Research

The Zia Research program is active in the following research areas:

  • Deciphering post-pulmonary embolism and post-thrombotic syndromes

  • The intersection of women's health and hematology

  • Global coagulation assays as biomarkers of hemostasis and thrombosis

  • Mentoring the next generation of physician-scientists

Deciphering post-pulmonary embolism and post-thrombotic syndromes

Venous thromboembolism affects approximately 1 in 200 hospitalized children. In this line of investigation, we study associations and hypotheses between the process of thrombus resolution or persistence, lasting hemodynamic changes following acute pulmonary embolism, and the consequences of a VTE diagnosis on long-term physical performance and quality of life.

We utilize state-of-the-art measures and imaging of extremities, heart, and lungs at rest and during exercise to investigate the central and peripheral mechanisms of these common symptoms to deeply phenotype pulmonary embolism patients (Multicenter FUVID Program). Our long-term objective is to provide novel and clinically relevant results that will alter approaches for preventing and treating exercise intolerance and dyspnea and improving the quality of life for children with VTE. Dr. Zia developed and lead the VTE Outcomes Program and The Pulmonary Embolism Response Team, which serve as clinical platforms for research being conducted.

This work is in collaboration with Tony Babb, Ph.D. (Institute of Exercise and Environmental Medicine), Michael Nelson, Ph.D. (Kinesiology, University of Texas Arlington), Tarique Hussain, MD, Ph.D. (Pediatric Cardiology, UTSW), and Jimin Ren. Ph.D. (Advanced Imaging Research Center at UTSW), funded by NIH (R56HL153963 and R01HL153963) and AHA (20IPA35320263) Awards.

Featured Publications

Featured
Clinical Care of Pediatric Patients with or at-risk of the post-thrombotic syndrome: Guidance from the Pediatric and Neonatal Thrombosis and Haemostasis Subcommittee of the ISTH

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.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism
Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism

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.

Physical activity in children at risk of postthrombotic sequelae: a pilot randomized controlled trial
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.

The intersection of women's health and hematology

Women with bleeding disorders are disproportionately affected compared to men because of specific bleeding challenges related to menstruation and childbirth. Heavy menstrual bleeding (HMB) is the most prevalent symptom in women with bleeding disorders, whatever the underlying diagnosis: von Willebrand disease, platelet disorders, hemophilia carriers, or other rare coagulation factor deficiencies. All these bleeding symptoms impair the quality of life by creating significant physical, emotional, sexual, social, and financial burdens. Accurate and timely diagnosis of bleeding disorders is essential to prevent adverse bleeding events and reduce potentially unnecessary surgical interventions such as hysterectomy for HMB or PPH. Access to care and timely diagnosis in women with bleeding disorders has been the focus of the Zia Research Group for over a decade and the impetus for developing the clinical "Young Women's Blood Disorders Program" led by Dr. Zia. Other areas of focus include anticoagulant-associated bleeding in women with thrombosis and lived experiences of patients with bleeding disorders.

This work is in collaboration with Dr. Sarah O'Brien, MD, MS (Nationwide Children's, OH), Ravi Sarode (Transfusion Medicine, UTSW), Peter Kouides, MD (Hematology, Rochester Regional Health, NY), and Dr. May Lau (Adolescent Medicine, UTSW), funded by intramural, CDC, HRSA and Shire investigator-initiated grants.

Featured Publications

Featured
Iron deficiency and fatigue among adolescents with bleeding disorders
Iron deficiency and fatigue among adolescents with bleeding disorders

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.

Standardizing care to manage bleeding disorders in adolescents with heavy menses-A joint project from the ISTH pediatric/neonatal and women's health SSCs
Standardizing care to manage bleeding disorders in adolescents with heavy menses-A joint project from the ISTH pediatric/neonatal and women's health SSCs

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.

Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort
Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort

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.

Global coagulation assays as biomarkers of hemostasis and thrombosis

Normal hemostasis requires the careful maintenance of equilibrium between the necessity to clot when bleeding and the retention of fluid phase at other times. A balance between platelet adhesion and aggregation on vascular endothelium, activation of the coagulation cascade, and fibrinolytic and anticoagulant mechanisms achieves in-vivo hemostasis. Disruption of this delicate equilibrium may result in the pathological states of thrombosis or bleeding.

Routine coagulation tests such as prothrombin time and activated partial thromboplastin time were developed primarily to monitor anticoagulants such as warfarin and heparin respectively, and are not useful for predicting the bleeding, thrombotic or cardiovascular risk. These tests only evaluate the time to the start of clot formation; however, 95% of thrombin generation occurs after this step. Logically, evaluation of total clot formation and lysis may provide a better assessment of in-vivo coagulation status and, therefore, the thrombotic and bleeding risk. Therefore, a more global assessment of the coagulation system, including the final products of the coagulation cascade, such as fibrin and thrombin, is required. A focus of Zia Research Program has been the use of global coagulation assays, such as thromboelastography and thrombin generation, as biomarkers of hemostasis and thrombosis, conducted routinely in her Translational Hemostasis Laboratory for various disorders.

This work is in collaboration with Madhvi Rajourkar (Central Michigan University, Michigan), Ravi Sarode (Laboratory and Transfusion Medicine, UTSW), and Sean Yates (Laboratory and Transfusion Medicine, UTSW).

Featured Publications

Featured
Thrombin generation in children with sickle cell Anemia is Higher in the presence of platelets
Thrombin generation in children with sickle cell Anemia is Higher in the presence of platelets

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.

Thrombin Generation in a patient with Triple Positive Antiphospholipid Syndrome Treated with Three Different Anticoagulants

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.

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).

Mentoring the next generation of physician-scientists

I conduct clinical and translational patient-oriented research in hemostasis and thrombosis via an established independent Program of Clinical Research. My mentees leverage existing resources and join existing or propose new projects to address knowledge gaps. Mentees learn research principles and analytic approaches, including epidemiology, clinical research designs, diagnostic accuracy studies, survey methodology, development of clinical prediction rules, qualitative studies, comparative effectiveness research, and designing and leading clinical trials. More importantly, mentees collaborate on problem-solving and proposing alternate approaches for ongoing projects. The experiences within the Program engage them in generating hypotheses, research data, and developing their careers in patient-oriented research, which is one of many missions of the Zia Research Program.

Featured Mentees’ Publications

Featured
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
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.

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).