Publications
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.
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.
The incidence of pediatric venous thromboembolism (VTE) is rising. Although VTE is perceived as an acute event, chronic complications such as a lack of thrombus resolution, recurrence, postthrombotic syndrome (PTS), and postpulmonary embolism syndrome are now better recognized. PTS, a form of chronic venous insufficiency, develops in one-third of children after extremity deep venous thrombosis (DVT). PTS is clinically significant because of its impact on functioning and health-related quality of life (HR-QoL).
There is scarce evidence to guide the management of pediatric PTS, resulting in heterogeneous clinical management. Additionally, the presentation of pediatric PTS is variable over time, leading to underrecognition and variation in care. This led the Post-Thrombotic Sequelae Working Group (WG) of the Scientific and Standardization Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis within the International Society on Thrombosis and Haemostasis to launch a project to provide guidance on key areas related to the care of pediatric PTS. This document summarizes the available evidence on PTS risk factors, PTS evaluation tools, prevention, and the treatment of pediatric PTS to guide clinicians regarding PTS prevention and treatment for children with or at risk of PTS following limb DVT.
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.
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.
Among patients younger than 21 years of age with acute provoked venous thromboembolism, is a 6-week duration of anticoagulant therapy noninferior to a conventional 3-month duration?
In this randomized clinical trial that included 417 patients with provoked venous thromboembolism, anticoagulant therapy for 6 weeks vs 3 months resulted in symptomatic recurrent venous thromboembolism in 0.66% vs 0.70%, respectively, and clinically relevant bleeding events in 0.65% vs 0.70% within 1 year. The differences met the criteria for noninferiority.
Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority based on a combination of recurrent venous thromboembolism risk and bleeding risk.
Iron deficiency anemia is associated with heavy menstrual bleeding (HMB) and, by extension, a bleeding disorder (BD). It is unknown if iron deficiency without anemia is associated with a BD in adolescents. Moreover, the threshold of ferritin associated with fatigue in adolescents with HMB is unclear. In this multicenter study, we enrolled adolescents with HMB without BD. Participants underwent BD and anemia work-up in Young Women's Hematology Clinics and completed the Peds QL™ fatigue scale. BDs were defined as von Willebrand Disease, platelet function defect, clotting factor deficiencies, and hypermobility syndrome. Two hundred and fifty consecutive adolescents were enrolled, of whom 196 met eligibility criteria. Overall, 43% (95% confidence interval: 36%-50%) were diagnosed with BD. A total of 61% (n = 119) had serum ferritin levels < 15 ng/mL, 23.5% (n = 46) had iron deficiency only, and 37% (n = 73) had iron deficiency anemia. Low ferritin or ferritin dichotomized as < 15 or ≥ 15 ng/mL was not associated with BD on univariable analysis (p = .24) or when accounting for age, race, ethnicity, body mass index, and hemoglobin (p = .35). A total of 85% had total fatigue score below the population mean of 80.5, and 52% (n = 102) were > 2 SD (or < 54) below the mean, the cut-off associated with severe fatigue. A ferritin threshold of < 6 ng/mL had a specificity of 79.8% but a sensitivity of 36% for severe fatigue. In conclusion, iron deficiency without anemia is not a predictor of BD in adolescents with HMB in a specialty setting. Severe fatigue, especially sleep fatigue, is prevalent in adolescents with BD. Ferritin of < 6 ng/mL has ~80% specificity for severe fatigue in adolescents with HMB.
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.
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.
Bleeding disorders (BD) are under-recognized in adolescents with heavy menstrual bleeding (HMB).
The lack of clinical guidelines and variable symptomatic management of HMB created the imperative to standardize HMB care to identify and manage BD in adolescents.
