Primary objectives:(i) To study the pathophysiology, in particular the role of disturbed ion channel function in hereditary haemolytic anaemia(ii) To define novel intra- and extracellular (bio)markers in hereditary haemolytic anaemia. Secondary…
ID
Source
Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
o Routine red blood cell characteristics (cytology)
o Red blood cell morphology
o Routine chemistry analysis; iron, ferritin, transferrin, vitamin B12, serum
folate and haptopglobin levels
o Eosin-5-maleimide (EMA) binding on surface of red blood cells
o Osmotic fragility
o Osmotic gradient ektacytometry (LoRRca MaxSis)
o Deformability (LoRRca MaxSis)
o Intracellular Na+ and K+ levels
o Flow cytometric analysis of red blood cells: phosphatidyl serine exposure,
CD47, band3, CD71, CD235a, intracellular Ca2+
o Glutathione measurement: ratio between GSH/GSSG
o Surface protein expression of RBC microvesicles
o Quantity and size distribution of RBC microvesicles
o Conductance and patch-clamp measurements of red blood cells
o Calcium homeostasis after chemical stimulation of red blood cells
o Hemoglobin oxygen affinity
o Red blood cell density; Percoll and filtration
o ATP levels
o DNA analysis (Next Generation Sequencing)
Secondary outcome
o Development of an optical sorting device with scanning ion conductance
microscope (end points: (1) percentage sorted and/or percentage of interesting
red cells based on morphology and/or fluorescent probes and (2) symmetry of
(sorted) red cells measured with SICM).
Background summary
Anaemia in general, is defined as a haemoglobin concentration less than 6,8 -
8,0 mmol/L depending on gender and age. It affects 1.6 billion individuals
worldwide.
Approximately 10% of these individuals are affected by rare anaemia. This
disease group includes approximately 90 different types of red blood cell (RBC)
diseases, of which 80% are hereditary or congenital in nature. Hereditary
haemolytic anaemia (HHA) constitutes an important subgroup of rare anaemias,
and is characterized by decreased red blood cell survival. As the
pathophysiology of the majority of rare anaemias is poorly understood,
appropriate treatment is often ineffective or even lacking. Although the total
number of affected individuals is substantial, the diversity in the underlying
causes has resulted in limited interest from the pharmaceutical industry.
Recent studies indicate that some forms of HHA are associated with altered
cellular ion homeostasis. Primary and secondary causes can be distinguished.
In primary causes defective function of the ion channel directly causes the
disease. Examples include hereditary xerocytosis, overhydrated hereditary
stomatocytosis, familial pseudohyperkalaemia, cryohydrocytosis and certain
types of spherocytosis.
Secondary causes are due to other structural and hereditary RBC abnormalities.
Examples are hereditary spherocytosis, haemoglobinopathies (e.g., sickle cell
anaemia, thalassemia and glucose transporter GLUT1 mutations. Moreover, enzymes
deficiencies (e.g., phosphofructokinase deficiency) may also be associated with
altered cellular ion homeostasis.
It also appears reasonable to assume that disturbed ion homeostasis may
significantly contribute to anaemia pathophysiology and, in addition, may
constitute an important group of undiagnosed cases of HHA.
Study objective
Primary objectives:
(i) To study the pathophysiology, in particular the role of disturbed ion
channel function in hereditary haemolytic anaemia
(ii) To define novel intra- and extracellular (bio)markers in hereditary
haemolytic anaemia.
Secondary objective:
To develop new diagnostic tools for yet undiscovered forms of hereditary
haemolytic anaemia
Study design
The proposed study is a mono-center descriptive cohort study.
In this study patients with known and unknown causes for hereditary haemolytic
anaemia will be recruited by the University Medical Centre Utrecht (Utrecht,
The Netherlands).
Study burden and risks
Burden is limitid to the donation of 42 ml of blood by venapuncture. Burden
from parents of patients suffering from hereditary hemolytic anaemia e.c.i.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
Patient suffering from HHA, based on the following criteria;
• A proposed RBC ion homeostasis disturbance due to a primary cause; membrane defects (spherocytosis, stomatocytosis) of the red blood cell (previously diagnosed by with a decreased EImax detected by osmotic gradient ektacytometry, or altered osmotic fragility, or altered EMA-binding test, or mutations found in SPTA1, SPTB, SLC4A1, ANK1, EPB41, EPB42, PIEZO1, RHAG.
• A proposed RBC ion homeostasis disturbance due to a secondary cause; hemoglobinopathies (sickle cell anaemia, thallasemia) or enzymopathies of the red cell (previously diagnosed by detection of HbA2, HbF, HbS, HbE, HbD, HbC by electrophoresis, or decreased enzyme activity in red blood cell enzymes (PK, HK, G6PD, GPI, F-ALD, TPI, PGK, BPGM, GSR), or mutations found in HBA1, HBA2, HBB, PFKM, PGK1, G6PD, GPI1, HK1, PKLR)
• Hemolytic anemia due to an unknown cause; patients previously screened for iron deficiency anaemia and other forms of nutritional deficiency anaemia, anaemia due to chronic illnesses or infection, membrane defects of the red cell, hemoglobinopathies and/or enzymopathies, without the detection of a (molecular) cause for the haemolytic anaemia.
- Biological parent of a patient suffering from haemolytic anaemia due to an unknown cause
Exclusion criteria
- Transfusion (erythrocyte concentrate) received in the last 90 days
- For children: body weight <= 18kg
- Age <= 3 years
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 | NL54017.041.15 |