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Pathophysiology of Acute Pain in Patients With Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT03049475
Recruitment Status : Recruiting
First Posted : February 10, 2017
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:

Background:

Sickle Cell Disease (SCD) is a blood disorder that occurs mainly in people of African descent. Researchers want to learn more about the painful attacks and complications associated with SCD. They want to look for a relationship between SCD and specific changes in the blood. They want to study the role of genetics, inflammation, and blood clotting factors in SCD. They will do this with blood samples collected during an acute painful attack and in between attacks.

Objective:

To learn more about the painful attacks and complications associated with SCD.

Eligibility:

People ages 18-80 with SCD or who are healthy Africans or African Americans without SCD

Design:

  • Participants will be screened with medical history and physical exam.
  • Healthy participants will have one visit.
  • Participants with SCD will have their first visit when they are not having a pain attack. They will have their next visit during a pain attack. About 3-4 months after this attack, they will have a final visit.
  • Visits will include a physical exam, and blood and urine tests.
  • Participants may have their blood samples used for genetic testing for research.

Condition or disease
Sickle Cell Disease

Detailed Description:

Episodic pain is the most common acute morbidity and the leading cause of hospitalization in patients with sickle cell disease. It is caused by microvaso-occlusion induced by sickled red blood cells, an outcome of the polymerization of deoxygenated hemoglobin S (HbS). Factors that contribute to the acute sickle pain include the release of cell-free DNA (cfDNA) and heme that initiate a downstream of events involving inflammation and thrombosis, and ischemia-reperfusion injury.

Cell-free DNA has been shown to be present in plasma of healthy subjects, but elevated in diseases and conditions that are characterized by increased cell death through necrosis or apoptosis. Indeed, we have previously shown that cfDNA in patients with sickle cell disease (SCD) increased dramatically during acute painful episodes. During acute sickle pain, marked elevation of plasma hemoglobin has also been observed due to the acute increase in sickled red blood cells and hemolysis. cfDNA, heme (break down product of hemoglobin), and high mobility group box I (HMGB1) act as damage-associated molecular pattern (DAMP) molecules, initiating endothelial inflammation, stimulation of neutrophil extracellular trap (NET) formation, leukocyte recruitment, and microvascular thrombosis.

Although there have been several studies of cytokines and chemokines in steady state and acute sickle cell disease, there has been no comprehensive study of how the inflammatory markers correlate with quantitative levels and profile of cfDNA. In this study, we would like to apply next generation sequencing (NGS) to analyze cfDNA from the plasma of patients with SCD in steadystate, and during painful crises to derive insights on the origin of tissue damage. In parallel with the free plasma DNA, we propose to measure markers of hemolysis and inflammation (cytokines, chemokines), and to investigate if interactions between these circulating molecules and blood

cells (e.g. neutrophils) have the potential to modulate the progress and severity of the disease. In addition, we would also like to explore if there is a distinctive cell-free DNA and inflammatory signature in SCD in steady-state and during acute vaso-occlusive crises.

Overall, this study provides an opportunity to evaluate new biomarkers of sickle cell pain crisis and to predict disease severity and prognosis. These measures may allow us to better understand the role of vaso-occlusion, hemolysis, and inflammation-related events and responses and serve as clinical endpoints in future studies of disease pathogenesis and/or therapeutic intervention for sickle cell disease.


Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
Actual Study Start Date : March 13, 2017
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : October 31, 2021

Resource links provided by the National Library of Medicine


Group/Cohort
Sickle Cell Disease
All genotypes
Healthy Volunteers
Healthy Volunteers



Primary Outcome Measures :
  1. To measure and compare defined sets of markers of obstruction ofblood vessels (vaso-occlusion), red cell breakdown (hemolysis), and inflammation during acute painful crisis vs steady state in patients withsickle cell disease. [ Time Frame: 1 Year ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients who are followed on other NHLBI sickle cell protocols may be asked to participate in this study, particularly subjects enrolled in the Natural History protocol (04-H-0161). We will recruit local patients from the DC Metropolitan area. 60 subjects with sickle cell disease; 40 healthy individuals to serve as controls.
Criteria
  • SUBJECT INCLUSION CRITERIA (SCD):

    1. Sickle cell disease (all genotypes) with a diagnosis of acute sickle cell pain not related to other cause (if the patient also presents with any other sickle related complication alongside acute sickle pain, including not limited to acute chest syndrome, renal dysfunction, liver dysfunction, stroke and priapism can also be included in the study)
    2. Between 18 and 80 years of age
    3. Ability to provide informed written consent

SUBJECT EXCLUSION CRITERIA (SCD):

  1. <18 years of age
  2. Pregnancy
  3. Chronic inflammatory condition (e.g. SLE, Rheumatoid arthritis or any other infectious process leading to chronic inflammation)
  4. Failed stem cell transplantation for SCD
  5. On active treatment with cytotoxic or immunosuppressive therapy

INCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

  1. Between 18 and 80 years of age
  2. African, of African descent
  3. Ability to provide informed written consent

EXCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

  1. Pregnancy
  2. Diagnosis of with any of the following chronic disease or conditions:

    1. Sickle cell disease or sickle cell trait
    2. Uncontrolled high blood pressure (systolic blood pressure must not be greater than 160 mmHg or diastolic pressure greater than 90 mmHg
    3. Uncontrolled diabetes (must not have both a documented history of diabetes and random blood glucose of greater than 200 mg/dL)
    4. History of coronary artery disease
    5. History of congestive heart failure
    6. Chronic kidney disease (serum creatinine must not be greater than 2mg/dL)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03049475


Contacts
Contact: James Nichols, R.N. (301) 402-2105 jim.nichols@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Swee Lay Thein, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT03049475     History of Changes
Other Study ID Numbers: 170056
17-H-0056
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 8, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Pain
Cell Free DNA
Inflammatory Markers
Microparticles
NETosis

Additional relevant MeSH terms:
Anemia, Sickle Cell
Acute Pain
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms