Validation of a predictive model for identifying an increased risk for recurrence in adolescents and young adults with a first provoked thromboembolism.

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.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Acquired von Willebrand syndrome in ECMO patients: A 3-year cohort study.

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.

Two Novel Variants in the Protein S Gene PROS1 Are Associated with Protein S Deficiency and Thrombophilia.

Protein S (PS) is an important anticoagulant. Its main function is to act as a non-enzymatical cofactor of activated protein C. PS deficiency is defined as low plasma levels of PS and/or loss of function associated with variable risk of venous thromboembolism (VTE). We report 2 novel variants in the PS gene (PROS1) which are associated with PS deficiency and severe thrombophilic diathesis in 2 patients. Patient 1 suffered from 3 VTE events, including a spontaneous VTE at the age of 19. Patient 2 suffered from 2 provoked VTE events. In both patients decreased plasma levels of PS antigen as well as decreased PS activity were found. Gene sequencing results showed a heterozygous deletion of 8 base pairs (c.938_945delTAAAATTT, p.Leu313Serfs13*) in exon 9 of the PROS1 gene in patient 1 and a missense variant (c.1613C>T, p.Ser538Phe) in patient 2. Due to the clinically proven history of recurrent VTE events in both patients, genetic testing of first-degree relatives is discussed.

Cross-Sectional and Longitudinal Construct Validity of the Generic KINDL-A(dult)B(rief) Questionnaire in Adults with Thrombophilia or with Hereditary and Acquired Bleeding Disorders.

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.

Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

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.

Age-Dependent Control of Collagen-Dependent Platelet Responses by Thrombospondin-1-Comparative Analysis of Platelets from Neonates, Children, Adolescents, and Adults.

Platelet function is developmentally regulated. Healthy neonates do not spontaneously bleed, but their platelets are hypo-reactive to several agonists. The mechanisms underlying immature platelet function in neonates are incompletely understood. This critical issue remains challenging for the establishment of age-specific reference ranges. In this study, we evaluated platelet reactivity of five pediatric age categories, ranging from healthy full-term neonates up to adolescents (11-18 years) in comparison to healthy adults (>18 years) by flow cytometry. We confirmed that platelet hypo-reactivity detected by fibrinogen binding, P-selectin, and CD63 surface expression was most pronounced in neonates compared to other pediatric age groups. However, maturation of platelet responsiveness varied with age, agonist, and activation marker. In contrast to TRAP and ADP, collagen-induced platelet activation was nearly absent in neonates. Granule secretion markedly remained impaired at least up to 10 years of age compared to adults. We show for the first time that neonatal platelets are deficient in thrombospondin-1, and exogenous platelet-derived thrombospondin-1 allows platelet responsiveness to collagen. Platelets from all pediatric age groups normally responded to the C-terminal thrombospondin-1 peptide RFYVVMWK. Thus, thrombospondin-1 deficiency of neonatal platelets might contribute to the relatively impaired response to collagen, and platelet-derived thrombospondin-1 may control distinct collagen-induced platelet responses.

Screening for Platelet Dysfunction and Use of Prophylactic Tranexamic Acid in Patients Undergoing Deep Brain Stimulation: A Retrospective Analysis of Incidence and Outcome of Intracranial Hemorrhage.

INTRODUCTION: The rate of intracranial hemorrhage (ICH) after deep brain stimulation (DBS) is between 1.5 and 6.1%, with prolonged deficits occurring in 0.4-2.5% of the patients. This retrospective study investigates whether the prophylactic administration of tranexamic acid (TA) to patients with abnormal platelet function detected preoperatively by platelet function analyzer (PFA) lowered the risk for an ICH event. METHODS: We performed a systematic review of the medical records of 485 consecutively admitted patients who underwent bilateral DBS surgery in a single-center university hospital setting between 2009 and 2018. The cohort was split into two groups. In one group, preoperative PFA screening was performed (n = 156, patients recruited from 2014 to 2018), and TA was administered if platelet function was abnormal. No preoperative PFA was performed in the second group (n = 359, patients recruited from 2009 to 2013). Both cohorts were analyzed for the occurrence of ICH, defined by (i) detection of ICH in routine postoperative magnetic resonance/computed tomography imaging or (ii) in non-routine imaging for the onset of new neurological symptoms. RESULTS: Fourteen of the 156 screened patients (9%) showed reproducible PFA-100 closure abnormalities (3 with von Willebrand disease, 11 with no identifiable cause of platelet dysfunction). Two of the 156 patients (1.3%) in this cohort revealed an ICH on imaging, 1 of whom (0.6%) exhibited a prolonged neurological deficit as a result of ICH. In the cohort without platelet testing, 11 of the 329 patients (3.3%) demonstrated ICH on imaging, of whom 5 (1.5%) suffered from a prolonged neurological deficit. CONCLUSION: In this retrospective study, the screening and the administration of TA appeared to lower the risk of an ICH by 1.8%. One patient with von Willebrand disease suffered an ICH despite TA treatment. A prospective study is needed to clarify the impact of platelet testing and TA administration on the of incidence ICH.

Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.