We convened an international working group (WG), utilized the results of a literature review to define knowledge gaps in HMB care, and used the collective clinical experience of the WG to develop care considerations for adolescents with BD and HMB. We then solicited input on the appropriateness of HMB care considerations from expert stakeholders representing hematology, adolescent medicine, and obstetrics-gynecology. We conducted an expert panel online, using the ExpertLens platform. During a three-round online modified-Delphi process, the expert panel rated the appropriateness of 21 care considerations using a 9-point scale to designate care as appropriate (7-9), uncertain (4-6), or inappropriate (1-3) covering screening for BD, the laboratory work-up, and management of adolescents with BD that present with HMB. We used the RAND/UCLA appropriateness method to determine the existence of consensus among the interdisciplinary panel of experts.
Thirty-nine experts participated in the panel. The experts rated fifteen HMB care considerations as appropriate, six as uncertain, and none as inappropriate.
The HMB care statements represent the first set of HMB care considerations in adolescents with BD, developed with broad expert input on appropriateness. Although likely to be of interest to a range of clinicians who routinely manage adolescents with HMB, additional research is required in many key areas.
Cellular and plasma interactions underlie hypercoagulability in sickle cell anemia (SCA). In healthy adults, thrombin generation (TG), a biomarker of hypercoagulability, is similar in plasma with and without platelets. Studies investigating TG in SCA using platelet-poor plasma (PPP) show conflicting results. There are no studies in SCA simultaneously comparing TG using platelet rich plasma (PRP) and PPP. This prospective study compares TG in children with SCA, at steady state, in PPP versus PRP and investigates the association of predefined clinical variables with the difference between PRP and PPP. Our secondary aim was to investigate derangements in the protein C and S pathway measuring TG with and without thrombomodulin (TM). In forty-three paired samples from SCA patients, aged 2-15 years, TG in the presence of platelets was 5.9 % higher [1239 nmol/(min*L) (SD: 224.1) vs. 1151 nmol/(min*L) (SD 223.3); p = 0.026]. The difference was highest in the 6-10 year age group (9.5 %; SD 14.1) followed by the 2-5 year age group (5.4 %; SD 21.4). In a multiple linear regression model, age, gender, current use of hydroxyurea, degree of hemolysis and severity of pain crises were not predictive of the difference between PRP and PPP. In PPP, TG reduction after TM addition was 7.4 % (SD 16.8), signifying activated protein C resistance. In conclusion, TG in children with SCA aged 2-10 years is higher in the presence of platelets. TG using PRP along with TM addition may be a useful biomarker of hypercoagulability in this population.
Venous and arterial thrombosis is one of the hallmarks of Antiphospholipid Antibody Syndrome (APS). The traditional treatment for individuals with APS and venous thrombosis has been vitamin K antagonists. However, with the widespread use of direct oral anticoagulants (DOACs) there has been conflicting evidence regarding their safety and failure rate as alternatives to warfarin. Reasons for this failure remain elusive. We utilized the thrombin generation assay (TGA) to investigate the anticoagulation efficacy of three different agents in a patient with triple-positive APS to acquire a better understanding of the pathophysiology of APS.
Blood samples were obtained from a single patient with APS at five distinct time points while on three different anticoagulants: rivaroxaban, warfarin, and enoxaparin. The effects of these anticoagulants on TG potential were evaluated using the TGA.
In the presence of thrombomodulin, rivaroxaban had the highest endogenous thrombin potential, thrombin peak, velocity index, and thrombin inactivation velocity (821.9 nMmin, 121.5 nM, 36.44 nM/min, 7.19 nM/min) when compared to warfarin (121-367 nMmin, 13.85-121.5 nM, 3.02-3.85 nM/min, 0.64-4.55 nM/min) and enoxaparin (242-378.8 nM min, 21.33-23.78 nM, 2.87-3.85 nM/min, 0.747-0.784 nM/min). This trend was also observed in the absence of thrombomodulin.
These results suggest that patients with APS treated with rivaroxaban may be at greater risk for thrombosis compared to warfarin or enoxaparin. The findings may provide insight into the recent studies in patients with triple positive APS randomized to different anticoagulants demonstrating high rates of thrombosis with rivaroxaban. Further studies are necessary to elucidate the clinical significance.
