New recommendations on cerebral venous and dural sinus thrombosis from the German consensus-based (S2k) guideline.

Over the last years, new evidence has accumulated on multiple aspects of diagnosis and management of cerebral venous and dural sinus thrombosis (CVT) including identification of new risk factors, studies on interventional treatment as well as treatment with direct oral anticoagulants. Based on the GRADE questions of the European Stroke Organization guideline on this topic, the new German guideline on CVT is a consensus between expert representatives of Austria, Germany and Switzerland. New recommendations include:• CVT occurring in the first weeks after SARS-CoV-2 vaccination with vector vaccines may be associated with severe thrombocytopenia, indicating the presence of a prothrombotic immunogenic cause (Vaccine-induced immune thrombotic thrombocytopenia; VITT).• D-dimer testing to rule out CVT cannot be recommended and should therefore not be routinely performed.• Thrombophilia screening is not generally recommended in patients with CVT. It should be considered in young patients, in spontaneous CVT, in recurrent thrombosis and/or in case of a positive family history of venous thromboembolism, and if a change in therapy results from a positive finding.• Patients with CVT should preferably be treated with low molecular weight heparine (LMWH) instead of unfractionated heparine in the acute phase.• On an individual basis, endovascular recanalization in a neurointerventional center may be considered for patients who deteriorate under adequate anticoagulation.• Despite the overall low level of evidence, surgical decompression should be performed in patients with CVT, parenchymal lesions (congestive edema and/or hemorrhage) and impending incarceration to prevent death.• Following the acute phase, oral anticoagulation with direct oral anticoagulants instead of vitamin K antagonists should be given for 3 to 12 months to enhance recanalization and prevent recurrent CVT as well as extracerebral venous thrombosis.• Women with previous CVT in connection with the use of combined hormonal contraceptives or pregnancy shall refrain from continuing or restarting contraception with oestrogen-progestagen combinations due to an increased risk of recurrence if anticoagulation is no longer used.• Women with previous CVT and without contraindications should receive LMWH prophylaxis during pregnancy and for at least 6 weeks post partum.Although the level of evidence supporting these recommendations is mostly low, evidence from deep venous thrombosis as well as current clinical experience can justify the new recommendations.This article is an abridged translation of the German guideline, which is available online.

Lack of evidence for the transmission of hepatitis E virus by coagulation factor concentrates based on seroprevalence data.

BACKGROUND: Whether hepatitis E virus (HEV) infection can be transmitted by coagulation factor concentrates remains unclear. OBJECTIVES: The HEV seroprevalence in blood donors and recipients of coagulation factor concentrates was compared to obtain evidence of whether a transmission of HEV by coagulation factor concentrates could occur. METHODS: Archived samples from whole blood donors and patients who had received coagulation factor concentrates were investigated for the presence of anti-HEV IgG by ELISA. Western blotting was used to confirm the positive samples that showed reactivity in the ELISA. RESULTS: Of 357 blood donors, 68 (19%) presented IgG antibodies against HEV. Two of 92 patients who had received coagulation factor concentrates (2·2%) and 1 of the 69 patients who had received plasma-derived products (1·5%) tested positive for anti-HEV IgG. The seroprevalence of HEV in the patient group was significantly lower (P = 0·038) than that in the donor group. The two positive patients were a 72-year-old man treated with plasma-derived products and a 5-year-old girl treated with a recombinant coagulation factor concentrate. CONCLUSION: HEV seroprevalence was significantly higher in the blood donors than in the patients with a history of coagulation factor concentrate administration. In one of two patients with detectable anti-HEV IgG antibodies, the coagulation factor concentrate was not the probable source of infection. Our data suggest that HEV is efficiently inactivated during the manufacturing process of coagulation factor concentrates. Thus, testing for the presence of HEV RNA in plasma donated for the preparation of coagulation factor concentrates may not be necessary.

The VKORC1 and CYP2C9 genotypes significantly effect Vitamin K antagonist dosing only in patients over the age of 20years.

INTRODUCTION: Given the qualitative differences in the role of VKORC1 and CYP2C9 polymorphisms in Vitamin K antagonists (VKA) dosing variation between adults and children, we were interested in determining at what age these polymorphism begin to play a more significant role. METHODS: A prospective cohort study of 190 patients aged 1-86years receiving VKA for treatment of venous thromboembolism. Blood samples were collected beyond the acute thrombotic event when patients were on stable targeted INR (2-3) for plasma testing and VKORC1/CYP2C9 genotyping. Patient demographics including VKA dose were collected. Simple and multiple linear regression was used to assess the relationship of VKA dose with polymorphisms and weight, adjusted for quality of anticoagulation (INR, D-Dimer), liver (AST, ALT) and renal function. RESULTS: In subjects 1-19years of age, weight explained 39.0% of dosing variation with VKORC1 and CYP2C9 playing a minor role. In contrast, in subjects 20-40years weight contributed 23%, VKORC1 44% and CYPC29 49% of the VKA dose variation. CONCLUSION: Until the age of 19, weight has a far greater effect on VKA dosing variation than VKORC1 and CYP2C9 polymorphisms. During the age of 20-40years, VKORC1 and CYP2C9 play a significant role.

