Identifying hemophilia B carriers: Utility of aPTT, factor IX levels and ratios of factor IX to other Vitamin K dependent factors.

INTRODUCTION: Diagnosing hemophilia B (HB) carrier status is important to manage bleeding in carriers and to prevent bleeding in potential offspring. Without a family history of hemophilia, diagnosing HB carrier status is challenging. Genetic testing is the gold-standard, however it is reserved for individuals with a high suspicion of carrier status. AIMS: To describe the distribution of activated partial thromboplastin time (aPTT) and factor IX coagulant (FIX:C) levels in HB carriers and assess the ratio of FIX:C to other Vitamin K dependent factors (FII:C, FVII:C, FX:C) as an indicator of HB carrier status. METHODS: In this retrospective, single-centre cohort study, subjects were included if they were obligate or genetically proven HB carriers. Distributions of aPTT and FIX:C were described and the relationship between FIX:C levels in carriers and severity of familial HB was analysed. Ratios of FIX:C to FII:C, FVII:C, FX:C were calculated. RESULTS: Seventy-two female HB carriers (median age: 34 years; IQR 24-43) were included. Median aPTT and FIX:C levels were 33.0 s [IQR 30.0-37.0] and 57 IU/dL [IQR 43-74]. Fifteen carriers (21%) had mild HB (FIX:C levels of 10-40 IU/dL). FIX:C levels trended higher in carriers of mild HB versus carriers of moderate/severe HB. In six carriers, the median ratio of FIX:C to other Vitamin K dependent factors was 0.44, with 92% of ratios being ≤ 0.75. CONCLUSION: aPTT and FIX:C levels were unreliable in diagnosing HB carrier status. A low ratio of FIX:C to other Vitamin K dependent factors may be a useful marker of HB carrier status.

Identifying and Treating Severe Bone Marrow Necrosis and Fat Embolism Syndrome in Pediatric Patients With Sickle Cell Disease: A Case Report.

Fat embolism syndrome after bone marrow necrosis is an extremely rare complication in sickle cell disease associated with significant morbidity and mortality. A high index of suspicion is required for diagnosis. This case report will assist pediatric clinicians and hematologists to recognize this severe complication in patients with sickle cell disease and to promptly initiate treatment. Red flags include severe bone pain, respiratory distress, neurological impairment, decreasing platelet count, peripheral leukocyte left shift, elevated nucleated red blood cells, and significant elevation in plasma ferritin and lactate dehydrogenase. We report a pediatric patient who was diagnosed early, received urgent red cell exchange transfusion and plasma exchange, and ultimately survived this devastating complication.

Increased levels of IL-10 and IL-1Ra counterbalance the proinflammatory cytokine pattern in acute pediatric immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease which leads to accelerated platelet clearance. We investigated the plasma cytokine, chemokine and growth factor signatures and their clinical significance in pediatric ITP patients during acute, chronic and follow-up stages as well as the effects of intravenous immunoglobulin (IVIg) treatment, by using the Multiplex technology. In acute ITP before and/or after IVIg treatment we found significantly increased plasma levels of the pro- (tumour necrosis factor-α (TNF-α), interleukin IL-15) and anti- (IL-1 receptor antagonist (Ra), IL-10 and the growth factor interferon γ-induced protein (IP-10)) inflammatory cytokines, compared to healthy controls. Except for IL1-Ra, these cytokines decreased to normal levels in chronic patients. In contrast, growth-regulated α protein (GRO) and soluble CD40 ligand (sCD40L), known as platelet-derived molecules, were found to be significantly decreased in acute and increased in chronic ITP patients compared to healthy controls. GRO levels positively correlated with the platelet counts in the follow-up and chronic cohort. Monocyte counts showed a significant positive correlation only with IP-10 levels in acute ITP after IVIg treatment and follow-up patients. Expression levels of mRNAs for macrophage inflammatory protein MIP1-ß, IL-1Ra and GRO determined in peripheral blood mononuclear cells (PBMCs) were significantly reduced in both acute and chronic ITP compared to controls. Our findings suggest that the different clinical presentation of acute and chronic pediatric ITP and to a lesser extent the IVIg treatment effects are characterized overall by a counterbalanced cytokine, chemokine and growth factor pattern response that might exert a pathogenic role in this disease.

The role of coagulation factors VIII, IX and XI in the prediction and mediation of recurrent thrombotic events in children with non-central venous catheter deep vein thrombosis.

