Featured Publications
Non-criteria antiphospholipid antibodies and calprotectin as potential biomarkers in pediatric antiphospholipid syndrome
Our study aimed to evaluate the presence, clinical associations, and potential mechanistic roles of non-criteria antiphospholipid antibodies (aPL) and circulating calprotectin, a highly stable marker of neutrophil extracellular trap release (NETosis), in pediatric APS patients. We found that 79% of pediatric APS patients had at least one non-criteria aPL at moderate-to-high titer. Univariate logistic regression demonstrated that positive anti-beta-2 glycoprotein I domain 1 (anti-D1) IgG (p = 0.008), anti-phosphatidylserine/prothrombin (aPS/PT) IgG (p < 0.001), and aPS/PT IgM (p < 0.001) were significantly associated with venous thrombosis. Positive anti-D1 IgG (p < 0.001), aPS/PT IgG (p < 0.001), and aPS/PT IgM (p = 0.001) were also associated with non-thrombotic manifestations of APS, such as thrombocytopenia. Increased levels of calprotectin were detected in children with APS. Calprotectin correlated positively with absolute neutrophil count (r = 0.63, p = 0.008) and negatively with platelet count (r = -0.59, p = 0.015). Mechanistically, plasma from pediatric APS patients with high calprotectin levels impaired platelet viability in a dose-dependent manner.
Pediatric patients diagnosed as overweight and obese have an elevated risk of dyspnea
We investigated whether pediatric patients with overweight and obesity are more likely to have dyspnea compared with those who are non-overweight. We collected de-identified data from TriNetX, a global federated multicenter research database, using both the UT Southwestern Medical Center and multinational Research Networks. Our analysis focused on patients aged 8-12 years. We identified overweight and obesity using ICD-10-CM codes E66 and dyspnea using code R06.0. Patients with overweight and obesity had a significantly higher risk of dyspnea compared with those who were non-overweight. This association was observed in both the UT Southwestern Network (risk ratio: 1.81, p < 0.001) and the Research Network (risk ratio: 2.70, p < 0.001). Furthermore, within the UT Southwestern Network, the risk was found to be higher in females compared with males (risk ratio: 2.17 vs. 1.67). These results have significant clinical implications, suggesting that clinicians should consider overweight and obesity as independent risk factors for dyspnea in pediatric patients after excluding other possible contributing factors.
Serious bleeds in pediatric persons with hemophilia A on emicizumab prophylaxis
Background: Clinical trials have shown success in bleed prevention with emicizumab, but real-world data on the effectiveness of emicizumab in preventing serious bleeds in the pediatric population are lacking.
Objectives: To report real-world data on the effectiveness of Emicizumab in pediatric persons with hemophilia A.
Methods: We completed a retrospective chart review of 37 pediatric male patients aged ≤18 years on emicizumab prophylaxis for a median duration of 30.5 months at Children's Medical Center in Dallas, Texas.
Results: We identified 4 pediatric persons with severe hemophilia A with and without inhibitors who experienced a provoked or unprovoked serious bleed requiring hospitalization.
Conclusion: This study highlights that serious bleeds, both provoked and unprovoked, can occur in pediatric persons with severe hemophilia A. These findings are important for clinicians to provide appropriate counseling/education and recommendation of treatment for pediatric persons with severe hemophilia A through shared decision making. Up-titration of emicizumab or factor VIII replacement needs consideration in persons with hemophilia with suboptimal bleeding control or who participate in activities categorized as moderate- to high-risk activities.
Potential drug-drug interaction between warfarin and norethindrone in adolescent females: A case series
Purpose: In the pediatric population, warfarin remains the recommended oral anticoagulant for valvular heart disease. Warfarin carries a risk of bleeding complications that can manifest as heavy menstrual bleeding (HMB) in postmenarchal adolescent females. As a result, these patients may be started on hormonal therapies, such as norethindrone, to suppress menstruation.
Summary: This case series describes a potential drug interaction between warfarin and norethindrone in 3 adolescent females with a history of mechanical mitral valve replacement who developed HMB. These patients were on stable warfarin regimens before the initiation of norethindrone and subsequently experienced increases in their international normalized ratio (INR). In response, they required an up to 50% reduction in their weekly warfarin dose over 5 to 12 weeks.
Conclusion: These observations suggest that use of norethindrone for the management of HMB may significantly potentiate the anticoagulant effect of warfarin. Close INR monitoring and aggressive dose adjustments during initiation and discontinuation of norethindrone are recommended in patients on warfarin.
Reduced Physical Activity Levels in Children After a First Episode of Acute Venous Thromboembolism
To assess physical activity in children following acute venous thromboembolism (VTE), examine predictors of reduced physical activity and its relationship to post-thrombotic syndrome (PTS).
Using a case-control study design, we enrolled 44 children with acute VTE, and compared physical activity using the Godin-Shephard Leisure-Time Physical Activity Questionnaire and health-related quality of life (HRQoL) at 3- and 6-months post-diagnosis relative to 44 age and sex-matched controls. We assessed PTS scores using the Manco-Johnson Instrument to measure symptoms and signs attributed to sequelae of DVT in cases.
The physical activity of VTE cases was decreased at 3 months post-diagnosis (36.6 (SD 29) vs. 56.8 (SD 25); P = .002), but the differences disappeared at six months (57.5 (SD 39) vs. 56.8 (SD 25); p=0.60) relative to controls. At three- and six-months post-diagnosis, overall, 70% and 50% of VTE cases were below their pre-VTE physical activity levels; providers did not address physical activity in the majority. In multivariable analysis, physical activity of cases was lower by 32 points for completely veno-occlusive thrombosis at diagnosis, 11 points for a diagnosis of pulmonary embolism relative to DVT and increased by 0.72 points for every unit increase in HRQoL score. Physical activity at 3 months post-diagnosis did not predict the short-term risk of PTS.