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.
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).
Heavy menstrual bleeding is common in adolescents. The frequency and predictors of bleeding disorders in adolescents, especially with anovulatory bleeding, are unknown. Adolescents referred for heavy menstrual bleeding underwent an evaluation of menstrual bleeding patterns, and bleeding disorders determined a priori The primary outcome was the diagnosis of a bleeding disorder. Two groups were compared: anovulatory and ovulatory bleeding. Multivariable logistic regression analysis of baseline characteristics and predictors was performed. Kaplan Meier curves were constructed for the time from the first bleed to bleeding disorder diagnosis. In 200 adolescents, a bleeding disorder was diagnosed in 33% (n=67): low von Willebrand factor levels in 16%, von Willebrand disease in 11%, and qualitative platelet dysfunction in 4.5%. The prevalence of bleeding disorder was similar between ovulatory and anovulatory groups (31% vs 36%; P=0.45). Predictors of bleeding disorder included: younger age at first bleed (OR: 0.83; 95%CI: 0.73, 0.96), Hispanic ethnicity (OR: 2.48; 95%CI: 1.13, 5.05), non-presentation to emergency department for heavy bleeding (OR: 0.14; 95%CI: 0.05, 0.38), and International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool score ≥4 (OR: 8.27; 95%CI: 2.60, 26.44). Time from onset of the first bleed to diagnosis was two years in the anovulatory, and six years in the ovulatory cohort (log-rank test, P<0.001). There is a high prevalence of bleeding disorders in adolescents with heavy periods, irrespective of the bleeding pattern. Among bleeding disorders, the prevalence of qualitative platelet dysfunction is lower than previously reported.
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.
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.
The incidence of pediatric venous thromboembolism (VTE) is rising. Although VTE is perceived as an acute event, chronic complications such as a lack of thrombus resolution, recurrence, postthrombotic syndrome (PTS), and postpulmonary embolism syndrome are now better recognized. PTS, a form of chronic venous insufficiency, develops in one-third of children after extremity deep venous thrombosis (DVT). PTS is clinically significant because of its impact on functioning and health-related quality of life (HR-QoL).
There is scarce evidence to guide the management of pediatric PTS, resulting in heterogeneous clinical management. Additionally, the presentation of pediatric PTS is variable over time, leading to underrecognition and variation in care. This led the Post-Thrombotic Sequelae Working Group (WG) of the Scientific and Standardization Subcommittee on Pediatric and Neonatal Thrombosis and Haemostasis within the International Society on Thrombosis and Haemostasis to launch a project to provide guidance on key areas related to the care of pediatric PTS. This document summarizes the available evidence on PTS risk factors, PTS evaluation tools, prevention, and the treatment of pediatric PTS to guide clinicians regarding PTS prevention and treatment for children with or at risk of PTS following limb DVT.
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.
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.
Among patients younger than 21 years of age with acute provoked venous thromboembolism, is a 6-week duration of anticoagulant therapy noninferior to a conventional 3-month duration?
In this randomized clinical trial that included 417 patients with provoked venous thromboembolism, anticoagulant therapy for 6 weeks vs 3 months resulted in symptomatic recurrent venous thromboembolism in 0.66% vs 0.70%, respectively, and clinically relevant bleeding events in 0.65% vs 0.70% within 1 year. The differences met the criteria for noninferiority.
Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority based on a combination of recurrent venous thromboembolism risk and bleeding risk.