Activity of Von Willebrand factor and levels of VWF-cleaving protease (ADAMTS13) in preterm and full term neonates.

Von Willebrand Factor (VWF) has a central role in primary hemostasis. Its biological activity is related to the size of VWF multimers, spontaneously binding to platelets and inducing circulating microthrombi formation. This process is down-regulated by the VWF cleaving protease ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin motif). To date, information regarding the levels of ADAMTS13 in neonates and preterm infants is scarce. Our aim was to study ADAMTS13, VWF antigen (Ag) and Ristocetin cofactor (RiCof) activity in neonates and evaluate potential correlations with perinatal complications. Our cohort consisted of 128 (48/128: born preterm) neonates, born in Sheba Medical Center and followed until hospital discharge. Control group consisted of 20 healthy adults. As expected, a significant elevation of VWF:Ag was observed in preterm and term infants compared to adults. VWF:Ag levels were highest in full term infants (Median 129.0 IQR 33.8) and lowest in adults (Median 119.0 IQR 58.5) (p<0.05), and RiCoF levels in neonates were higher than in adults. ADAMTS13 was significantly (p<0.05) higher in preterm babies in comparison to full term and adult controls. Neonates that underwent stressful conditions or experienced vascular complications such as IUGR, ROP, NEC, had lower levels of ADAMTS13 in our study. Further studies are required to validate and asses potential significance of these findings.

Patients with Bernard-Soulier syndrome and different severity of the bleeding phenotype.

Bernard-Soulier syndrome is a rare (1:1million), hereditary bleeding disorder caused by defects of the platelet GPIb-IX-V complex. Patients suffer from mucocutaneous bleedings. Typical are thrombocytopenia, giant platelets and impaired agglutination after stimulation with ristocetin. In populations in which consanguineous marriages are common the frequency of the disorder is increased because Bernard-Soulier syndrome is mostly inherited autosomal recessively. Genetic analyses of the disease-related genes may help to gain more insights regarding the phenotype/genotype correlation. Here, we investigated several patients with Bernard-Soulier syndrome from different families. We analyzed two patients with severe bleeding symptoms from one family of middle east origin and confirmed the diagnosis by identifying a pathogenic variant in GP1BB. We compared phenotype/genotype correlation of this GP1BB mutation with the GP9 (p.Asn61Ser) European founder mutation present in 9 patients out of 4 families for whom we also performed molecular genetic analysis.

Quantitative Systems Pharmacology Model to Predict the Effects of Commonly Used Anticoagulants on the Human Coagulation Network.

Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment. The model allowed for estimation of all factor rate constants and production rates. Predictions of individual coagulation factor time courses under steady-state warfarin, enoxaparin, and rivaroxaban treatment reflected the suppression of protein C and protein S under warfarin compared to rivaroxaban and enoxaparin. The model may be used as a tool during clinical practice to predict effects of anticoagulants on individual clotting factor time courses and optimize antithrombotic therapy.

Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

UNLABELLED: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.

Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study.

OBJECTIVES: We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). METHODS: Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. RESULTS: Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9-12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. CONCLUSIONS: Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted.

[Bridging: Perioperative management of chronic anticoagulation or antiplatelet therapy]. / Bridging: Perioperatives Vorgehen bei dauerhafter oraler Antikoagulation oder Plättchenfunktionshemmung.

Oral anticoagulants [Vitamin-K-Antagonists, Dabigatran, Rivaroxaban, Apixaban] or antiplatelet agents [Aspirin, 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] 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 oral anticoagulants.

Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and antithrombin deficiency. An observational multicentre cohort study.

Venous 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 unselected 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.

Efficacy and safety of Wilate in paediatric VWD patients under 6 years of age - results of a prospective multicentre clinical study including recovery information.

Treatment with exogenous von Willebrand factor (VWF) is indicated in patients with von Willebrand disease (VWD) in whom treatment with 1-deamino-8-d-arginine vasopressin/desmopressin is contraindicated. Wilate is a new generation plasma-derived concentrate of native VWF and coagulation factor VIII (FVIII) (in a physiological 1:1 ratio) developed for the treatment of VWD. This is the first study to report safety, efficacy and in vivo recovery (IVR) data from 15 paediatric patients less than 6 years of age who received Wilate for either prophylaxis, on-demand treatment or for treatment in surgical procedures during a prospective open-label trial (VWD type 1: 5, type 2A: 1, type 2B: 2, type 3: 6, unknown type: 1 patients). Analysis of IVR for VWF and FVIII suggested an appropriate and consistent rise in coagulation activity after Wilate administration. Overall efficacy was rated as excellent or good for 99.7% [prophylactic infusions] and 100% [bleeding episodes/surgical procedures]. More than 82% of bleeding episodes resolved after 1 day of treatment, and a Wilate dosage of 20-50 IU kg(-1) was sufficient to achieve haemostasis in 97% of bleeding episodes. All surgical procedures were successfully managed with Wilate. No thromboembolic events were observed during the study, and no patient developed anti-VWF antibodies or FVIII inhibitors. In conclusion, this study confirms both the expected IVR profile in paediatric patients and the excellent efficacy, tolerability and safety profile of Wilate observed previously in adults. Wilate showed excellent efficacy in the treatment of bleeding when used prophylactically or on-demand, and in the treatment of surgical procedures.

