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BACKGROUND: To develop and validate a predictive model to determinate patients at increased risk to suffer from recurrence following a first provoked deep vein thrombosis (VTE).METHODS: Predictive variables, i.e. male sex [1 point], inherited thrombophilia (IT) status (none [0 points], single [1 point], combined variants [2 points]), blood group non-0, and age at first VTE onset were included into a risk assessment model, which was derived in 511 patients and then validated in 509 independent subjects.RESULTS: VTE recurrence risk score (maximum 4 points, range 0-3) was below two for patients scored as low-risk (LRS) and ≥2 for patients at high-risk (HRS). Within a median time of 3 years after withdrawal of anticoagulation (AC) recurrence rate in LRG (derivation) was 11.8% versus 26.0% in HRS (p < 0.001). In the validation cohort within 2.2 years the recurrence rate was 9.8% in LRS versus 30.1% in HRS (p < 0.001). In multivariable analysis adjusted for age at first VTE and blood group the recurrent risk in HRS was significantly increased compared with the LRS (derivation: hazard/95% confidence interval: 3.7/1.75-7.91; validation: 4.7/2.24-9.81; combined 5.2/1.92-13.9). Model specificity (sensitivity) was 79.0% (52.0%) in the derivation cohort compared with 78.0% (43.0%) in the validation group. In conclusion, in the prediction model presented here the risk of VTE recurrence was associated with male gender and combined ITs. Based on the negative predictive value calculated the model may identify patients with a first provoked VTE not being at risk for recurrence.

The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG “non-O” was significantly more often diagnosed in patients compared to BG “O” (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia. Electronic supplementary material The online version of this article (10.1007/s11239-020-02169-6) contains supplementary material, which is available to authorized users.

Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association (p ≤ 5 × 10−8). Our results add to the strong support for the association of genetic variants in F5, NME7, ABO, and FGA with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS 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 harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

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.

Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P

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: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VIE]. Primary study objective was to evaluate if the clinical presentation at first VTE onset differs between children and adults and to compare the individual recurrence risk among patients with respect to age at onset and their thrombophilia status ATD, PCD or PSD. Methods/Patients/Results: In 137 of 688 consecutively enrolled pediatric and adult VTE patients we calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia and positive family VTE history. At first VTE children manifested i) with a lower rate of pulmonary embolism, ii) a higher rate of cerebral vascular events or multiple VIES, and showed a higher proportion of unprovoked VIE compared to adolescents and adults. Adult patients reported more often a positive VIE history compared to younger study participants. The adjusted odds of recurrence in adults was 2.05 compared to children. Conclusion: At disease manifestation children and adults differ with respect to i) thrombotic locations, ii) percentage of unprovoked versus provoked VIE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children. (C) 2016 ELSEVIER. All rights reserved.

ZusammenfassungDie chronische Niereninsuffizienz (chronic kidney disease; CKD) stellt einen bekannten Risikofaktor für die Entwicklung einer arteriellen und venösen Thromboembolie (TE) dar. Das Risiko für eine TE ist bei moderat eingeschränkter Nierenfunktion ca. 2,5-fach erhöht und steigt mit zunehmender Insuffizienz auf etwa das 5,5-Fache. Vergleicht man Patienten mit einer chronischen Niereninsuffizienz mit Patienten, die zusätzlich folgende Risikofaktoren aufweisen, erhöht sich das TE-Risiko erheblich: CKD und arterielle Thrombose: OR 4.9, CKD und maligne Grunderkrankung: OR 5.8, CKD und chirurgischer Eingriff: OR14.0; CKD und angeborene Thrombophilie (OR 4.3).Die Behandlung der terminalen Niereninsuffizienz besteht in Dialyse, Peritonaldialyse und Nierentransplantation. Bei allen Verfahren sind thromboembolische Komplikationen beschrieben. TEs, insbesondere aber Katheter-assoziierte Thrombosen oder Shuntverschlüsse treten in bis zu 25% der Dialysepatienten auf. Die Inzidenz einer Nierenvenenthrombose als Komplikation nach Nierentransplantation – verbunden mit hoher Wahrscheinlichkeit eines Organverlustes – wird mit 2–12% angegeben.Da TE häufig multifaktoriell bedingt sind, erscheint ein generelles Screening auf Thrombophilie in diesem Patientenklientel nicht indiziert. Ein Screening sollte diskutiert werden bei Patienten, die entweder TEs vor Auftreten ihrer Nierenerkrankung entwickelt haben oder die eine positive Familienanamnese hinsichtlich VTE aufweisen. Auch Patienten, die unter Dialyse oder nach Transplantation multiple TEs erleiden und solche, die auf der Warteliste für eine Nierentransplantation (insbesondere Lebendspende) stehen, sollten hinsichtlich Thrombophilie untersucht werden.

