Exercise Intolerance and Skeletal Muscle Bioenergetics in Children With Deep Venous Thrombosis

This is a prospective cohort study of 30 patients who are 8-21 years of age with venous thromboembolism (VTE)- either lower extremity deep venous thrombosis (DVT) or pulmonary embolism (PE).

Participants will be in three groups- those with lower extremity DVT, those with PE, or those with both lower extremity DVT and PE. Patients will have blood drawn for thrombin generation assay, thromboelastography assay, and thromboinflammatory panel in addition to standard of care labs for diagnosis of VTE and management of anticoagulation. The patients will then fill out questionnaires on quality of life and level of exercise at their first outpatient visit 4 weeks after diagnosis. At approximately 3-6 months after diagnosis, patients will undergo two days of testing for the research study. All patients will have exercise testing using bicycle ergometry to measure global aerobic fitness. They will once again fill out questionnaires about their quality of life and level of physical activity. After a 24 hour rest period, DVT patients will undergo 31P-MR Spectroscopy and non-invasive spin labeling MRI to provide data on skeletal muscle bioenergetics (phosphocreatine metabolism), and lymphatic and venous flow respectively in the affected leg compared to the unaffected leg. This will allow each patient to be his or her own control. After these research procedures, patients will continue to receive standard of care treatment for their VTE in the Bleeding and Thrombosis clinic.

A. Phosphorous 31 MR Spectroscopy to evaluate skeletal muscle metabolism via measurement of depletion and recovery of phosphocreatine (PCr) B. Non-invasive arterial spin labeling MRI to evaluate lymphatic flow velocities and venous flow

A. Inflammatory lab panel (IL-6, IL-8, TNF alpha, P-selectin, high sensitivity CRP, IL-6 receptor, TNF R1/R2) drawn at diagnosis B. Thrombin Generation Assay to measure hypercoagulability and Thromboelastography prior to initiating anticoagulation

A. Dalhousie Dyspnea Scale B. Godin Leisure Time Exercise Questionnaire C. Pediatric Venous Quality of Life Questionnaire

Phosphocreatine (PCr) will be measured at baseline, during performance of submaximal exercise to fatigue and then at rest in the 31 P MR Spectroscopy Scan.

Arterial spin labeling MRI will be utilized to examine venous flow in bilateral lower extremities to assess for venous occlusion.

Arterial spin labeling MRI will be utilized to assess lymphatic flow in bilateral lower extremities to assess for adequate lymphatic drainage.

A custom blood assay will be used to assess inflammation at the time of the thrombotic event. Assay will include measurements of IL-6, IL-8, TNF-alpha, CRP, IL-10, IL-6 receptor, TNF alpha receptors.

Thrombin generation assay (TGA) will be used to assess hypercoagulability, and thromboelastography will be used to assess fibrinolysis. These will be drawn at the time of the thrombotic event.

Pulmonary embolism patients will undergo this testing at 4-6 weeks after diagnosis. Deep venous thrombosis only patients will undergo testing at 3 months.

Patients will be asked to fill out a questionnaire to determine levels of physical activity for comparison at different time points throughout treatment.

Questionnaire to be filled out to assess activity at baseline, then one month after diagnosis, and 3-6 months after diagnosis.

Questionnaire to determine quality of life in various areas including school, leisure time, home, and relationships with peers.

Participants will be asked to fill this questionnaires 4 weeks after diagnosis, and 3-6 months after diagnosis.

Patients will be asked to complete this questionnaire to assess sleep quality and screen for obstructive sleep apnea.

Inclusion Criteria: Age 8- ≤ 21 years old AND Lower extremity deep venous thrombosis OR Lower extremity deep venous thrombosis AND pulmonary embolism OR Pulmonary Embolism Exclusion Criteria: Contraindications to exercise, such as post-surgical patients with cast immobility or fractures Patients unable to follow instructions/commands at baseline due to developmental delay Patients with congenital heart disease and abnormal pulmonary circulation/perfusion Contraindications to undergoing magnetic resonance imaging