Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell; Acute Pain
Study type: Observational

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.
    

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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        60 subjects with sickle cell disease 40 healthy individuals to serve as controls
      
Keywords: Pain; Cell Free DNA; Inflammatory Markers; Microparticles; NETosis; Natural History