Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

NCT02577731 | Recruiting

• 5 other identifiers: IRB201601386-N1R01GM113945-01IRB 106-20135R01GM105893OCR30562
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 1

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.

Conditions

Trauma Injury

Keywords

Trauma

Outcome Measures

Primary Outcomes (5)

• Analyze the genomics response of hematopoietic cells between the groups

  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.

  Baseline

• Analyze the muscle dysfunction between the groups for oxidative stress

  Baseline

• Analyze the muscle dysfunction between the groups for mitochondrial activity

  Baseline

• Analyze the muscle dysfunction between the groups for apoptosis

  Baseline

• Analyze the muscle dysfunction between the groups for autophagy

  Baseline

Secondary Outcomes (2)

• 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

Other Outcomes (5)

• Analyze the genomics response of hematopoietic cells between the groups at additional follow-up surgery

  Approximately 8 months

• Analyze the muscle dysfunction between the groups at additional follow-up surgery for oxidative stress

  Approximately 8 months

• Analyze the muscle dysfunction between the groups at additional follow-up surgery for mitochondrial activity

  Approximately 8 months

Study Arms (3)

Severe Trauma

OTHER

Bone marrow collection. Blood collection. Clinical data collection.

Other: Bone marrow collection; Other: Blood collection; Other: Clinical data collection

Elective Hip Repair

OTHER

Bone marrow collection. Blood collection. Clinical data collection.

Other: Bone marrow collection; Other: Blood collection; Other: Clinical data collection

Healthy Young Bone Marrow Control

OTHER

Deidentified freshly isolated bone marrow samples from healthy young control subjects will be purchased for a tissue bank.

Other: Bone marrow collection

Interventions

Bone marrow collection OTHER

Bone marrow will be collected from the patient at time of orthopedic repair in the operating room. A second sample may be collected if the patient is required to return to the operating room for further repair of orthopedic injury.

Elective Hip Repair; Healthy Young Bone Marrow Control; Severe Trauma

Blood collection OTHER

Blood sample collection will be collected from the patient at time of orthopedic repair in the operating room. A second sample may be collected if the patient is required to return to the operating room for further repair of orthopedic injury.

Elective Hip Repair; Severe Trauma

Clinical data collection OTHER

Clinical data collection will encompass demographic information, past and present medical records, laboratory, microbiology, and all other test results, x-ray, CT, MRI, US and all other imaging test results, records about any medication received during admission, records of physical exam during admission, records of all vital signs and hemodynamic monitoring during admission, records of any procedure or intervention during admission, records of any procedure or intervention during hospital admission, condition at the discharge and discharge facility.

Elective Hip Repair; Severe Trauma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All adults (age ≥18 to 54)
• Blunt and/or penetrating trauma resulting in long bone or pelvic fractures requiring ORIF or closed reduction percutaneous pinning (CRPP).
• Blunt and/or penetrating trauma patient with either:
• hemorrhagic shock defined by: i. systolic BP (SBP) ≤ 90 mmHg or ii. mean arterial pressure≤ 65 mmHg or iii. base deficit (BD) ≥ 5 meq or iv. lactate ≥ 2
• Or injury severity score (ISS) greater than or equal to 15.
• All adults (age 55 and older) require:
• Blunt and/or penetrating trauma resulting in log bone or pelvic fractures requiring ORIF or CRPP
• Either hemorrhagic shock defined by: i. Systolic BP (SBP) ≤ 90 mmHg or ii. Mean arterial pressure ≤ 65 mmHg or iii. Base deficit (BD) ≥5 meq or iv. Lactate ≥ 2
• Or Injury Severity Score (ISS) greater than or equal to 15.
• Ability to obtain Informed Consent prior to OR repair of injury.

You may not qualify if:

• Patients not expected to survive greater than 48 hours.
• Prisoners.
• Pregnancy.
• Patients receiving chronic corticosteroids or immunosuppression therapies.
• Previous bone marrow transplantation.
• Patients with End Stage Renal Disease.
• Patients with any pre-existing hematological disease.
• Elective Hip Repair Population
• All adults (age ≥18)
• Patient undergoing elective hip repair for non-infectious reasons.
• Ability to obtain Informed Consent prior to operation.
• Pregnancy.
• Prisoners.
• Patients receiving chronic corticosteroids or immunosuppression therapies.
• History of receiving Chemotherapy or Radiation within the last 6 months

Sponsors & Collaborators

• National Institute of General Medical Sciences (NIGMS): collaborator
• University of Florida: lead

Study Sites (1)

UF Health Shands Hospital at the University of Florida

Gainesville, Florida, 32610, United States

RECRUITING

Related Publications (2)

• Munley JA, Willis ML, Gillies GS, Kannan KB, Polcz VE, Balch JA, Barrios EL, Wallet SM, Bible LE, Efron PA, Maile R, Mohr AM. Exosomal microRNA following severe trauma: Role in bone marrow dysfunction. J Trauma Acute Care Surg. 2024 Apr 1;96(4):548-556. doi: 10.1097/TA.0000000000004225. Epub 2023 Dec 28.

  PMID: 38151766 DERIVED

• Munley JA, Kelly LS, Gillies GS, Kannan KB, Pons EE, Bible LE, Efron PA, Mohr AM. EFFECTS OF TRAUMA PLASMA-DERIVED EXOSOMES ON HEMATOPOIETIC PROGENITOR CELLS. Shock. 2023 Apr 1;59(4):591-598. doi: 10.1097/SHK.0000000000002094. Epub 2023 Feb 16.

  PMID: 36772985 DERIVED

MeSH Terms

Conditions

Accidental Injuries; Wounds and Injuries

Interventions

Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Philip Efron, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jennifer D Lanz, MSN

CONTACT

352-273-5497; jennifer.lanz@surgery.ufl.edu

Ruth J Davis, ASN

CONTACT

352-273-8759; ruth.davis@surgery.ufl.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2015
• First Posted: October 16, 2015
• Study Start: January 1, 2014
• Primary Completion (Estimated): December 28, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: January 15, 2026

Record last verified: 2025-04

Locations

US (1)