The DRAIHA study: Data Registry of AutoImmune Hemolytic Anemia, to improve diagnostic testing for the development of personalized treatment protocols in AIHA patients

In autoimmune hemolytic anemia (AIHA) auto-antibodies directed against red
blood cells (RBCs) lead to increased RBC clearance (hemolysis). This can result
in a potentially life-threatening anemia. AIHA is a rare disease with an
incidence of 1-3 per 100,000 individuals. An unsolved difficulty in diagnosis
of AIHA is the laboratory test accuracy. The current *golden standard* for AIHA
is the direct antiglobulin test (DAT). The DAT detects autoantibody- and/or
complement-opsonized RBCs. The DAT has insufficient test characteristics since
it remains falsely negative in approximate 5-10% of patients with AIHA, whereas
a falsely positive DAT can be found in 8% of hospitalized individuals. Also
apparently healthy blood donors can have a positive DAT. The consequences of
DAT positivity are not well known and may point to early, asymptomatic disease,
or to another disease associated with formation of RBC autoantibodies, such as
a malignancy or (systemic) autoimmune disease. Currently, there are no
guidlines to follow-up DAT positive donors.
A second unsolved difficulty is the choice of treatment in AIHA. Hemolysis can
be stopped or at least attenuated with corticosteroids, aiming to inhibit
autoantibody production and/or RBC destruction. Many patients do not respond
adequately to corticosteroid treatment or develop severe side effects.
Currently, it is advised to avoid RBC transfusions since these may lead to
aggravation of hemolysis and RBC alloantibody formation. But in case
symptomatic anemia occurs, RBC transfusions need to be given. An evidence-based
transfusion strategy for AIHA patients is needed to warrant safe transfusion in
this complex patient group.
To design optimal diagnostic testing and (supportive) treatment algorithms, we
aim to study a group well-characterized patients with AIHA and blood donors
without AIHA, via a prospective centralized clinical data collection and
evaluation of new laboratory tests. With this data we want to improve the
knowledge of the AIHA pathophysiology and to evaluate diagnostic testing in
correlation with clinical features and treatment outcome.

Primary objective
1. The primary aim of the study is to answer the question whether specification
of a positive direct antiglobulin test and/or red blood cell autoantibody
specification is correlated with the clinical course in patients with AIHA. We
will set up a registry and databank for DAT positive persons to achieve a
centralized collection of clinical data in combination with laboratory data of
AIHA patients and DAT positive donors. This data will be analyzed to quantify
the potential risk factors for the cause of AIHA. We also aim to determine the
causal contribution of standard laboratory and experimental test results to
predict the clinical course of AIHA.

Secondary objectives
1. Determine diagnostic predictors for safe and efficient blood transfusion in
AIHA patients.
2. Determine the clinical consequences of DAT-positivity in blood donors to
develop a clinical guideline for follow up and counseling.

An observational cohort study:

Intervention: Patients, from the age of 16 with a positive DAT, a positive
eluate and signs of hemolysis and patients with a positive DAT for complement
only, with a negative eluate and signs of hemolysis, and blood donors with a
positive DAT and a positive eluate and/or clinically relevant cold
autoantibodies, will be informed about the DRAIHA study and requested to
participate by their (donor) physician.
Around diagnosis and concomitantly with a standard blood test performed in the
hospital or at Sanquin, 35-50 ml* of blood will be additionally collected for
experimental diagnostic testing. No extra venipuncture has to be done.
Physician and blood donor need to fill in a questionnaire about their history,
health, medication and diagnostic test results.
After 1-1,5 year the participant will be requested to once again donate an
additional amount of 35-50 ml* of blood at time of a standard blood test to
perform the same experimental diagnostic tests. At that time point clinical
data will also be collected by a structured report form for donor and
(donor)physician.
In the patients from the age of 3 months until 16 years, no extra blood will be
collected. They will be registered in the databank and experimental diagnostic
testing will be performed on residual blood obtained from routine diagnostic
testing.

* Depending on the available blood tubes in each participating center.

1. AIHA patients and blood donors:
After informed consent, an additional blood will be collected for experimental
diagnostic testing. No additional (medical) procedures will be performed, and
all blood samples for experimental testing will be collected during routine
diagnostic testing of patient and/or donor at time of inclusion and after 1-1,5
years of follow up.

2. AIHA patients from 3 months - 16 years of age:
After informed consent, no additional blood collection will be performed. All
clinical and routine laboratory results will be registered in the databank.
Experimental diagnostic testing will only be performed on residual blood
obtained from routine diagnostic testing.

Venipuncture for blood collection is seen as a minimal risk procedure, however,
there is a possibility of complications. The main risks are discomfort and
bruising at the site of the venipuncture, and in rare cases this site may
become infected. Since nerves are very close to veins and arteries, there is a
small risk a nerve is hit by the needle. This is a rare out-come of
venipuncture which may lead to, an almost often transient, pain or numbness
sensation.

Participation in the study does not result in individual benefits. Nor the
patient/blood donor, nor the physician will be informed about the results of
the experimental testing. Thus no additional information can be used to change
the current standard care of the patient/blood donor.