Pathophysiology of Acute Pain in Patients With Sickle Cell Disease

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.

Study Overview

• Status: Completed
• Conditions: 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. Both cfDNA and heme (break down product of hemoglobin), 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
• Enrollment (Actual): 99

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

60 subjects with sickle cell disease 40 healthy individuals to serve as controls

Description

• 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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Control; Healthy, between age 18-80, African/African decent
Subjects in steady State; Steady state is defined as the period from at any time 8 weeks prior to or after a crisis and samples obtained during this time would be considered steady state samples .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
1. To measure and compare defined sets of markers of obstruction of blood vessels (vaso-occlusion), red cell breakdown (hemolysis), and inflammation during acute painful crisis vs steady state in patients with sickle cell disease.	1 year

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Swee Lay Thein, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Tumburu L, Ghosh-Choudhary S, Seifuddin FT, Barbu EA, Yang S, Ahmad MM, Wilkins LHW, Tunc I, Sivakumar I, Nichols JS, Dagur PK, Yang S, Almeida LEF, Quezado ZMN, Combs CA, Lindberg E, Bleck CKE, Zhu J, Shet AS, Chung JH, Pirooznia M, Thein SL. Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021 Jun 3;137(22):3116-3126. doi: 10.1182/blood.2020009063. Erratum In: Blood. 2022 Sep 15;140(11):1327.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Actual): December 9, 2019
• Study Completion (Actual): December 9, 2019

Study Registration Dates

• First Submitted: February 9, 2017
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (Actual): February 10, 2017

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: July 28, 2023

More Information

Terms related to this study

• Keywords: Pain; Natural History; Inflammatory Markers; Microparticles; Cell Free DNA; NETosis
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Acute Pain; Anemia, Sickle Cell
• Other Study ID Numbers: 170056; 17-H-0056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .The team is working on a decision.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No