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Asymptomatic central venous catheter (CVC)–related thrombosis in children varies in incidence from 5% to 69%. The rate of acute and long-term complications, such as postthrombotic syndrome (PTS), from asymptomatic CVC-related thrombosis is unknown. This article reports the outcomes of a prospective study of 189 children in pediatric intensive care that aimed to determine the frequency of asymptomatic CVC-related thrombosis during hospital admission, and the incidence of residual CVC-related thrombosis and clinically significant PTS 2 years later. Risk factors associated with CVC-related thrombosis were also identified. This study is distinct from previous work as children identified to have asymptomatic CVC-related thrombosis were not treated (clinical team kept blinded) and the entire cohort was followed for 2 years to determine the natural history of asymptomatic thrombosis. Ultrasounds of 146 children determined a 21.9% incidence of acute CVC-related thrombosis. Two children were symptomatic. No radiological thrombosis extension or clinical embolization occurred in the 126 children assessed at follow-up. Using 2 recognized PTS scales, clinically significant PTS was reported in 2 children (1 symptomatic, 1 asymptomatic CVC-related thrombosis), however, neither had functional impairment. Cardiac arrest was a risk factor for CVC-related thrombosis during admission and femoral CVC placement was predictive of residual thrombosis 2 years later. This study challenges the notion that critically ill children with asymptomatic CVC-related thrombosis require anticoagulant treatment, as the results demonstrate that the incidence of acute or long-term complications is low. A larger confirmatory study of nontreatment of CVC-related thrombosis in critically ill children is justified.

Background: A growing number of randomized clinical trials (RCTs) provide promising data on pharmacokinetics/ pharmacodynamics, efficacy and safety of DOAC in children and the first DOACs have recently been approved for treatment of thromboembolism in children. Based on the risk benefit profiles published so far, we expect DOACs to be widely used for treatment and prophylaxis of thrombosis in children. The strict inclusion criteria for participation in the RCTs limit their generalizability, particularly to those with more serious acute and chronic medical conditions that account for a significant proportion of pediatric VTE patients in clinical practice. Real world data complements evidence from randomized clinical trials, and is urgently needed to improve patient care.

Background: In multiple myeloma (MM), inactivating mutations and loss of the histone demethylase KDM6A (also named UTX, Ubiquitously transcribed Tetratricopeptide repeat, X chromosome) locus are found in up to 50% of patients and are associated with poorer prognosis. KDM6A belongs to a family of Jumonji-C (Jmj-C)-containing demethylases that work as a scaffold for a multiprotein complex containing H3K4 specific methyltransferases KMT2D and/or KMT2C (MLL2/3), the histone acetyltransferase CBP/p300 and members of the SWI/SNF chromatin-remodeling complex. In a concerted manner this complex activates enhancers by adding activation marks on histones and removing methylation of lysine 27 on histone H3 (H3K27me) associated with gene repression. The H3K27me3 methyltransferase EZH2 that catalyzes the reverse reaction of KDM6A, is often overexpressed in MM and this also correlates with poor prognosis. As well, KMT2C, KMT2Dand SWI/SNFcomponents of its complex are all found significantly mutated in MM which emphasize the importance of enhancer deregulation in myeloma.

Young: Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria. Lensing:Bayer: Employment. Male:Bristol Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Bayer: Consultancy. Kubitza:Bayer: Employment.Pediatric treatment of VTE for a drug approved only in adults.

Liem: Global Blood Therapeutics: Consultancy; Fresenius Kabi: Other: DSMB; NHLBI: Research Funding.

