Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand ...factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.
•VWF gene variants that modify FVIII binding influence FVIII PK.•Variants in clearance receptors for VWF-FVIII influence FVIII PK.
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Summary
Introduction
As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this ...patient group is not always sufficiently considered or treated in an effective manner.
Aim
The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group.
Method
The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts’ clinical experience, the participants developed a set of recommendations presented in this paper.
Results
Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients’ quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.
Background
Childhood and adolescence are critical periods of bone mineral acquisition. Children on anticoagulation (AC) might have an increased risk for reduced bone mineral density (BMD). Risk ...factors for impaired bone accumulation include chronic diseases, immobility, and medication. Vitamin K (VK) deficiency reflected by undercarboxylated osteocalcin levels (ucOC) has been identified as a predictor of osteoporosis and fractures. Data on bone health in children under AC are sparse.
Aims
To evaluate BMD in children on AC and characterize the risk factors of low BMD, including VK and Vitamin D (VD) status.
Methods
Single-center cross-sectional study of clinical, biochemical, and densitometric parameters. Assessment of VK surrogate parameters included ucOC and matrix gla protein (MGP).
Results
A total of 39 children (4–18 years; 12 females) receiving AC were included, 31 (79%) on VK antagonists and 8 (21%) on direct oral anticoagulants. Overall, BMD was decreased for both the lumbar spine (LS; −0.7SDS) and total body less head (TBLH; −1.32SDS) compared with pediatric reference data. Significant associations were found between early pubertal development and TBLH-BMD, and between BMI and LS-BMD. VK surrogate parameters were highly related to patients’ age and pubertal development. Neither serum parameters nor AC-related factors predicted BMD. VD was detected in 10/39 patients with lower values during puberty.
Conclusion
Our data indicate BMD reduction in pediatric patients on AC. Although AC-related factors did not predict reduced BMD, low BMI and pubertal stages represented important risk factors. Awareness of risk factors for low BMD and high prevalence of VD deficiency during puberty could contribute to the improvement of bone health in this vulnerable patient group.
Advances in medical and surgical care have resulted in improved survival of patients with congenital heart disease (CHD). Parallel to these progresses, an increasing number of immediate and long-term ...complications have been recognized. One important complication in CHD is the development of thrombosis. Children with a single functional cardiac ventricle usually require sequential steps of surgery: the initial Blalock-Taussig shunts (BTS) during the neonatal period, followed by the Glenn shunt, and finally, the Fontan shunt, the "definitive palliative" procedure. Surgery mostly involves cardiopulmonary bypass (CPB), which also affects the coagulation system and causes an inflammatory response. This article will review surgical procedures, such as BTS, Glenn shunt, and Fontan shunt, prosthetic mechanical valves, and CPB, and their risk of thrombotic complications. There is insufficient evidence and no consensus for optimal anticoagulant prophylaxis or treatment in children with CHD. Current recommendations are mostly based on adult data.
Introduction
Pediatric inflammatory multisystem syndrome – temporally associated with SARS-CoV-2 infection (PIMS –TS)
comprises a new disease entity having emerged after the COVID-19 outbreak in ...2019.
Materials and Methods
For this multicenter, retrospective study children between 0 and 18 years with PIMS-TS between March 2020 and May 2021 were included, before availability of vaccination for children. Frequent SARS-CoV-2 variants at that period were the wildtype virus, alpha, beta and delta variants. Inclusion criteria were according to the PIMS-TS criteria, proposed by the Royal College of Pediatrics and WHO. Study aim was to review their clinical, laboratory and echocardiographic data with a focus on cardiac involvement.
Results
We report 45 patients, median age 9 years, 64% male. SARS-CoV-2 antibodies were positive in 35/41 (85%). PIMS occurrence followed local COVID-19 peak incidence periods with a time lag. The most common symptoms at presentation were fever (98%), abdominal pain (89%) and rash (80%). Fever history of > 5 days was associated with decreased left ventricular function (
p
= 0.056). Arterial hypotension and cardiac dysfunction were documented in 72% patients, increased brain natriuretic peptide in 96% and increased cardiac troponin in 64% of the children. Echocardiography revealed mitral valve regurgitation (64%), coronary abnormalities (36%) and pericardial effusions (40%). Increased NT-proBNP was significantly associated with the need of inotropics (
p
< 0.05), which were necessary in 40% of the patients. Treatment comprised intravenous immunoglobulin (93%), systemic steroids (84%) and acetylsalicylic acid (100%; 26/45 started with high dosages). For insufficient response to this treatment, five (11%) children received the interleukin-1 receptor antagonist anakinra. All patients were discharged with almost resolved cardiac signs.
