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ID
Source
Brief title
Health condition
sickle cell anemia, sikkelcelziekte, sikkelcelanemie, sikkel cel, thalassemia, thalassemie, unstable Hb, instabiel hb, haemoglobinopathies, haemoglobinopathie
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main objective:
- To investigate pyruvate kinase thermal stability in haemoglobinopathies.
Secondary outcome
Secondary objectives:
- To investigate the possibility of stimulation of PK activity and thermal stability in haemoglobinopathies by use of allosteric activators
- To investigate oxidative stress as a cause of decreased pyruvate kinase thermal stability in haemoglobinopathies
- To investigate the role of PK thermal stability related to clinical symptoms and disease severity
Background summary
Rationale:
Haemoglobinopathies encompass all genetic diseases of haemoglobin. Patients with haemoglobinopathies suffer from anaemia because of premature red blood cell destruction.
The pathophysiology behind this is multifactorial and complex. However, increased oxidative stress is a common pathophysiologic feature that is shared by all haemoglobinopathies.
Pilot studies in our laboratory have shown that pyruvate kinase shows decreased stability in haemoglobinopathies. Since pyruvate kinase is essential for red blood cell energy supply and anti-oxidative defence we postulate that this instability could compromise red cell metabolism, and thereby, cellular survival. Also, by retrograde accumulation, loss of pyruvate kinase activity could lead to an increase in 2,3-DPG, which in turn is an important regulator of oxygen affinity of haemoglobin. Lowering 2,3-DPG levels is currently used as a therapeutic target in several clinical trials in sickle cell disease, a common form of haemoglobinopathy.
Currently, in our laboratory and clinic, pyruvate kinase-activators are tested that have been designed to treat the rare hereditary disease pyruvate kinase deficiency. Recently, the use of these allosteric activators has been extended to the field of thalassaemia, another common form of haemoglobinopathy. A study in a mouse model of thalassaemia showed successful stimulation of pyruvate kinase function resulting in increased haemoglobin levels in vivo. We therefore aim to further explore the role of decreased stability of PK in several forms of haemoglobinopathies in humans, and study the effect of restoring this instability by the use of allosteric activators ex vivo.
Objective:
Main objective:
- To investigate pyruvate kinase thermal stability in haemoglobinopathies.
Secondary objectives:
- To investigate the possibility of stimulation of PK activity and thermal stability by use of allosteric activators
- To investigate oxidative stress as a cause of decreased pyruvate kinase thermal stability in haemoglobinopathies
- To investigate the role of PK thermal stability related to clinical symptoms and disease severity
Study design: Case control study
Study population:
45 adult haemoglobinopathy patients, 15 hereditary anemia patients and 10 healthy controls.
Intervention (if applicable): not applicable
Main study parameters/endpoints:
Pyruvate kinase thermal stability, pyruvate kinase activity, 2,3-DPG/ATP, Emden Meyerhof pathway enzymes, reactive oxygen species, methaemoglobin
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients and healthy controls are asked for a single blood donation of 57 ml via venepuncture. Physical discomfort may include bruising. Also patients are asked permission for medical chart review.
Study objective
Observational study. We aim to investigate (thermal) stability of the enzyme pyruvate kinase in haemoglobinopathies. Secondary, we aim to investigate the possibility of stimulating the PK activity and stability ex vivo by use of allosteric activators. We aim to ibvestigate oxidative stress as a cause of decreased stability and we aim to investigate the role of PK thermal stability related to clinical symptoms and disease severity.
Study design
enrollment, end of study
Intervention
No intervention. This is an observational study
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- Adult patients (18 years or older) with a diagnosis as listed above
- Participant is willing and able to give informed consent
Exclusion criteria
Exclusion criteria:
- Inability to give informed consent.
- Need for regular red blood cell transfusions (more than 8 transfusions a year)
- Recent transfusion, defined as within 2 months prior to enrolment).
The last two criteria do not lead to exclusion for patients with Unstable Hb, because of the extreme rarity of the diagnosis.
Design
Recruitment
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL6288 |
| NTR-old | NTR6462 |
| CCMO | NL59957.041.17 |
| OMON | NL-OMON55777 |