Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
Maneno muhimu
Kikemikali
Maelezo
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.
Tarehe
| Imethibitishwa Mwisho: | 03/17/2020 |
| Iliyowasilishwa Kwanza: | 02/08/2017 |
| Uandikishaji uliokadiriwa Uliwasilishwa: | 02/08/2017 |
| Iliyotumwa Kwanza: | 02/09/2017 |
| Sasisho la Mwisho Liliwasilishwa: | 03/18/2020 |
| Sasisho la Mwisho Lilichapishwa: | 03/19/2020 |
| Tarehe halisi ya kuanza kwa masomo: | 03/12/2017 |
| Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 12/08/2019 |
| Tarehe ya Kukamilisha Utafiti: | 12/08/2019 |
Hali au ugonjwa
Awamu
Vikundi vya Arm
| Mkono | Uingiliaji / matibabu |
|---|---|
| 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 . |
Vigezo vya Kustahiki
| Zama zinazostahiki Kujifunza | 18 Years Kwa 18 Years |
| Jinsia Inastahiki Kujifunza | All |
| Njia ya sampuli | Non-Probability Sample |
| Hupokea Wajitolea wa Afya | Ndio |
| Vigezo | - 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) |
Matokeo
Hatua za Matokeo ya Msingi
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. [1 Year]