Iron deficiency anemia is associated with heavy menstrual bleeding (HMB) and, by extension, a bleeding disorder (BD). It is unknown if iron deficiency without anemia is associated with a BD in adolescents. Moreover, the threshold of ferritin associated with fatigue in adolescents with HMB is unclear. In this multicenter study, we enrolled adolescents with HMB without BD. Participants underwent BD and anemia work-up in Young Women's Hematology Clinics and completed the Peds QL™ fatigue scale. BDs were defined as von Willebrand Disease, platelet function defect, clotting factor deficiencies, and hypermobility syndrome. Two hundred and fifty consecutive adolescents were enrolled, of whom 196 met eligibility criteria. Overall, 43% (95% confidence interval: 36%-50%) were diagnosed with BD. A total of 61% (n = 119) had serum ferritin levels < 15 ng/mL, 23.5% (n = 46) had iron deficiency only, and 37% (n = 73) had iron deficiency anemia. Low ferritin or ferritin dichotomized as < 15 or ≥ 15 ng/mL was not associated with BD on univariable analysis (p = .24) or when accounting for age, race, ethnicity, body mass index, and hemoglobin (p = .35). A total of 85% had total fatigue score below the population mean of 80.5, and 52% (n = 102) were > 2 SD (or < 54) below the mean, the cut-off associated with severe fatigue. A ferritin threshold of < 6 ng/mL had a specificity of 79.8% but a sensitivity of 36% for severe fatigue. In conclusion, iron deficiency without anemia is not a predictor of BD in adolescents with HMB in a specialty setting. Severe fatigue, especially sleep fatigue, is prevalent in adolescents with BD. Ferritin of < 6 ng/mL has ~80% specificity for severe fatigue in adolescents with HMB.
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.
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.
Bleeding disorders (BD) are under-recognized in adolescents with heavy menstrual bleeding (HMB).
The lack of clinical guidelines and variable symptomatic management of HMB created the imperative to standardize HMB care to identify and manage BD in adolescents.
We convened an international working group (WG), utilized the results of a literature review to define knowledge gaps in HMB care, and used the collective clinical experience of the WG to develop care considerations for adolescents with BD and HMB. We then solicited input on the appropriateness of HMB care considerations from expert stakeholders representing hematology, adolescent medicine, and obstetrics-gynecology. We conducted an expert panel online, using the ExpertLens platform. During a three-round online modified-Delphi process, the expert panel rated the appropriateness of 21 care considerations using a 9-point scale to designate care as appropriate (7-9), uncertain (4-6), or inappropriate (1-3) covering screening for BD, the laboratory work-up, and management of adolescents with BD that present with HMB. We used the RAND/UCLA appropriateness method to determine the existence of consensus among the interdisciplinary panel of experts.
Thirty-nine experts participated in the panel. The experts rated fifteen HMB care considerations as appropriate, six as uncertain, and none as inappropriate.
The HMB care statements represent the first set of HMB care considerations in adolescents with BD, developed with broad expert input on appropriateness. Although likely to be of interest to a range of clinicians who routinely manage adolescents with HMB, additional research is required in many key areas.
Cellular and plasma interactions underlie hypercoagulability in sickle cell anemia (SCA). In healthy adults, thrombin generation (TG), a biomarker of hypercoagulability, is similar in plasma with and without platelets. Studies investigating TG in SCA using platelet-poor plasma (PPP) show conflicting results. There are no studies in SCA simultaneously comparing TG using platelet rich plasma (PRP) and PPP. This prospective study compares TG in children with SCA, at steady state, in PPP versus PRP and investigates the association of predefined clinical variables with the difference between PRP and PPP. Our secondary aim was to investigate derangements in the protein C and S pathway measuring TG with and without thrombomodulin (TM). In forty-three paired samples from SCA patients, aged 2-15 years, TG in the presence of platelets was 5.9 % higher [1239 nmol/(min*L) (SD: 224.1) vs. 1151 nmol/(min*L) (SD 223.3); p = 0.026]. The difference was highest in the 6-10 year age group (9.5 %; SD 14.1) followed by the 2-5 year age group (5.4 %; SD 21.4). In a multiple linear regression model, age, gender, current use of hydroxyurea, degree of hemolysis and severity of pain crises were not predictive of the difference between PRP and PPP. In PPP, TG reduction after TM addition was 7.4 % (SD 16.8), signifying activated protein C resistance. In conclusion, TG in children with SCA aged 2-10 years is higher in the presence of platelets. TG using PRP along with TM addition may be a useful biomarker of hypercoagulability in this population.
