To identify pertinent clinical variables discernible on the day of hospital admission that can be used to assess risk for hospital-acquired venous thromboembolism (HA-VTE) in children.
The Children's ...Hospital-Acquired Thrombosis Registry is a multi-institutional registry for all hospitalized participants aged 0-21 years diagnosed with a HA-VTE and non-VTE controls. A risk assessment model (RAM) for the development of HA-VTE using demographic and clinical VTE risk factors present at hospital admission was derived using weighted logistic regression and the least absolute shrinkage and selection (Lasso) procedure. The models were internally validated using 5-fold cross-validation. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Hosmer–Lemeshow goodness of fit, respectively.
Clinical data from 728 cases with HA-VTE and 839 non-VTE controls, admitted between January 2012 and December 2016, were abstracted. Statistically significant RAM elements included age <1 year and 10-22 years, cancer, congenital heart disease, other high-risk conditions (inflammatory/autoimmune disease, blood-related disorder, protein-losing state, total parental nutrition dependence, thrombophilia/personal history of VTE), recent hospitalization, immobility, platelet count >350 K/μL, central venous catheter, recent surgery, steroids, and mechanical ventilation. The area under the receiver operating characteristic curve was 0.78 (95% CI 0.76-0.80).
Once externally validated, this RAM will identify those who are at low-risk as well as the greatest-risk groups of hospitalized children for investigation of prophylactic strategies in future clinical trials.
Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin ...(AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements. Cumulative understanding of the regulation of thrombin generation and its central role in hemostasis and bleeding disorders has led to the clinical development of therapeutic strategies that aim to rebalance hemostasis in individuals with hemophilia and other coagulation factor deficiencies to improve bleeding phenotype. The aim of this review is to discuss the rationale for AT lowering in individuals with hemophilia, with a focus on fitusiran, its mechanism of action, and its potential as a prophylactic therapy for individuals with hemophilia A or B, with or without inhibitors. Fitusiran is an investigational, small interfering RNA therapeutic that targets and lowers AT. It is currently in phase III clinical trials and results have shown its potential to increase thrombin generation, leading to enhanced hemostasis and improved quality of life while reducing the overall treatment burden.
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•Hemostasis is achieved when sufficient thrombin is generated to form a stable fibrin clot.•Fitusiran is a nonfactor therapy that lowers antithrombin (AT) to enhance thrombin generation.•Fitusiran dosing now targets AT levels of 15% to 35% aiming to enhance its benefit-risk profile.•Risk of thrombosis is greater with AT levels <10%, even in individuals with hemophilia.
To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care.
Evolving Treatment of Hemophilia's Impact on ...Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1–21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurologic examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills.
Five hundred and fifty-one males with hemophilia A (n = 433) or B (n = 101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4–5 and 10–21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n = 64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population.
In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlight the importance of screening and intervention for challenges with cognitive and adaptive skills in this population.
Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK); NCT03660774; https://clinicaltrials.gov/ct2/show/NCT03660774.
Kasposiform hemoangioendothelioma (KHE) and tufted angioma (TA) are classifed as vascular tumors with locally aggressive and benign growth potential, respectively, within the classification schema ...proposed by the International Society for the Study of Vascular Anomalies. A unique feature of these vascular tumors is the risk of Kasabach-Merritt phenomenon (KMP), a severe thrombocytopenia with mild to moderate coagulopathy resulting from intralesional platelet trapping. As with many vascular anomalies, accurate description of clinical course, responses to therapy, and long-term outcomes have been hindered by lesion misidentification, imprecise nomenclature, and lack of prospective, randomized clinical trials to assess therapeutic efficacy. The classic dermatologic features of these lesions can facilitate diagnosis for the astute provider; however, the absence of or unusual integumentary involvement or presentation in a less common age group (adolescents/adults) poses a diagnostic challenge. Current approaches to the management of KHE/TA are often informed by lesion features such as presence of KMP, extent and location of the tumor, and symptomatology. Evidence-based treatment guidelines are limited. Corticosteroids, vincristine, interferon, multi-agent regimens and newer therapies, such as sirolimus, have demonstrated efficacy in patient series. The use of surgical excision and interventional radiology guided therapies have been described with mixed clinical benefit. Collaboration among emerging vascular anomaly centers and an increasing number of providers across subspecialties with interest in this field are facilitating the development of standardized approaches to diagnosis and management. The rarity of KHE-spectrum lesions and the heterogeneity of clinical manifestations necessitate rationally designed, multisite clinical trials to investigate risk stratification schemas and formally evaluate the short and long-term efficacy of available and novel therapies.
Background
Bleeding phenotypes among individuals with severe factor VIII (FVIII) deficiency are variable, even with routine prophylactic FVIII administration. Activated platelets, in addition to ...their role in primary hemostasis, play a major role in coagulation by providing a phospholipid surface to which coagulation factors bind.
Objectives
The aim of this study was to determine whether platelet function is associated with past and/or future bleeding in patients with severe FVIII deficiency on prophylaxis.
Patients/Methods
Platelet function quantified by platelet surface expression of phosphatidylserine, platelet surface glycoprotein (GP) VI, platelet surface activated GPIIb‐IIIa, platelet surface P‐selectin, the percentage of coated platelets, and the percentage of platelet‐derived microparticles in the presence or absence of in vitro activation by various agonists was assessed in 34 patients.
Results
Decreased platelet surface phosphatidylserine expression (identified by annexin V binding), both in the presence and absence of ADP/thrombin receptor activating peptide, demonstrated a significant association with both prior and subsequent bleeding in any location and specifically with hemarthrosis. No significant difference between patients with and without bleeding was observed in any of the other platelet activity markers.
Conclusions
Decreased platelet surface phosphatidylserine expression measured by annexin V binding predicts increased bleeding in severe FVIII deficient patients on prophylaxis.