VTE limits physical activity in children in the first three months after the acute event, but the differences were non-existent at six months. 50% of VTE survivors resume their pre-VTE physical activity levels within six months following diagnosis.
Physical activity in children at risk of postthrombotic sequelae: a pilot randomized controlled trial
Increased physical activity is protective against worsening of postthrombotic syndrome (PTS) in adults. We assessed patient eligibility, consent, adherence, and retention rates in a pilot trial of prescribed physical activity following venous thromboembolism (VTE) in children. Secondary objectives were to describe the within-subject changes in PTS, quality of life, and coagulation biomarkers before and after the intervention in each group. We enrolled and randomized patients between 7 and 21 years of age to the physical activity group or the standard care (education-only) group in a 1:1 allocation ratio. The physical activity group wore a Fitbit for 4 weeks to determine habitual activity and then increased activity over an 8-week “active” period, followed by a 4-week “do-as-you-wish” period. Two hundred thirty-five children were diagnosed with VTE; 111 patients were screened, of whom 40 (36%) met study eligibility criteria. Of these, 23 (57%) consented to participate and were randomized (Fitbit,11; standard group, 12). The trial was of greater interest to overweight and obese children, as they comprised 83% of consented patients. Only 33% adhered to the activity prescription, and 65% (15/23) completed the trial. The PTS scores (P = .001) improved in the physical activity group compared with the education-only group. It is feasible to enroll and randomize pediatric VTE patients to a prescribed physical activity regimen 3 months following VTE. Metrics for adherence to enhanced physical activity and retention were not met. These results provide the rationale to explore low adherence and retention rates before moving forward with a larger trial of exercise training following VTE. This trial was registered at www.clinicaltrials.gov as #NCT03075761.
Hasan R, Hanna M, Malone K, Zhang S, Sarode R, Journeycake J, Zia A. Physical activity in children at risk of post-thrombotic sequelae: a pilot randomized controlled trial. Blood Advances. 2020 Aug 11:4(15):3767-3775
Increased physical activity is protective against worsening of postthrombotic syndrome (PTS) in adults. We assessed patient eligibility, consent, adherence, and retention rates in a pilot trial of prescribed physical activity following venous thromboembolism (VTE) in children. Secondary objectives were to describe the within-subject changes in PTS, quality of life, and coagulation biomarkers before and after the intervention in each group. We enrolled and randomized patients between 7 and 21 years of age to the physical activity group or the standard care (education-only) group in a 1:1 allocation ratio. The physical activity group wore a Fitbit for 4 weeks to determine habitual activity and then increased activity over an 8-week "active" period, followed by a 4-week "do-as-you-wish" period. Two hundred thirty-five children were diagnosed with VTE; 111 patients were screened, of whom 40 (36%) met study eligibility criteria. Of these, 23 (57%) consented to participate and were randomized (Fitbit,11; standard group, 12). The trial was of greater interest to overweight and obese children, as they comprised 83% of consented patients. Only 33% adhered to the activity prescription, and 65% (15/23) completed the trial. The PTS scores (P = .001) improved in the physical activity group compared with the education-only group. It is feasible to enroll and randomize pediatric VTE patients to a prescribed physical activity regimen 3 months following VTE. Metrics for adherence to enhanced physical activity and retention were not met. These results provide the rationale to explore low adherence and retention rates before moving forward with a larger trial of exercise training following VTE. This trial was registered at www.clinicaltrials.gov as #NCT03075761.
The gut microbiome and thromboembolism
The gut microbiome plays a critical role in various inflammatory conditions, and its modulation is a potential treatment option for these conditions. The role of the gut microbiome in the pathogenesis of thromboembolism has not been fully elucidated. In this review, we summarize the evidence linking the gut microbiome to the pathogenesis of arterial and venous thrombosis. In a human host, potentially pathogenic bacteria are normal residents of the human gut microbiome, but significantly outnumbered by commensal anaerobic bacteria. Several disease states with an increased risk of venous thromboembolism (VTE) are associated with an imbalance in the gut microbiome characterized by a decrease in commensal anaerobic bacteria and an increase in the abundance of pathogenic bacteria of which the most common is the gram-negative Enterobacteriaceae (ENTERO) family. Bacterial lipopolysaccharides (LPS), the glycolipids found on the outer membrane of gram-negative bacteria, is one of the links between the microbiome and hypercoagulability. LPS binds to toll-like receptors to activate endothelial cells and platelets, leading to activation of the coagulation cascade. Bacteria in the microbiome can also metabolite compounds in the diet to produce important metabolites like trimethylamine-N-oxide (TMAO). TMAO causes platelet hyperreactivity, promotes thrombus formation and is associated with cardiovascular disease. Modulating the gut microbiome to target LPS and TMAO levels may be an innovative approach for decreasing the risk of thrombosis.
Congenital disorders of glycosylation as an unusual cause of antithrombin deficiency and elevated thrombin generation
This case was previously presented as a poster at the 2019 meeting of American Society of Pediatric Hematology Oncology (New Orleans, LA) on May 2, 2019. Congenital glycosylation disorders as a usual cause of thrombophilia (http://doi.org.ezproxy.library.wisc.edu/10.1002/pbc.27713).