SummaryVenous thromboembolism [TE] is a multifactorial disease, and protein S deficiency [PSD] constitutes a major risk factor. In the present study the prevalence of PSD and the clinical presentation at TE onset in a cohort of children is reported. In 367 unselected paediatric patients with TE (age 0.1–18 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Thirty of 367 paediatric patients (8.2 %) derived from 27 families had PSD. Mean age at first TE onset was 14.5 years (range 0.1 to 18). Thrombotic locations were cerebral veins (n=8), calf vein TE (n=3) deep veins (DVT) of the leg (n=12), DVT & pulmonary embolism (n=5) and intra-cardiac veins (n=1) or purpura fulminans (n=1). PSD co-occurred with the factor 5 mutation at rs6025 or the homozygous factor 2 susceptibility variant at rs1799963 in one case each. The Heerlen polymorphism detected in five children presented with milder PSD. In 18 patients (60 %) a concomitant risk factor for TE was identified. A second TE event within primarily healthy siblings occurred in three of 27 PSD families (11.0 %). In this cohort of children with symptomatic TE, the prevalence of PSD adjusted for family status was 7.4 %. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.

Oral anticoagulants (Vitamin-K-Antagonists, Dabigatran, Rivaroxaban, Apixaban, Edoxaban) or antiplatelet agents (Acetylsalicylic acid, Clopidogrel, Prasugrel, Ticagrelor) are effective in preventing thromboembolic diseases. In case of interventional of surgical procedures patients with indications for chronic anticoagulation (atrial fibrillation, valve prosthesis, venous thromboembolism) or use of antiplatelet agents (cerebrovascular events, cardiovascular events) will require interruption of antithrombotic/antiplatelet therapy with the need of replacement with a short-acting agent. Due to limited data available from randomized studies and meta-analyses the evidence level is low in the majority of recommendations. Therefore for each patient the bleeding and thrombosis risk depending on the individual patient constitution and the planned intervention must be weighted. In patients with an intermediate risk for thrombosis the bleeding risk of the scheduled intervention will influence the bridging recommendation: In patients with a low bleeding risk oral anticoagulation/ antiplatelet therapy can be continued or reduced in intensity. In patients with an intermediate or high bleeding risk along with a low thrombosis risk a temporary interruption of the anticoagulation/antiplatelet therapy is feasible. In patients with a high thrombosis and bleeding risk anticoagulation should be bridged with unfractionated heparin (renal insufficiency) or low molecular weight heparin. In the latter risk situation, inhibition of platelet function can be achieved with short-lasting GPIIb-IIIa inhibitors (Eptifibatide, Tirofiban). Prior to intervention patients treated with the new oral anticoagulants (Dabigatran; Rivaroxaban; Apixaban; Edoxaban) are requested to temporary interrupt the anticoagulation depending on the individual drug half-life and their renal function. Bridging therapy with heparin prior to intervention is not necessary with the new/ direct oral anticoagulants.

Platelet function might play an essential role in the pathogenesis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH). Thus, impaired platelet function and disturbed primary haemostasis induced by intake of acetylsalicylic acid (ASA) might influence the rate of DCI. Primary haemostasis and platelet function can be measured with in vitro diagnosis (platelet function analyser test, PFA 100). The aim of this study is to evaluate the rate of DCI, haemorrhagic complications and the neurological outcome. Two groups were compared (patients with regular platelet function versus patients with impaired platelet function). This is a retrospective observational study. An initial cohort of 787 patients with SAH has been treated from January 2005 to September 2012. Seventy-nine patients (10%) with aneurysmal SAH, a history of ASA medication and PFA testing within the first 24 h after aneurysm rupture have been included. The overall rate of DCI in the present study was 43%. In vitro platelet function testing showed pathological primary haemostasis in 69.6%. The DCI rate was higher in patients with regular tested primary haemostasis (p = 0.02, OR = 3.16, 95%CI = [1.19; 8.83]). However, outcome assessment by mGOS did not show a significant difference between the groups. Patients with impaired primary haemostasis did not display a higher rate of haemorrhagic complications. Impairment of primary haemostasis resulting from an impairment of platelet function at an early stage after SAH might lead to a lower rate of DCI. In vitro testing of platelet function might be useful to predict the occurrence of DCI in the course.