Conclusion
Our analysis of non-vaccinated children with PIMS-TS demonstrates that a considerable number have associated myocarditis requiring intensive care and inotropic support. Most children showed adequate response to intravenous immunoglobulin and steroids and good recovery. Further evaluation of pediatric patients with COVID-19 associated diseases is required to evaluate the impact of new virus variants.
Thrombotic events in children differ from those in adults in epidemiology, pathophysiology, and anatomical location. However, anticoagulation in children is mostly based on evidence from adults while ...scarce evidence exists from children. The classical anticoagulants currently used in children have several limitations, resulting in the need for regular monitoring.
Several direct oral anticoagulants (DOACs) are now authorized for adults in whom they have established efficacy and safety without the need for monitoring. Given their pharmacological properties and the special characteristics of children requiring anticoagulation, the DOACs have the potential to be particularly suitable for children.
All currently approved DOACs have paediatric development plans, targeting various indications for prevention and treatment of thrombosis. Paediatric formulations are being developed and systematic age-specific dosing information will be generated. Whether therapeutic drug monitoring will be necessary in certain situations in children remains to be elucidated. The results of ongoing clinical studies still need to demonstrate whether there is a positive benefit-risk balance in all targeted paediatric indications and age-groups, particularly in indications that have not been explored in adults, such as catheter-related thrombosis or congenital heart disease.
If the advantages of DOACs bear out in the results of the current paediatric studies, they will likely be used widely in children. As of now, the DOACs should not be used routinely in children as there is still insufficient information on appropriate dosing, safety and efficacy. The paediatric community is encouraged to promote participation of children and adolescents into the multiple ongoing studies of DOACs.
•The classical anticoagulants have several limitations for use in children.•The direct oral anticoagulants (DOACs) may be particularly suitable for children.•All DOACs have developmental plans ongoing in children for various indications.•Paediatric formulations, dosing, efficacy and safety are being assessed in children.•Participation of children in studies of DOACs should be encouraged.
We report four children from different families with homozygous antithrombin (AT) deficiency type II affecting the heparin binding site (p.Leu131Phe mutation). All children had severe spontaneous ...venous and/or arterial thromboembolic events shortly after birth. This report intends to raise awareness among clinicians about this rare but severe condition. When thrombosis occurs in an otherwise healthy newborn, a severe congenital thrombophilic disorder should be considered. In homozygous AT deficiency type II, AT activity is typically reduced but may also be in the normal range, posing a diagnostic challenge. Rapid diagnosis is important to initiate appropriate therapy. Standard anticoagulation with heparin may prove ineffective in severe AT deficiency, requiring substitution of AT concentrate and early switch to alternative anticoagulants such as vitamin K antagonists.
•Homozygous antithrombin (AT) deficiency type II can cause neonatal thrombosis.•Low AT activity levels can be difficult to interpret in critically ill neonates.•Heparin therapy is only effective with AT concentrate substitution.•Early switch to alternative anticoagulants is necessary.
Monitoring unfractionated heparin (UFH) is crucial to prevent over- or under-anticoagulation. However, the optimal parameters for monitoring UFH in children are not well established. The study ...objectives were to investigate (1) the relationship between UFH dose and its anticoagulant effect as assessed by anti-Xa, activated partial thromboplastin time (aPTT) and activated clotting time (ACT); (2) other factors influencing UFH effect; (3) the agreement between the assays; and (4) the association between UFH effect and clinical outcome. HEARTCAT was a parallel-cohort randomized controlled trial comparing high-dose (100 U/kg bolus followed by age-based continuous infusion in randomized children) vs low-dose UFH (50 U/kg bolus) during cardiac catheterization in children. Blood samples were drawn before and after UFH administration at 30, 60, and 90 minutes. Four-hundred and two samples of 149 patients were evaluable. Anti-Xa, aPTT, and ACT all showed good discrimination between UFH doses. Regression models demonstrated the following determinants of UFH effect: UFH dose, age, baseline antithrombin (for anti-Xa), and baseline levels of aPTT and ACT, respectively. UFH effects were lower in infants compared with older children, which was more pronounced at low-dose than at high-dose UFH. Agreement between the 3 assays was poor. Most aPTT values were above therapeutic range or beyond measuring limit and thus of limited value for UFH monitoring. No association of UFH dose or effect with clinical outcome could be observed. In conclusion, all assays reflected a significant UFH dose-effect relationship, however, with poor agreement between the respective tests. The age-dependency of UFH effect was confirmed. Notably, the influence of age on UFH effect was dose-dependent.
•Anti-Xa, aPTT, and ACT discriminate well between different heparin dose protocols but the assays are poorly correlated with each other.•The heparin effect was lower in younger children. This influence of age was dose-dependent and more pronounced at low- vs high-dose heparin.
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