The overall aim of this project is to delineate the role of neutrophil activity and diversity in the pathogenesis of acute (e.g. vaso-occlusive crisis (VOC) and Acute chest syndrome (ACS)) and chronic complications in sickle cell didease and its…
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Source
Brief title
Condition
- Haemoglobinopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint of this studie is the difference in activity and phenotypes of
neutrophils in patients with sickle cell disease compared to those of healthy
controls.
We aim to address the following questions:
- Is neutrophil activity (as measured by flow cytometry and in vitro release of
NETs) altered in patients with SCD and does this differ in various
circumstances, such as VOC/steady state?
- Which subtypes (anti-inflammatory/pro-angiogenic (N2) vs. pro-inflammatory
(N1)) of neutrophils are present in steady state SCD? Is there a relation with
hemolytic vs. vaso-occlusive phenotype of SCD?
- How does the neutrophil phenotype alter during vaso-occlusive crisis with
increased inflammation and hypoxia as a result of this vaso-occlusion?
Secondary outcome
- The effect of hydroxyurea and red blood cell transfusion on neutrophil
phenotype and activity in SCD
- The relation of neutrophil phenotype and activity with iron overload in
transfused patients
- Formation of aggregates between neutrophils and platelets
- To elucidate and identify stimulating signals in the vascular
microenvironment that drive phenotypic switching of neutrophils. Potential
candidates are inflammatory cytokines, danger signals such as cell-free heme
and labile iron and pro-angiogenic factors.
- We will identify prime candidates that correlate with disease severity and
neutrophil phenotypic changes in in vitro blocking experiments.
- Is sickle red blood cell deformability as measured by Oxygen-scan (LORRCA)
associated with neutrophil activation and phenotype?
- To evaluate the relation between the above mentioned markers during painful
crisis and clinical parameters of disease severity (pain score, duration of
hospitalization, time to next crisis/readmission and other acute complications
of painful crisis such as ACS).
Background summary
Sickle cell disease is a severe hereditary hemoglobinopathy that results in a
reduced qualitity of life and life expectancy. Uptill now, only one FDA
approved drug is available specifically for sickle cell disease, which has side
effects and does not provide enough results for the majority of patients. New
therapeutic options are desired. From previous research, we know that
neutrophils play an important role in the development of microvascular
obstruction and sickle cell disease-related complications. Even in steady
state, neutrophilia is associated with severity of disease. Evidence is
emerging of different neutrophil phenotypes, with different characteristics.
Their precise role in sickle cell disease and the potential therapeutic value
are not well understood. This could possibly be a new therapeutic target.
Study objective
The overall aim of this project is to delineate the role of neutrophil activity
and diversity in the pathogenesis of acute (e.g. vaso-occlusive crisis (VOC)
and Acute chest syndrome (ACS)) and chronic complications in sickle cell
didease and its potential applicability in a clinical setting. We will aim to
address the following questions:
To evaluate neutrophil activity and diversity (pro- or anti-inflammatory
phenotype) in sickle cell disease both in steady state and during painful
vaso-occlusive crisis and the potential relation with disease severity.
Furthermore, effects of treatment with hydroxyurea and red blood cell
transfusion on neutrophil activity and phenotype will be evaluated .
Study design
We will measure neutrophil activity and phenotype cross-sectionally, in a
cohort of patients with SCD that are in steady state (n=30). Within this steady
state population, we will evaluate neutrophil activity and phenotype in
patients starting with hydroxyurea (n=30) longitudinally both before start
(baseline), after 4 weeks and at 3 months after using the optimal hydroxyurea
dose. Another group of steady state patients using or starting with chronic
transfusion therapy (n=10) will be included for measurements just before the
transfusion and 24-48 hours after the transfusion. In addition, we will measure
neutrophil activity and phenotype in patients admitted to the hospital because
of vaso-occlusive crisis (n=20). Part of these VOC patients we will try to
include in the Flevohospital. We estimate this will be a 6 vs 14 spread (since
the AMC is a bigger hospital with more SCD patients). However this numbers will
also depend on the current pandemic, since now relatively more SCD patients are
transferred to the Flevohospital, but this can differ. SCD patients receiving
allogeneic stem cell transplantation will be included for measurements before
and 3-6 months after complete engraftment (n=5). Race-matched non-SCD
volunteers will be included as healthy controls (n=20). Participants will be
asked to donate 30 ml of blood at each time point.
Study burden and risks
Blood draws will be combined as much as possible with sample collection for
diagnostic purposes. Risks associated with participation in this study is
limited to hematoma at the site of puncture. For children venipuncture will
always be combined with blood draws for diagnostic purposes. There is no
individual benefit to participation in this study.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1.Sickle cell disease patients (age >= 6 years) with high performance liquid
chromatography (HPLC) confirmed diagnosis of HbSS, HbSβ0-thalassemia, HbSC or
HbSβ+- thalassemia genotype
2. Willing and able to provide written informed consent
3. For the steady state/transfusion/hydroxyurea subgroup: visiting outpatient
clinic
4. For the subgroup of patients during painful crisis: inclusion should be
performed within 36 hours of admission to the hospital
Exclusion criteria
1. Unable to sign informed consent
2. VOC within 4 weeks of the outpatient clinic visit (steady state subgroup)
3. Pregnancy
4. Active cancer
5. Chronic HIV infection
6. Use of immunosuppressive drugs
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
CCMO | NL71277.018.19 |