Age specific differences in the function and concentration of haemostatic proteins are well established and are thought to contribute to the lower incidence of thromboembolism in infants and children compared to adults. We hypothesized that there are age-specific differences in the fibrin clot nanostructure and that these differences impact on fibrinolytic and anticoagulant treatment.To determine the differences in fibrin clot nanostructure and response to tissue Plasminogen Activator (tPA) and Unfractionated Heparin (UFH) in infants compared to adults.Four plasma samples from infants (0.86±0.16 years) and four samples from adults (32.04±15.80 years) were investigated. Thrombin generation (TG) was performed on paper discs in a microplate with 300mmol/L rhodamine substrate (P2Rho), 4mmol/L phospholipids, 5x10-9 mmol/L tissue factor and 16.7 mmol/L CaCl2; with and without additional 50ng/ml tPA, and 0.01IU/ml UFH. Fluorescence signal was recorded with a Fluoroskan Ascent fluorometer, with samples tested in triplicate. The resulting fibrin clots were fixed with 2.5% glutaraldehyde; washed with PBS and fixed with osmium tetroxide OsO4. The clots were dehydrated in ethanol and hexamethyldisilazane and were placed on carbon adhesive tabs. Each clot was coated with gold and studied using Scanning Electron Microscopy (SEM) on a Phenom Pro desktop SEM. The age-specific differences in fibrin fibre thickness and pore size were quantified using the Fibermetric software, with 36 representative images for infants and the same number for adults at each baseline, tPA and UFH, at magnification 10.000, counting 500 fibres per image.We observed significant differences in fibrin clot nanostructure between infants and adults (Fig 1). Results are expressed as median and range. Fibrin fibers were thicker in infants compared to adults (343.3nm, 61.2nm to 997.1nm vs 352.3nm, 26.1nm to 997.5nm, p<0.001). In addition, the pore size was larger in infants (0.057pm2, 0.0041pm2 to 19.97pm2 vs 0.052pm2, 0.001pm2 to 15.24pm2, p<0.001).In the presence of tPA in the adult sample, the fibrin fibers were thicker (352.3nm, 26.1nm to 997.5nm vs 355.8nm, 70.0nm to 999.6nm, p<0.05) and pore sizes larger (0.052pm2, 0.001pm2 to 15.24pm2 vs 0.049pm2, 0.0041pm2 to 20.26pm2, p<0.001) compared to baseline. Strikingly, in children, tPA did not induce changes in the fibrin fiber thickness (343.3nm, 61.2nm to 997.1nm vs 343.0nm, 65.6nm to 998.8nm, p>0.05) and pore size (0.057pm2, 0.0041pm2 to 19.97pm2 vs 0.050pm2, 0.0041pm2 to 19.34pm2, p>0.05).In the presence of UFH in adults fibrin fibers were thicker (352.3nm, 26.1nm to 997.5nm vs 339.0, 66.9nm to 996.4nm, p<0.001) and pore sizes larger (0.052pm2, 0.001pm2 to 15.24pm2 vs 0.0540pm2, 0.0041pm2 to 21.87pm2, p<0.001) compared to baseline. In infants, in the presence of UFH, fibrin fibers were thicker (343.3nm, 61.2nm to 997.1nm vs 369.5nm, 109.1nm to 998.4nm, p<0.001), and pore sizes larger (0.057pm2, 0.0041pm2 to 19.97pm2 vs 0.055pm2, 0.0041pm2 to 24.25pm2, p<0.05).Our study suggests that the fibrin clots in infants are weaker compared to those of adults and is consistent with the lower TG in infants. This is further supported by published evidence that clots produced with low thrombin concentrations are composed of thick fibrin fibres, whereas those generated with high thrombin concentrations are composed of a tight network of thin fibres.The effect of both tPA and UFH on fibrin clots nanostructure in adults is consistent with published literature and is investigated in children for the first time. The fact that tPA did not have an effect on the fibrin clots of infants is not surprising considering that the concentration of plasminogen is 39%, tPA is 40% and TAFI function is 60% of the adult value; while PAI function is 50% higher compared to adults. UFH had an effect of the fibrin clot nanostructure in both infants and adults, with the effect on pore size being more pronounced in adults.While developmental haemostasis has been understood for many years, this is the first study to provide definitive proof that the end product of coagulation is a different clot structure in children. This further enhances our understanding of why thrombosis are less common in children, and has significant implications for treatment.No relevant conflicts of interest to declare.

Developmental Haemostasis, the concept describing maturation of the haemostatic system is based on established age specific differences in the quantity and function of haemostatic proteins. Interestingly, infants and children have a lower incidence of thromboembolic events than adults. Understanding the precise mechanism of thromboprotection in infants and children may therefore provide novel prevention and treatment strategies for adults. We hypothesized that a significant component of the thromboprotective mechanism is contributed to by the age-specific differences in thrombin generation.This study was designed to investigate differences in thrombin generation in different age groups from infants to adults, to obtain more insight into age related differences in thromboembolic rates.Plasma samples from 86 infants, children and adults were tested individually and the results were grouped according to age: 1 month to 1 year (N=13), 1-5 years (N=20), 6-10 years (N=19), 11-16 years (N=16) and adults (N=18). Thrombin generation (TG) was measured using Calibrated Automated Thrombinography (CAT) triggered with tissue factor (TF) at 5pM and 1pM final concentration. Parameters measured from the TG curve included: lag time, maximal thrombin concentration (peak), time to peak, as well as the area under the curve (endogenous thrombin potential, ETP). The raw data from TG was also used to calculate the overall, as well as alpha-2-macroglobulin (A2M) dependent decay constants. A2M function was measured with a thrombin inhibition assay developed in house.Both ETP and peak thrombin in infants and children was consistently significantly lower than in adults at both 1pM and 5pM tissue factor concentrations. The difference in ETP ranged from 27% to 35% (p<0.0001), while the difference in peak thrombin generated ranged from 28% to 37% (p<0.005). The thrombin decay constant (total inhibition of thrombin) was 15% (p<0.01) higher in infants and children compared to adults. The A2M-specific decay constant was on average 93% (p<0.001) higher in the younger populations and represented 14% of the total thrombin inhibition, compared to 9% in adults. The functional A2M-levels were 54% (p<0.05) higher in infants and children compared to adults; and correlated significantly with age (r=0.564, p<0.001).This study confirms that TG in children (including adolescents) is lower than in adults and shows for the first time that this is predominantly caused by higher thrombin inhibition, largely due to an increase of A2M activity.Considering that the levels of A2M are increased by 50%, Antithrombin is decreased by approximately 37%, whilst the levels of Prothrombin, Fibrinogen and Heparin Cofactor II remain the same in infants and children compared to adults; therefore A2M is an important inhibitor of thrombin in early life and during childhood.Age-specific differences in thrombin generation as demonstrated by our study possibly play an important role in the thromboprotective mechanism functioning in infants and children.No relevant conflicts of interest to declare.

