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Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

Primary Purpose

Trauma Injury

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Bone marrow collection

Blood collection

Clinical data collection

About this trial

This is an interventional basic science trial for Trauma Injury focused on measuring Trauma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Severe Trauma Population

Inclusion criteria will be:

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:
1. 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
2. Or injury severity score (ISS) greater than or equal to 15.
All adults (age 55 and older) require:
1. Blunt and/or penetrating trauma resulting in log bone or pelvic fractures requiring ORIF or CRPP
2. 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
3. Or Injury Severity Score (ISS) greater than or equal to 15.
Ability to obtain Informed Consent prior to OR repair of injury.

Exclusion Criteria will be:

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

Inclusion criteria will be:

All adults (age ≥18)
Patient undergoing elective hip repair for non-infectious reasons.
Ability to obtain Informed Consent prior to operation.

Exclusion Criteria will be:

Pregnancy.
Prisoners.
Patients receiving chronic corticosteroids or immunosuppression therapies.
History of receiving Chemotherapy or Radiation within the last 6 months
Previous bone marrow transplantation

7. Patients with End Stage Renal Disease 8. Patients with any pre-existing hematological disease

Sites / Locations

UF Health Shands Hospital at the University of FloridaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Arm Label

Severe Trauma

Elective Hip Repair

Healthy Young Bone Marrow Control

Arm Description

Bone marrow collection. Blood collection. Clinical data collection.

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

Outcomes

Primary Outcome Measures

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.

Analyze the muscle dysfunction between the groups for oxidative stress

Analyze the muscle dysfunction between the groups for mitochondrial activity

Analyze the muscle dysfunction between the groups for apoptosis

Analyze the muscle dysfunction between the groups for autophagy

Secondary Outcome Measures

The pathophysiology of injury-associated persistent anemia through PB colony assays of blood.

The pathophysiology of injury-associated persistent anemia through ELISA test of blood.

Full Information

NCT ID

NCT02577731

First Posted

October 1, 2015

Last Updated

October 27, 2022

Sponsor

University of Florida

Collaborators

National Institute of General Medical Sciences (NIGMS)

1. Study Identification

Unique Protocol Identification Number

NCT02577731

Brief Title

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

Official Title

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury: Chronic Stress and Anemia Recovery Following Major Trauma

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 2014 (Actual)

Primary Completion Date

July 31, 2023 (Anticipated)

Study Completion Date

July 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

National Institute of General Medical Sciences (NIGMS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Trauma Injury

Keywords

Trauma

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Severe Trauma

Arm Type

Other

Arm Description

Bone marrow collection. Blood collection. Clinical data collection.

Arm Title

Elective Hip Repair

Arm Type

Other

Arm Description

Bone marrow collection. Blood collection. Clinical data collection.

Arm Title

Healthy Young Bone Marrow Control

Arm Type

Other

Arm Description

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

Intervention Type

Other

Intervention Name(s)

Bone marrow collection

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Blood collection

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Clinical data collection

Intervention Description

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.

Primary Outcome Measure Information:

Title

Analyze the genomics response of hematopoietic cells between the groups

Description

Time Frame

Baseline

Title

Analyze the muscle dysfunction between the groups for oxidative stress

Time Frame

Baseline

Title

Analyze the muscle dysfunction between the groups for mitochondrial activity

Time Frame

Baseline

Title

Analyze the muscle dysfunction between the groups for apoptosis

Time Frame

Baseline

Title

Analyze the muscle dysfunction between the groups for autophagy

Time Frame

Baseline

Secondary Outcome Measure Information:

Title

The pathophysiology of injury-associated persistent anemia through PB colony assays of blood.

Time Frame

Baseline

Title

The pathophysiology of injury-associated persistent anemia through ELISA test of blood.

Time Frame

Baseline

Other Pre-specified Outcome Measures:

Title

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

Description

Time Frame

Approximately 8 months

Title

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

Time Frame

Approximately 8 months

Title

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

Time Frame

Approximately 8 months

Title

Analyze the muscle dysfunction between the groups at additional follow-up surgery for apoptosis

Time Frame

Approximately 8 months

Title

Analyze the muscle dysfunction between the groups at additional follow-up surgery for autophagy

Time Frame

Approximately 8 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Severe Trauma Population Inclusion criteria will be: 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. Exclusion Criteria will be: 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 Inclusion criteria will be: All adults (age ≥18) Patient undergoing elective hip repair for non-infectious reasons. Ability to obtain Informed Consent prior to operation. Exclusion Criteria will be: Pregnancy. Prisoners. Patients receiving chronic corticosteroids or immunosuppression therapies. History of receiving Chemotherapy or Radiation within the last 6 months Previous bone marrow transplantation 7. Patients with End Stage Renal Disease 8. Patients with any pre-existing hematological disease

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jennifer D Lanz, MSN

Phone

352-273-5497

jennifer.lanz@surgery.ufl.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Ruth J Davis, ASN

Phone

352-273-8759

ruth.davis@surgery.ufl.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Philip Efron, MD

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

Facility Information:

Facility Name

UF Health Shands Hospital at the University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jennifer Lanz, MSN

Phone

352-273-5497

jennifer.lanz@surgery.ufl.edu

First Name & Middle Initial & Last Name & Degree

Ruth Davis, ASN

Phone

352-273-8759

ruth.davis@surgery.ufl.edu

First Name & Middle Initial & Last Name & Degree

Frederick Moore, MD

First Name & Middle Initial & Last Name & Degree

Christiaan Leeuwenburgh, PhD

First Name & Middle Initial & Last Name & Degree

Alicia Mohr, MD

First Name & Middle Initial & Last Name & Degree

Moldawer Lyle, MD

First Name & Middle Initial & Last Name & Degree

Kalia Sadasivan, MD

First Name & Middle Initial & Last Name & Degree

Hari Parvateneni, MD

First Name & Middle Initial & Last Name & Degree

Philip Efron, MD

12. IPD Sharing Statement

Learn more about this trial

Hematopoietic Stem Cell Dysfunction in the Elderly After Severe Injury

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