Venous and arterial thrombosis is one of the hallmarks of Antiphospholipid Antibody Syndrome (APS). The traditional treatment for individuals with APS and venous thrombosis has been vitamin K antagonists. However, with the widespread use of direct oral anticoagulants (DOACs) there has been conflicting evidence regarding their safety and failure rate as alternatives to warfarin. Reasons for this failure remain elusive. We utilized the thrombin generation assay (TGA) to investigate the anticoagulation efficacy of three different agents in a patient with triple-positive APS to acquire a better understanding of the pathophysiology of APS.
Blood samples were obtained from a single patient with APS at five distinct time points while on three different anticoagulants: rivaroxaban, warfarin, and enoxaparin. The effects of these anticoagulants on TG potential were evaluated using the TGA.
In the presence of thrombomodulin, rivaroxaban had the highest endogenous thrombin potential, thrombin peak, velocity index, and thrombin inactivation velocity (821.9 nMmin, 121.5 nM, 36.44 nM/min, 7.19 nM/min) when compared to warfarin (121-367 nMmin, 13.85-121.5 nM, 3.02-3.85 nM/min, 0.64-4.55 nM/min) and enoxaparin (242-378.8 nM min, 21.33-23.78 nM, 2.87-3.85 nM/min, 0.747-0.784 nM/min). This trend was also observed in the absence of thrombomodulin.
These results suggest that patients with APS treated with rivaroxaban may be at greater risk for thrombosis compared to warfarin or enoxaparin. The findings may provide insight into the recent studies in patients with triple positive APS randomized to different anticoagulants demonstrating high rates of thrombosis with rivaroxaban. Further studies are necessary to elucidate the clinical significance.
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.
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).
Heavy menstrual bleeding is common in adolescents. The frequency and predictors of bleeding disorders in adolescents, especially with anovulatory bleeding, are unknown. Adolescents referred for heavy menstrual bleeding underwent an evaluation of menstrual bleeding patterns, and bleeding disorders determined a priori The primary outcome was the diagnosis of a bleeding disorder. Two groups were compared: anovulatory and ovulatory bleeding. Multivariable logistic regression analysis of baseline characteristics and predictors was performed. Kaplan Meier curves were constructed for the time from the first bleed to bleeding disorder diagnosis. In 200 adolescents, a bleeding disorder was diagnosed in 33% (n=67): low von Willebrand factor levels in 16%, von Willebrand disease in 11%, and qualitative platelet dysfunction in 4.5%. The prevalence of bleeding disorder was similar between ovulatory and anovulatory groups (31% vs 36%; P=0.45). Predictors of bleeding disorder included: younger age at first bleed (OR: 0.83; 95%CI: 0.73, 0.96), Hispanic ethnicity (OR: 2.48; 95%CI: 1.13, 5.05), non-presentation to emergency department for heavy bleeding (OR: 0.14; 95%CI: 0.05, 0.38), and International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool score ≥4 (OR: 8.27; 95%CI: 2.60, 26.44). Time from onset of the first bleed to diagnosis was two years in the anovulatory, and six years in the ovulatory cohort (log-rank test, P<0.001). There is a high prevalence of bleeding disorders in adolescents with heavy periods, irrespective of the bleeding pattern. Among bleeding disorders, the prevalence of qualitative platelet dysfunction is lower than previously reported.