Cerebral venous thrombosis in the mediterranean area in children.

Cerebral Venous Sinus (sinovenous) Thrombosis (CSVT) is a serious and rare disorder, increasingly recognized and diagnosed in pediatric patients. The etiology and pathophisiology has not yet been completely clarified, and unlike adults with CSVT, management in children and neonates remains controversial. However, morbidity and mortality are significant, highlighting the continued need for high-quality studies within this field. The following review will highlight aspects of CSVT in the mediteranian area in children.

Plasma glutathione peroxidase in pediatric stroke families.

BACKGROUND/OBJECTIVES: Promoter polymorphisms in the plasma glutathione peroxidase gene (GPX3), which encodes a major antioxidant enzyme implicated in post-translational modification of fibrinogen, have been implicated as risk factors for arterial ischemic stroke (AIS) and cerebral sinovenous thrombosis (CSVT) in young adults. However, the contribution of these polymorphisms could not be confirmed by other studies. PATIENTS/METHODS: The aim of the present study was to investigate the association of three haplotype-tagging single-nucleotide polymorphisms (htSNPs) in GPX3 in a large family-based study sample comprising 268 nuclear families with different pediatric AIS subtypes, i.e. arteriopathy stroke (AS) and thromboembolic stroke (TS). In addition, an independent study sample comprising 154 nuclear families of pediatric CSVT was investigated. Single-point and haplotype association was assessed with the transmission disequilibrium test implemented in haploview. RESULTS: Single-point analysis revealed that the G allele of htSNP rs8177412 was significantly overtransmitted to affected AS children (T/U = 25 : 11, χ(2) = 5.54, P = 0.019), but not to affected TS children (T/U = 49 : 40, χ(2) = 0.91, P = 0.34). The corresponding GG haplotype (H2: frequency 0.18) was also significantly overtransmitted to AS children (T/U = 23 : 11, χ(2) = 4.28, P= 0.03), but not to TS children or in children with CSVT. These results remained significant following 10,000 bootstrap permutations. Our findings indicate that genetic variants of GPX3 are risk factors for AS, but not for thromboembolic AIS or CSVT, in children. CONCLUSIONS: Our results further highlight the need to analyze the contribution of genetic variants to pediatric AS, TS or CSVT separately, as these subcategories probably result from different combinations of risk-conferring and protective genetic variations.

Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.

BACKGROUND: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off-label and little is known about the pharmacokinetics in children. OBJECTIVES: The aim of the present study was to evaluate whether a once- or twice-daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin. PATIENTS/METHODS: A population pharmacokinetic model was developed using anti-factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once- or twice-daily dosing regimen. RESULTS: A two-compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h⁻¹ kg⁻¹, central volume of distribution 169 mL kg⁻¹, intercompartmental clearance 58 mL h⁻¹, peripheral volume of distribution 10 L and absorption rate 0.414 h⁻¹. Interindividual variability was found to be 54% for clearance and 42% for volume of distribution. CONCLUSION: The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once-daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL⁻¹ anti-FXa activity for prophylaxis therapy.

Diagnostic and therapeutic considerations on inherited platelet disorders in neonates and children.

Inherited disorders of platelets constitute a group of rare diseases that give rise to bleeding syndromes of variety severity, with more severe cases being first diagnosed during infancy and childhood. To appropriate diagnose a platelet function disorder during early childhood the knowledge of the physiological characteristics of platelets in the paediatric population is mandatory. Apart from thrombocytopenia which is quite common in neonates and children the present overview is aimed to focus on inherited platelet function disorders. Furthermore, knowledge on platelet maturation and reference values according to age are given, and a diagnostic strategy specifically adapted to a pediatric population is presented on the bases of plasmatic and molecular laboratory methodologies. Finally, therapeutic approaches are briefly summarized (antifibrinolytic agents, Desmopressin, HLA-matched platelets, recombinant factor VIIa).

Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents.

BACKGROUND: The aim of the present study was to evaluate paediatric reference values for platelet function using a point-of-care whole blood impedance aggregometry. METHODS, RESULTS & CONCLUSION: In 265 healthy infants and children aged