BACKGROUND: The role of elevated coagulation factors VIII (FVIII), FIX, FXI for the prediction of recurrent thrombotic events in children after an index non-central venous catheter (non-CVC) related deep vein thrombosis (DVT) remains unclear. OBJECTIVE: This study investigates the predictive role of FVIII, FIX, and FXI for recurrent thrombosis in children with index non-CVC DVTs, and the mediation effect of FVIII on chronic inflammation and recurrent thrombosis. METHODS: Children aged 0-18 years diagnosed with an index non-CVC related DVT (1993-2020) were included in this single-center retrospective cohort study. Plasma levels of FVIII, FIX, FXI were measured cross-sectionally ≥30 days after the acute DVT. The association between the continuous variables FVIII, FIX, FXI and thrombosis recurrence was investigated using uni- and multivariable logistic regression, adjusting for age, sex, and chronic inflammation. Mediation analysis assessed the role of FVIII as a mediator between chronic inflammation and recurrent thrombosis. Ethics approval was obtained. RESULTS: A total of 139 children with an index non-CVC related DVT were included. Thirty-eight (27 %) had a recurrent thrombosis at a median of 237 days (P25-P75 65-657 days) after the index DVT. In uni- and multivariable-analysis, FVIII, FIX or FXI did not predict thrombosis recurrence; However, chronic inflammation was an independent predictor. There was no evidence that FVIII mediated the effect of chronic inflammation on thrombosis recurrence. CONCLUSION: We found no evidence that elevated FVIII, FIX or FXI predicted thrombosis recurrence, or evidence of a mediating role of FVIII. Underlying chronic inflammation predicted venous recurrent thrombotic events in this cohort.

Role of factor VIII, IX, and XI in venous thrombosis recurrence risk in adults and children: A systematic review.

Background: Predicting recurrent venous thromboembolic events (VTEs) is challenging in clinical practice for both adults and children, but it is relevant for clinical management. Identifying laboratory risk factors for VTE recurrence may aid in clinical decision-making. Objective: The goal of this systematic review is to investigate the predictive role of FVIII, IX, or XI in recurrent VTE in adult and pediatric patients with a first VTE. Methods: A systematic review of the published literature was conducted in databases MEDLINE In-Process, Other Nonindexed Citations, MEDLINE Epub Ahead of Print, EMBASE Classic + EMBASE (OvidSP), and Cochrane (Wiley). We included observational and interventional studies that comprised adults or children with a first VTE, FVIII, FIX, and/or FXI and objectively confirmed VTE recurrence. The quality in prognosis studies tool was used to assess the risk of bias. Results: We identified 2177 unique studies, of which 19 were included (18 for adults and 1 for children). The risk of bias was overall low to moderate. The studies were heterogenous with regards to population (provoked/unprovoked primary VTE), exposure (type of assay and cut-off values), and statistical analysis results (measures of association and modeling strategy). In adults, contradictory evidence was found for FVIII and FXI as outcome predictors, while no research could establish if FIX predicts VTE recurrence. Data in pediatrics were limited. Given the extensive heterogeneity of the literature, a meta-analysis was not performed. Conclusions: Overall, there is contradictory evidence that FVIII, FIX, or FXI predict recurrent VTE in adults and children. Addressing heterogeneity is a relevant aspect to consider in future studies investigating prognostic factors for VTE recurrence.

Case Report: A Case of Bone Marrow Necrosis and Hyperinflammation in a 10-Year-Old Boy after Plasmodium falciparum Infection.

A 10-year-old boy with sickle cell disease (SCD) type SC presented with fever and abdominal pain after travel to Ghana and was diagnosed with Plasmodium falciparum infection. Despite adequate antimalarial treatment, he developed evidence of hyperinflammation with marked elevated ferritin, C-reactive protein, and triglycerides and subsequent bone marrow necrosis, characterized by elevated nucleated red blood cells and significant bone pain. This case report highlights the possible association between malaria and bone marrow necrosis in patients with SCD. Important considerations in treatment and workup of patients presenting with malaria and hyperinflammation are discussed.

Adverse Events of DOACs in Children.

Venous thromboembolism (VTE) has an increasing rate of significance in pediatric patients. The currently standardized anticoagulants (unfractionated heparin, low molecular weight heparin and vitamin K antagonists) and their dose regimens were not comprehensively trialed in pediatric patients. Recently, several direct oral anticoagulants (DOACs) have been studied in clinical trials in the pediatric population and further trials are ongoing. Dabigatran etexilate and rivaroxaban results show that these DOACs are safe and efficient in the treatment and secondary prevention of pediatric VTE. This review will focus on adverse events (AEs) between specific DOACs reported in the clinical trials in children and compare them to standard of care. This will assist clinicians in decision making of selecting the right anticoagulation for their pediatric patients.

Management of Venous Thromboembolism in Children: Current Recommendations and Therapeutic Options.

Venous thromboembolism has an increasing significance in the pediatric patient population. Due to the lack of well-designed pediatric clinical trials, recommendations for the treatment of venous thromboembolic events in children have low evidence and are mainly extrapolated from adult guidelines. This review summarizes and compares recommendations for the treatment of several venous thromboembolic events in children from CHEST, ASH, and the UK guidelines.