Adapted from the adult definition, pediatric antiphospholipid syndrome [APS] has been defined as one or more arterial or venous thrombosis associated with persistent antiphospholipid antibodies, i.e. IgM or IgG anticardiolipin antibodies [ACL: cut-off > 99th age-dependent percentile] or the presence of lupus anticoagulants confirmed in at least one follow-up visit more than 8 to 12 weeks apart. Antiphospholipid antibodies play an important role in the development of pediatric thromboembolism [TE] with arterial TE or stroke being more often associated with primary APS compared to deep venous thrombosis [DVT], which is observed predominantly in children with secondary APS. However, results of single studies on the risk thromboembolism onset associated with APS have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of APS on risk of childhood arterial and venous TE via meta-analysis of published observational studies.A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2010 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, laboratory methodologies, country of origin, number of patients/controls, ethnicity, type and location of TE were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models.Eight of 319 (DVT) and seven out of 185 (arterial TE) references found met inclusion criteria: In total 1403 patients and 1904 population-based controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. In addition, regression analysis did not reveal statistical significant differences between locations of TE, age at first disease onset, study country, or publication year. Thus, data from arterial and venous TE were analyzed together. A statistically significant association with a first TE onset was demonstrated with a cumulative summary ORs/CIs (fixed-effects model) of 5.9/3.6-9.7.The present meta-analysis indicates that APS serves as a clinical meaningful risk factor for a first symptomatic TE in children. However, the impact of APS upon outcome and recurrence risk needs to be further investigated.No relevant conflicts of interest to declare.

The incidence of stroke in children is estimated at about 2.6 per 100,000 per year. Risk factors include congenital heart malformations, trauma, hemolytic anemias, collagen tissue diseases, inborn metabolic disorders, and infectious diseases. Apart from acquired thrombophilic risk factors, such as the presence of antiphospholipid antibodies, inherited thrombophilias (IT) have been found to be associated with stroke in infants and children. However, results of single studies on the risk of stroke onset associated with IT have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of thrombophilia (IT) on risk of childhood stroke via meta-analysis of published observational studies.A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, stroke type (arterial ischemic stroke [AIS]; cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models. Twenty-one of 185 references found met inclusion criteria. 1698 patients (AIS: 1291; CSVT: 407) and 2913 controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with stroke onset was demonstrated for each IT trait evaluated, with no difference found between AIS (table) and CSVT. Summary ORs/CIs (random-effects model) for AIS & CSVT cohorts were as follows: Protein C-deficiency (8.76/4.53-16.96), FV G1691A (3.34/2.66-4.26), FII G20210A (2.50/1.67-3.74), MTHFR T677T (1.61/1.21-2.14), antiphospholipid antibodies (5.84/3.06-11.18), elevated lipoprotein (a) (6.24/4.51-8.64), and combined ITs (8.85/3.32-23.57). Carrier rates reported for antithrombin- or protein S deficiency among patients were 1.5% and 1.6% as compared with 0.06% (p<0.001) and 0.4% (p=0.003) in healthy controls.The present meta-analysis indicates that IT serve as risk factors for incident stroke. However, the impact of IT upon outcome and recurrence risk needs to be further investigated.Manco-Johnson: Baxter BioScience: Honoraria; Bayer HealthCare: Honoraria; CSL Behring: Honoraria; NovoNordisk: Honoraria; Octapharma: Honoraria. Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.