Zia Research Group Publications
Jain S, Zhang S, Acosta M, Malone K, Kouides P, Zia A*. Prospective Evaluation of ISTH-BAT as a Predictor of Bleeding Disorder in Adolescents Presenting with Heavy Menstrual Bleeding. JTH, 2020 October:18(10):2542-2550
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
Menon N, Riley P, Journeycake J, Zia A. Thrombin Generation in Children with Sickle Cell Anemia is Higher in the Presence of Platelets. Transfus Apher Sci.2020 Oct:59 (5):102852
Hasan R, Koh A, Zia A* The role of gut microbiome in thromboembolism. Thrombosis Research 2020; 189:77-87
Zia A*, Zhang Y, Zhang S, Babb T. Reduced Physical Activity Levels in Children after First Episode of Acute Venous Thromboembolism. J Peds 2020; 219 :229-235
Hasan R, Kayani S, Zia A* Congenital disorders of glycosylation as an unusual case of antithrombin deficiency and elevated thrombin generation. Pediatr Blood Cancer 2020 Feb 67(2):e28069
Zia A*, Stanek J, Rancy-Cristian M, Ahuja S, Sevalli S, O'Brien SH. Utility of a screening tool for hemostatic disorders in a multicenter cohort of adolescents with heavy menstrual bleeding. Haemophilia 2018;00:1-7
Menon NM, Sarode R, Zia A*. Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency. Blood Advances 2018 2:142-145
Gava C, Sarode R, Zia A*. A clinical audit of thrombophilia testing in pediatric patients with acute thromboembolic events: impact on management. Blood Advances 2017 1:2386-2391
Zia, A*, Russell J, Sarode R, Veeram SR, Josephs S, Malone K, Zhang S, Journeycake J. Markers of coagulation activation and fibrinolysis as predictors of poor outcomes after pediatric venous thromboembolism: a systematic review. Thrombosis Research 2017 Dec; 160:1-8
Publications from Dr. Zia's post-doctoral work
Zia A*, Callaghan MU, Callaghan JH, Sawni A, Bartlett H, Backos A Marshall S, Chitlur M, Rajpurkar M. Hypercoagulability in adolescent girls on oral contraceptives- Global coagulation profiles and estrogen receptor polymorphisms. Am J Hematol. 2015 Aug;90(8):725-31
Zia AN*, Chitlur M, Rajpurkar M,Ozgonenel B, Lusher J, Callaghan JH, Callaghan M. Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype. Haemophilia. 2015 Jan;21(1):124-132
Ozgonenel B, Zia, A, Chitlur M, Lusher M. Emergency department visits in Children with Hemophilia. Pediatr Blood Cancer. 2013 Jul; 60(7): 1188-91
Zia A, Fışgın T, Sokolowski C, Tanner S, Savaşan S "Acute lymphoblastic leukemia in a patient with Vitamin B12 Deficiency due to gastric intrinsic factor deficiency" Pediatr Blood Cancer. 2012 Oct; 59(4): 766-7
Zia A*, Chitlur M. Management of Thrombotic Complications in Acute Lymphoblastic Leukemia. Indian J Pediatr. 2013 Oct; 80(10): 853-62
Zia A and Meera Chitlur "Abnormalities of Fibrinogen- Afibrinogenemia and hypodysfibrinogenemia" Advances in Medicine and Biology. Volume 67 Editor: Leon V. Berhardt (2013)
Books
Evaluation of the Adolescent with Heavy Menstrual Bleeding. Editor: Lakhsmi Srivaths
Zia A, Lau M (2020), Springer Nature SPi GlobalAnticoagulation in Pediatric Extracorporeal Membrane Oxygenation. Editor: Michael S. Firstenberg
Weller J, Raman L, Zia A, McMichael A (2019), IntechOpenPediatric Coagulation in Pediatric Laboratory Medicine. Editors: Patti Jones, Dennis Dietzen, Shannon Haymond and Michael Bennet
Zia A, Luu, H (2017), McGraw Hill EducationPediatric Hematology and Hemoglobinopathies in Pediatric Laboratory Medicine. Editors: Patti Jones, Dennis Dietzen, Shannon Haymond and Michael Bennet
Luu H, Zia A, Timmons C (2017), McGraw Hill EducationAbnormalities of Fibrinogen- Afibrinogenemia and hypodysfibrinogenemia in Advances in Medicine and Biology. Volume 67. Editor: Leon V. Berhardt
Zia A and Meera Chitlur (2013), Nova Publishers