Standard of care for bleed prevention in patients with severe congenital hemophilia A is continuous prophylaxis with factor VIII (FVIII), typically administered intravenously 2-3 times per week in ...the home setting. Nonfactor prophylaxis and gene therapy are emerging novel prophylaxis strategies for hemophilia A, and it is important to compare their health economics with that of FVIII prophylaxis. Current data on resource utilization and costs in the adult hemophilia A prophylaxis population are limited, and a structured approach to analyze annual costs in these patients using administrative claims data has not been previously reported.
To assess health care resource utilization and costs of continuous FVIII prophylaxis in commercially insured adults with hemophilia A without inhibitors.
Administrative claims records from beneficiaries covered by major selfinsured companies in the United States from January 1999 through March 2017 (OptumHealth Care Solutions) were queried, and records for adult patients (aged 18-64 years) diagnosed with hemophilia A who received FVIII were extracted. Three criteria were defined to distinguish patients most likely to be managed with continuous FVIII prophylaxis from those on episodic treatment based on the frequency and timing of FVIII claims over a 12-month period of continuous enrollment: (1) having ≥ 4 FVIII claims, (2) having ≥ 6 FVIII claims, or (3) having no gaps > 60 days between FVIII claims. Patients with evidence of bypassing agent use were excluded. Health care resource utilization and costs were assessed for all patients with any FVIII use and for patients defined as being managed with continuous FVIII prophylaxis based on each criterion.
The analysis included 189 patients with a diagnosis code for hemophilia A (ICD 9-CM code 286.0; ICD-10-CM code D66) from January 1999 through March 2017 who had at least 12 months of continuous enrollment and at least 1 noninpatient/nonemergency department claim for FVIII concentrate (any type) during their last 12 months of continuous enrollment (overall cohort). Within the overall cohort, 118, 94, and 61 patients met the criteria for FVIII prophylaxis based on the first, second, and third definitions, respectively. Per patient mean (SD) total health care costs for the overall cohort was $287,055 (306,933). For patients meeting criteria 1 through 3, per patient costs ranged from $407,752 (321,036) to $551,645 (302,841). FVIII concentrate accounted for over 90% of costs, with mean (SD) annual FVIII costs of $264,777 (292,423) in the overall cohort and $384,197 (303,826), $433,029 (313,711), and $531,098 (297,142) among patients meeting the respective definitions for prophylaxis.
This analysis highlights the substantial economic burden associated with managing adults with hemophilia A on FVIII prophylaxis, where per patient mean total annual health care costs ranged from $407,752 to $551,645. Over 90% of such costs were attributable to FVIII concentrate dispensed.
This study was funded by BioMarin Pharmaceutical, which was involved in protocol development, analysis plan development, data interpretation, manuscript preparation, and publication decisions. All authors contributed to protocol development, analysis plan development, data interpretation, and manuscript development. All authors maintained control over the final content. Sammon, Solari, Kim, and Hinds are employees and shareholders of BioMarin Pharmaceutical. Cook, Sheikh, and Chawla are employees of Analysis Group, a consulting company that was contracted by BioMarin Pharmaceutical to conduct this study and develop the manuscript. Croteau has received professional fees from BioMarin Pharmaceutical, Bayer, CSL Behring, Genentech, and Pfizer. Thornberg has received professional fees from BioMarin Pharmaceutical, Genentech, Novo Nordisk, Sanofi, and Spark Therapeutics, as well as research funding from Novo Nordisk and Sanofi.
Acutely ill and medically complex children frequently rely on central venous catheters (CVCs) to provide life-sustaining treatment. Unfortunately, catheter-related thrombosis (CRT) is a serious and ...common complication. Little is known why some with a CVC develop CRT and others develop venous thromboembolism unrelated to the CVC (non-CRT).
The aim of this study was to identify factors associated with CRT in children with hospital-acquired venous thromboembolism (HA-VTE).
This case-case study included participants in the Children's Hospital Acquired Thrombosis Registry with HA-VTE and CVC aged 0 to 21 years from 8 US children's hospitals. Participants were excluded if they developed HA-VTE prior to CVC insertion or if the CVC insertion date was unknown. Logistic regression models were used to assess associations between clinical factors and CRT status.
There were 1144 participants with HA-VTE who had a CVC. CRT developed in 833 participants, and 311 developed non-CRT. Multivariable analysis showed increased odds of CRT (compared with non-CRT) in participants with peripherally inserted central catheters (odds ratio OR, 3.80; 95% CI, 2.04-7.10; p < .001), CVCs inserted in the femoral vein (OR, 4.45; 95% CI, 1.70-11.65; p = .002), multiple CVCs (OR, 1.42; 95% CI, 1.18-1.71; p < .001), and CVC malfunction (OR, 3.30; 95% CI, 1.80-6.03; p < .001).
The findings of this study provide new insights on risk factor differences between CRT and non-CRT. Prevention efforts should be directed at modifying the type of CVC, insertion location, and/or number of CVCs placed, if possible, to decrease the incidence of CRT.
Background
Correction of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti‐VWF alloantibodies (i.e., VWF inhibitors) in patients with ...severe von Willebrand disease (VWD).
Objective
Locate inhibitor‐reactive regions within VWF using phage display.
Methods
We screened a phage library displaying random, overlapping fragments covering the full‐length VWF protein sequence for binding to a commercial anti‐VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma‐derived VWF. Immunoreactive phage clones were identified and quantified by next‐generation DNA sequencing (NGS).
Results
Next‐generation DNA sequencing markedly increased the number of phages analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma‐derived VWF replacement products.
Conclusion
These results demonstrate the utility of phage display and NGS to characterize diverse anti‐VWF antibody reactivities.
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