Orale Antikoagulanzien [Vitamin-K-Antagonisten, Dabigatran, Rivaroxaban, Apixaban] und Plattchenfunktionshemmer (PH) [ASS, Clopidogrel, Prasugrel, Ticagrelor] werden alleine oder kombiniert zur Pravention und Behandlung thromboembolischer Erkrankungen eingesetzt. Patienten mit Indikation zu einer dauerhaften Antikoagulation [Vorhofflimmern, mechanischer Herzklappenersatz, venose Thromboembolie] oder PH-Therapie [zerebro- oder kardiovaskulare Ereignisse] benotigen bei interventionellen oder chirurgischen Eingriffen eine vorubergehende Umstellung auf entsprechende Medikamente mit einer kurzen Wirkungsdauer. Die aktuellen Empfehlungen fur das praktische Vorgehen drucken sich aufgrund einer begrenzten Datenlage in schwachen Empfehlungsgraden aus, sodass zur Planung einer uberbruckenden gerinnungshemmenden Therapie [„Bridging“] bei jedem Patienten das Blutungs- und Thromboembolierisiko gegeneinander abgewogen werden mussen. Bei einem mittleren Thromboembolierisiko bestimmt das individuell zu ermittelnde Blutungsrisiko der geplanten Intervention die uberbruckende Therapie: Ist das Blutungsrisiko durch die geplante Intervention gering, kann die orale Antikoagulation/PH-Therapie in den meisten Fallen unverandert weitergefuhrt oder in ihrer Intensitat geringfugig reduziert werden. Ist bei mittlerem bis hohem Blutungsrisiko das Thromboserisiko gering, kann die gerinnungshemmende Therapie auch kurzfristig pausiert werden. Bei hohem Thromboembolie- und Blutungsrisiko wird die Umstellung der oralen Antikoagulation mit unfraktioniertem [eingeschrankte Nierenfunktion] oder fraktioniertem Heparin durchgefuhrt. Die PH-Therapie kann bei hohem Thromboembolie- und Blutungsrisiko mit kurzwirksamen GPIIb-IIIa Antagonisten [Eptifibatide; Tirofiban] uberbruckt werden. Patienten, die auf die neuen oralen Antikoagulanzien [Dabigatran, Rivaroxaban, Apixaban] eingestellt sind, benotigen vor elektiven Interventionen in Abhangigkeit von der Halbwertszeit und der individuellen Nierenfunktion eine Behandlungspause und mussen vor OP nicht mit Heparinen uberbruckt werden.

ObjectiveThe present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA].Patients and Methods216 patients with F8

Venous thrombosis (VTE) in children is increasingly diagnosed, as advanced medical care has increased treatment intensity of hospitalized pediatric patients. The aim of this review was to summarize the data available and to discuss the controversial issue of thrombophilia screening in the light of the pediatric data available. Follow-up data for VTE recurrence in children suggest a recurrence rate between 3% (neonates) and 21% in individuals with unprovoked VTE. Apart from underlying medical conditions, recently reported systematic reviews on pediatric VTE (70% provoked) have shown significant associations between thrombosis and presence of protein C-, protein S- and antithrombin deficiency, factor 5 (F5: rs6025), factor 2 (F2: rs1799963), even more pronounced when combined inherited thrombophilias [IT] were involved. The F2 mutation, protein C-, protein S-, and antithrombin deficiency did also play a significant role at VTE recurrence. Although we have learned more about the pathophysiology of VTE with the increased discovery of IT evidence is still lacking as to whether IT influence the clinical outcome in pediatric VTE. It still remains controversial as to whether children with VTE or offspring from thrombosis-prone families benefit from IT screening. Thus, IT testing in children should be individualized.

