Clinical sequelae and pathophysiology of rare congenital hemolytic anemias

Hemolytic anemia is defined as anemia due to a shortened survival of
circulating red blood cells. In congenital or hereditary hemolytic anemia
patients suffer of inherited membrane, enzyme or hemoglobin disorders.

Due to the rarity of the diagnoses, to date little is known about the natural
history, epidemiology and comorbidities of the different rare hereditary
hemolytic anemias.
With the treatment approach for symptomatic hemolysis being mainly supportive,
including blood transfusions and long term monitoring, the importance of better
understanding of this complex disorder cannot be overstated, in the context of
developing future monitoring and treatment regimens for both patients and
asymptomatic carriers.

Due to impaired red cell survival, intravascular hemolysis and frequent blood
transfusion, excessive iron accumulation can occur, necessitating chelation
therapy.
Previous research suggested a link between high intracellular iron exposure and
increased inflammation and mortality in patients with sickle cell anemia, a
relatively more prevalent form of congenital hemolytic anemia.
In some patients, in order to reduce the blood transfusion burden, splenectomy
is performed as a last resort to improve anemia. However, splenectomy is not a
curative intervention and earlier findings suggest that some patients develop a
hypercoagulative state resulting in a higher risk of thrombosis. This might be
due to a high level of red blood cell derived microvesicles with presentation
of phosphatidylserine on the outer membrane, causing a strong procoagulant
effect.

For rare diseases, an up to date registry of patients is the only way to
provide prompt eligibility data. To our knowledge, an observational cohort
study like this is not yet performed. This study will substantially increase
the understanding of the pathophysiology of rare hereditary hemolytic anemia.

1.To create insight in current disease burden by creating a descriptive cohort
of patients, diagnosed with rare congenital hemolytic anemia. Points of
interest are:
- Prevalence and incidence of disease
- Quality of life
- Prevalence and incidence of iron overload
- Prevalence and incidence of comorbidities and related silent organ damage
- Prevalence and incidence of splenectomy and complications

2: To further analyze the pathophysiology of congenital hemolytic anemia: to
perform a case control study comparing patient parameters and healthy control
parameters.
Points of interest are:
To determine:
- the tolerability of low hemoglobin levels in rare congenital hemolytic anemia
patients.
- Patterns in laboratory parameters: pro-inflammatory profile, Red blood cell
characteristics, microparticle analysis, and markers of coagulation activation,
- RNA seq parameters for peripheral blood mononuclear cell transcriptome
mapping using blood sample analysis and then compare and relate outcome to
other results of the study.

The proposed study is a longitudinal retrospective and prospective cohort
study, coordinated from the Van Creveldkliniek of the University Medical
Hospital of Utrecht. Secondary: a case-control study in which blood parameters
and the results of the 6 minute walking test will be compared to results of the
healthy populations. For this existing references will be used where possible.
For remaining results blood samples of ten healthy controles will be obtained
form the Mini Donor Service.

Patients are asked to yearly fill out two short questionnaires about quality of
life.

Patient participation comprises the donation of a limited amount of blood.
Physical discomfort is limited but may include bruising.

Patients also undergo a 6 minute walking test.
Patients choose their own intensity of exercise and are allowed to stop and
rest during the test. .
The test, has been performed in thousands of older persons and thousands of
patients with heart failure or cardiomyopathy, without serious adverse events .

The burden and risk associated with participation are minimal.