Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

Not Applicable

Recruiting

• Conditions: Trauma Injury
• Interventions: Other: Bone marrow collection; Other: Blood collection; Other: Clinical data collection

• Registration Number: NCT02577731
• Lead Sponsor: University of Florida

Brief Summary

Traumatic injury is a leading cause of morbidity and mortality in young adults, and remains a substantial economic and health care burden. Despite decades of promising preclinical and clinical investigations in trauma, investigators understanding of these entities is still incomplete, and few therapies have shown success. During severe trauma, bone marrow granulocyte stores are rapidly released into the peripheral circulation. This release subsequently induces the expansion and repopulation of empty or evacuated space by hematopoietic stem cells (HSCs). Although the patient experiences an early loss of bone marrow myeloid-derived cells, stem cell expansion is largely skewed towards the repopulation of the myeloid lineage/compartment. The hypothesis is that this 'emergency myelopoiesis' is critical for the survival of the severely traumatized and further, failure of the emergency myelopoietic response is associated with global immunosuppression and susceptibility to secondary infection. Also, identifying the release of myeloid derived suppressor cells (MDSCs) in the circulation of human severe trauma subjects. This process is driven by HSCs in the bone marrow of trauma subjects. Additionally, MDSCs may have a profound effect on the nutritional status of the host. The appearance of these MDSCs after trauma is associated with a loss of muscle tissue in these subjects. This muscle loss and possible increased catabolism have huge effects on long term outcomes for these subjects. It is the investigator's goal to understand the differences that occur in these in HSCs and muscle cells as opposed to non-injured and non-infected controls. This work will lead to a better understanding of the myelopoietic and catabolic response following trauma.

Detailed Description

This is a prospective study to understand how trauma injuries changes the hematopoeitic stem cells (HSCs) in the bone marrow and muscle cells after trauma injury in elderly subjects is different when compared to non-injured subjects.

There will be three groups for this study: 1) Elective hip surgery subjects, 2) Trauma subjects and 3) deidentified bone marrow of healthy controls.

Samples of bone marrow and a blood sample will be collected at the time of surgery. The deidentified bone marrow of healthy controls will come from a tissue bank.

The blood will be used to perform PB colony assays, ELISAs to test for the following parameters: EPO, G-CSF, Reticulocyte, iron levels and cytokines and inflammatory markers.

The bone marrow and blood samples will be processed and sorted to isolate hematopoeitic stem cells for genomic content to determine genomic expression, oxidative stress, mitochondrial activity, apoptosis, autophagy, analysis of circulating erythroid progenitor cells, reticulocytes, granulocyte-colony stimulating factor assays, erythropoietin and iron levels.

Clinical data and hemodynamic measurements will be collected daily while subjects are hospitalized and trauma surgery subjects will be followed to evaluate for malunion and subsequent additional surgical procedures for repair.

Study Timeline

• Study Start: 2014-01
• Study First Submitted: 2015-10-01
• Study First Submitted QC: 2015-10-13
• Study First Posted: 2015-10-16
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-07
• Last Update Posted: 2024-05-08
• Primary Completion: 2024-12-28
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Elective Hip Repair	Bone marrow collection	Bone marrow collection. Blood collection. Clinical data collection.
Severe Trauma	Bone marrow collection	Bone marrow collection. Blood collection. Clinical data collection.
Elective Hip Repair	Clinical data collection	Bone marrow collection. Blood collection. Clinical data collection.
Severe Trauma	Blood collection	Bone marrow collection. Blood collection. Clinical data collection.
Severe Trauma	Clinical data collection	Bone marrow collection. Blood collection. Clinical data collection.
Elective Hip Repair	Blood collection	Bone marrow collection. Blood collection. Clinical data collection.
Healthy Young Bone Marrow Control	Bone marrow collection	Deidentified freshly isolated bone marrow samples from healthy young control subjects will be purchased for a tissue bank.

Primary Outcome Measures

Name	Time	Method
Analyze the muscle dysfunction between the groups for mitochondrial activity	Baseline
Analyze the muscle dysfunction between the groups for apoptosis	Baseline
Analyze the genomics response of hematopoietic cells between the groups	Baseline	Through negative isolation columns and flow sorting to isolate the hematopoietic stem cells (HSCs) from a sample for appropriate analysis. The sample will then be enriched using a lineage depletion column which will remove all mature hematopoietic cells. The HSCs will be phenotyped and sorted as CD34+ CD38- Thy1+ CD45RA-. HSCs will be lysed and the RNA genomic content will be isolated. The genomic content will then be processed onto a GeneChip® microarray to analyze the genomic expression.
Analyze the muscle dysfunction between the groups for oxidative stress	Baseline
Analyze the muscle dysfunction between the groups for autophagy	Baseline

Secondary Outcome Measures

Name	Time	Method
The pathophysiology of injury-associated persistent anemia through PB colony assays of blood.	Baseline
The pathophysiology of injury-associated persistent anemia through ELISA test of blood.	Baseline

Trial Locations

Locations (1)

UF Health Shands Hospital at the University of Florida; 🇺🇸 Gainesville, Florida, United States