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.

Deficiency of antithrombin (AT), protein C (PC) or protein S (PS) constitutes a major risk factor for venous thromboembolism (VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non-central-venous-catheter-associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46-17·2) and female gender (2·6/1·1-6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6-10) in AT-deficient children, 1·3% (0·3-3·8) in patients with PC deficiency, 0·7% (0·08-2·4) in the PS-deficient cohort and 0·9% (0·4-1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE.

Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1-18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.

SummaryVenous thromboembolism [TE] is a multifactorial disease and antithrombin deficiency [ATD] constitutes a major risk factor. In the present study the prevalence of ATD and the clinical presentation at TE onset in a cohort of paediatric index cases are reported. In 319 un - selected paediatric patients (0.1–18 years) from 313 families, recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. 21 of 319 paediatric patients (6.6%), corresponding to 16 of 313 families (5.1%), were AT-deficient with confirmed underlying AT gene mutations. Mean age at first TE onset was 14 years (range 0.1 to 17). Thrombotic locations were renal veins (n=2), cerebral veins (n=5), deep veins (DVT) of the leg (n=9), DVT & pulmonary embolism (n=4) and pelvic veins (n=1). ATD co-occurred with the factor- V-Leiden mutation in one and the prothrombin G20210A mutation in two children. In 57.2% of patients a concomitant risk factor for TE was identified, whereas 42.8% of patients developed TE spontaneously. A second TE event within primarily healthy siblings occurred in three of 313 families and a third event among siblings was observed in one family. In an unselected cohort of paediatric patients with symptomatic TE, the prevalence of ATD adjusted for family status was 5.1%. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population.

Die tiefe Beinvenenthrombose (TVT) mit Lungenembolie zahlt zu den fuhrenden Todesursachen in Schwangerschaft und Wochenbett; jeder Verdacht muss deshalb sofort und definitiv abgeklart werden. Ihre Inzidenz wird auf 0,76–1,72 pro 1000 Schwangerschaften geschatzt und ist damit 4-mal so hoch wie auserhalb der Schwangerschaft (Marik u. Plante 2008).

Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombin [ATD]-, protein C [PCD]- or protein S [PSD]-deficiency constitutes a major risk factor. Since screening for thrombophilia is controversial, individuals at high risk for recurrence who benefit from screening need to be identified. Primary study objective was to determinethe individual recurrence risk in children compared to adults with TE with respect to their thrombophilia status. Methods: In 142 consecutively enrolled TE patients (children n=85; adults n=57) with ATD, PCD or PSD after exclusion of six children with purpura fulminans due to homozygous PCD or PSD we calculated i) the cumulative recurrence rates (CRR) at 1, 5 and 10 year following the first TE onset and, ii) in addition, the absolute recurrence risk (ARR) per 100 patient years (%). Results: At first TE onset in univariate analysis a higher rate of unprovoked TE was found in children, whereas adults presented with a higher rate of a positive TE family history and a higher rate of recurrence: 40 out of 136 patients showed a second TE after withdrawal of anticoagulation (AC) or insufficient AC [n=6]. Two events in children were fatal [pulmonary embolism]. The overall CRR at 1, 5 and 10 years was 10.9%, 20.4% and 29.2% with total ARR [95% CIs] of 5.3 [3.4-7.8] in adults compared to 2.1 [1.0-5.3] in children [p=0.004]. Whereas the ARR was no different between adults and children in ATD patients [5.1 versus 4.7; p=0.85] and in symptomatic PCD subjects [3.9 versus 1.6; p=0.17], adults with PSD showed a higher ARR compared to children [6.3 versus 0.1; p=0.001]. Positive family TE history did not predict recurrence. Conclusion: Given the high ARR of 5.3% in adults and 2.1% in children we suggest screening for ATD, PCD and PSD in adult and pediatric TE patients. The high rate of ARR should be taken into account when initiating future therapeutic trials. Duration and intensity of AC should be carefully reevaluated in patients with ATD, PCD or PSD. Disclosures Young: Baxter, Grifols: Consultancy, Honoraria. Nowak-Gottl:Bayer, LFB: Membership on an entity's Board of Directors or advisory committees.