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 < 10-5). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and ß-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of P = 1.42 × 10-6/2.0 × 10-6 and P = 6.11 × 10-6/1.8 × 10-5, respectively. Rs2748331 was replicated (P = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined P = 7.88 × 10-7). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in SMAP1 and 3 in RIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: P = .08326, SMAP1; rs767118962: P = .08326, RIMS1; and rs41265501: P = .05778, RIMS1). In conjunction, our data provide compelling evidence for SMAP1, B3GAT2, and RIMS1 as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.

Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population.

Risk factors for arterial ischemic stroke in children include vasculopathy and prothrombotic risk factors but their relative importance to recurrent stroke is uncertain. Data on recurrent stroke from databases held in Canada (Toronto), Germany (Kiel-Lübeck/Münster), and the UK (London/Southampton) were pooled. Data were available from 894 patients aged 1 month to 18 years at first stroke (median age, 6 years) with a median follow-up of 35 months. Among these 894 patients, 160 (17.9%) had a recurrence between 1 day and 136 months after the first stroke (median, 3.1 months). Among 288 children with vasculopathy, recurrence was significantly more common [hazard ratio (HR) 2.5, 95% confidence interval (95% CI) 1.92-3.5] compared to the rate in children without vasculopathy. Adjusting for vasculopathy, isolated antithrombin deficiency (HR 3.9; 95% CI: 1.4-10.9), isolated elevated lipoprotein (a) (HR 2.3; 95% CI: 1.3-4.1), and the presence of more than one prothrombotic risk factor (HR 1.9; 95% CI: 1.12-3.2) were independently associated with an increased risk of recurrence. Recurrence rates calculated per 100 person-years were 10 (95% CI: 3-24) for antithrombin deficiency, 6 (95% CI: 4-9) for elevated lipoprotein (a), and 13 (95% CI: 7-20) for the presence of more than one prothrombotic risk factor. Identifying children at increased risk of a second stroke is important in order to intensify measures aimed at preventing such recurrences.

Hemostasis in the Very Young.

Hemostasis is a dynamic process that starts in utero. The coagulation system evolves with age, as evidenced by marked physiological differences in the concentration of the majority of hemostatic proteins in early life compared with adulthood. This concept, known as "developmental hemostasis," has important biological and clinical implications. Overall, impaired platelet function, along with physiologically reduced levels of vitamin K-dependent and contact coagulation factors, may cause poorer clot firmness even in healthy neonates. However, increased activity of von Willebrand factor and low levels of coagulation inhibitors that promote hemostasis counterbalance the delicate and immature hemostatic system. Since this hemostatic system has little reserve capacity, preterm neonates or sick infants are extremely vulnerable and predisposed to either hemorrhagic or thrombotic complications. This review will address the concept and manifestations of developmental hemostasis with respect to clinical disease phenotypes. It will discuss bleeding diagnosis in neonates, dealing especially with the devastating complications of intracerebral and pulmonary hemorrhage in preterm infants. Neonates, especially the sickest preterm ones, are also extremely susceptible to thrombotic complications; thus, thrombosis in neonates will be reviewed, with special focus on arterial ischemic perinatal stroke. Based on the concept of developmental hemostasis, the phenotypes of clinically relevant bleeding or thrombotic disorders among neonates may differ from those of older infants and children. Treatment options for these conditions will be suggested and reviewed.

Psychometric Properties of a Modified KINDL-R Questionnaire for Adolescents and Adults, and Construction of a Brief Version, the KINDL-A(dult)B(rief) Questionnaire, KINDL-AB.

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.

Risk factors for symptomatic venous and arterial thromboembolism in newborns, children and adolescents - What did we learn within the last 20years?

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.

Developmental hemostasis: A lifespan from neonates and pregnancy to the young and elderly adult in a European white population.

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".

Health-related quality of life in children, adolescents and adults with hereditary and acquired bleeding disorders.

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 8-18years 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.

Impact of high-risk thrombophilia status on recurrence among children with a first non-central-venous-catheter-associated VTE: an observational multicentre cohort study.

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.

Impact of high risk thrombophilia status on recurrence among children and adults with VTE: An observational multicenter cohort study.

BACKGROUND: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VTE]. 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 VTEs, and iii) showed a higher proportion of unprovoked VTE compared to adolescents and adults. Adult patients reported more often a positive VTE 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 VTE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children.

Advances in understanding stroke risk in children--a geneticist's view.

The advent of the genomic era has provided novel insights into the genetic architecture of common complex diseases, such as thrombophilia and stroke. Since 2006, a growing number of genome wide association studies (GWAS) for common complex diseases have revealed new candidate loci and genomic regions that play an important role in disease aetiology and progression. While GWAS on the above mentioned traits are abundant in adults, similar studies in paediatric study cohorts are lagging behind. However, genetic research in this important clinical area has gained momentum and starts to provide us with exciting insights into the genetic underpinnings of stroke with paediatric onset. Here we review recent advances in genetic association studies underlying stroke in children and aim to translate the results to clinical utility. These studies comprise candidate gene approaches and GWAS, and represent the current status on what we have learnt about the genetic architecture underlying paediatric stroke, and how this may affect medical practice in the years to come.

Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study.

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.