Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
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.
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.
-  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)