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.

Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombin [ATD] -, protein C [PCD] - or protein S [PSD] -deficiency constitutes a major risk factor. The objective of the present study was to i) evaluate the prevalence of ATD, PCD and PSD in a white Israeli-German cohort of children with TE, ii) the underlying gene mutations, and iii) the clinical presentation of ATD, PCD and PCS on symptomatic TE in children. Methods: In 367 unselected children (0.1-18 years) with TE recruited between July 1996 and December 2013 from Germany & Israel, a comprehensive thrombophilia screening was performed. Along with standardized plasma-based coagulation assays and the use of age-dependent reference values ATD, PCD and PSD were confirmed by family studies and/or molecular diagnosis [gene sequencing & multiplex ligation-dependent probe amplification]. Apart from descriptive analysis non-parametric statistics was performed. To compare the rates of deficiency phenotypes, locations of TE, spontaneous versus provoked TE, presence or absence of a positive family history of TE, Chi-square or Fisher’s exact test was applied. Results: 6.6% of children were ATD, 6.8% PCD including purpura fulminans (1.4%) and 8.2% patients carried PSD. Mean age at first TE was 13 years (range 0.1 to 18) with no statistically significant difference found between deficiency phenotypes (p=0.32). 38 children were male. 72 of 76 children (95%) showed type 1 deficiency, whereas in 4 cases [ATD] a type 2 deficiency was found (p=0.004). Underlying gene mutations were in the majority of cases missense mutations (SERPINC1: 75%; PROC: 93%; PROS1: 72%), with 24% presence of the Herleen polymorphism (CM951058) in children with PSD. Homozygous genotypes were found in 4 cases [ATD], 6 cases [PCD] and in one PSD carrier [p=0.07]. ATD co-occurred with the factor 5 mutation [F5] at rs6025 in one and the factor 2 susceptibility variant [F2] at rs1799963 in two children. PSD co-occurred with the F5 or the homozygous F2 in one case each. Apart from purpura fulminans which was seen only in neonates with homozygous PCD, thrombotic locations were similarly distributed (p=0.11): multiple veins (n=7), cerebral veins/stroke of venous origin (n=18), deep veins [DVT; n=38], DVT & pulmonary embolism (n=13). The rates of provoked TE were 57% [ATD], 48% [PCD] and 60% in PCD (p=0.06). A positive family history was present in 43% [ATD], 40% [PCD] and 57% [PSD; p=0.41]. After withdrawal of anticoagulation, - performed on an individual basis according to CHEST guidelines (updated according to year of publication) -, recurrence rates were 38% [ATD], 24% [PCD] and 6.6% in carriers of PSD (p=0.017). Conclusion: Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population Disclosures No relevant conflicts of interest to declare.

Objective To determine the importance of antithrombin [AT] deficiency as risk factor or predictor for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. Methods In the present cohort of 874 consecutively enrolled pediatric patients with VTE aged newborn to Results Of the 170 children enrolled 26 [AT n=9; F5 n=17] had recurrent VTE at a median of 15 months [95%CI: 12-36] following VTE onset: two of nine [AT] and two of 17 [F5] children suffered recurrent VTE while on anticoagulation with warfarin. The overall incidence rate of recurrence was 61.5 in patients with AT-deficiency compared to 23.5 for pediatric F5 carriers [p=0.02]. The recurrent-free survival probability is shown in the figure [logrank p-value: p=0.001]. When comparing AT patients and F5 children multivariate analysis [Cox regression] adjusted for age, sex and duration of anticoagulation treatment showed that AT deficiency [HR/95%CI: 4.1/1.8-9.4] significantly influenced the hazard for recurrent VTE. Conclusions Based on multivariate analysis, the presence of AT deficiency was associated with an increased risk of VTE recurrence. AT-deficiency in pediatric patients should be identified at VTE onset and the possible influence of intensified treatment protocols on recurrence should be studied in future prospective international studies. Condensed abstract To determine the relative importance of antithrombin deficiency or factor V (FV) mutations as risk factors for fatal/non-fatal recurrence in pediatric thromboembolism (VTE). Antithrombin deficiency influenced the hazard for recurrent VTE. Disclosures: No relevant conflicts of interest to declare.