during routine follow-up visits in the study centers on a monthly (RIVA start) to 3-months (maintenance) interval. Apart from descriptive analysis non-parametric statistics was performed. In addition, chi-square or Fisher’s exact test was applied. Results: During the study period of 15 months in 140 pts 210 follow-up visits including analyses of 420 individual blood samples were performed. Median pt age was 49yrs, with no difference between males and females. Median (min-max) body weight [bw] per kg was 85 (50-151). Median (min-max) daily RIVA dose per kgbw was 0.2 mg (0.09-0.51).Due to a significant lower bw the median daily RIVA dose of 0.24 mg (0.1-0.51) in females was significantly higher compared to males with 0.20 mg (0.09-0.4; p Conclusion: In conclusion, data of this cohort study demonstrated that efficacy of RIVA in outpts with TE is good, however, the bleeding rate of 7.86% is too high. With respect to this safety endpoint we have demonstrated a dose - and a drug-level-dependency of RIVA standard therapy. We suggest that drug monitoring is mandatory in selected pts, especially in cases of bleeding-related co-mediations or concomitant bleeding disorders. Disclosures No relevant conflicts of interest to declare.