You have produced several papers on

DR STEFAN HANSSON
An impressive career
researching preeclampsia
Being last year’s recipient of Sweden’s most prestigious clinical research prize, the Athena prize,
is sure evidence that Dr Stefan Hansson’s work developing new diagnostics and treatments for
preeclampsia has every potential to save lives and help to make an impact on women’s health
You have produced several papers on
preeclampsia so far and your work is
ongoing. How do you hope this research will
help to develop effective therapies?
By discovering and understanding early
mechanisms for preeclampsia, we believe that
more specific therapies can be developed.
Yearly, around 8.5 million cases of preeclampsia
are reported worldwide, of which 5,000 are
in Sweden. The unique potential therapy
being developed in this translational project
addresses a very important issue for women’s
health during pregnancy and meets a major
worldwide apparent clinical need. Our therapy
will support the development of a specific,
rather than symptomatic, treatment. Today the
only curative intervention is to induce delivery,
whether the baby is ready or not. It is estimated
that US $30 billion is spent worldwide each
year in healthcare costs to treat women with
preeclampsia and their newborns. Our work will
help to address this cost and help women with
this disease around the world.
What do you hypothesise is the likely cause
of preeclampsia?
Our gene and protein profiling studies
have revealed a new potential aetiology for
preeclampsia. The first stage, caused by a
defect formation of the placenta, gives rise
to uneven blood perfusion, oxidative stress,
production and the accumulation of free
foetal Hb (fHb). Stage two is characterised
by a general, systemic endothelial damage
and inflammation. Our recent results have
shown that the free fHb cause inflammation
and damage to the blood-placenta barrier.
As a consequence, free fHb leaks over
to the maternal blood circulation. The
plasma concentration is increasing from
early pregnancy and later correlates to the
severity of the disease. Free fHb and its toxic
metabolite heme are well known to have
pro-inflammatory, pro-oxidative, kidney
and endothelial damaging effects as well
as inducing vasoconstriction by being an
NO-scavenger. Hb is released from the red
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blood cells during haemolysis, which occurs
in diseases like autoimmune haemolytic
anaemia, sickle cell anaemia and malaria. In
fact, free heme, bilirubin and biliverdin have
been identified among the 14 metabolites in a
metabolomics signature of preeclampsia using
first trimester plasma. Free heme can enter cells
by dissolving the cell membranes and possibly
also the extracellular matrix.
Is there a current method of prevention for
this condition?
Low dose asprin has some preventive effects if
treatment is initiated early in pregnancy, however
since it is difficult to identify high-risk pregnancies
in early stages (first trimester), the numbers
needed to treat is high (about 25).
Can you explain what is meant by an ELISA
technique? How is it used to diagnose
preeclampsia?
We have raised antibodies specific for free fHb
and the adult form Hb-A by immunising with
specific chains purified from cord blood fHb
and adult blood, and developed ELISAs specific
for free fHb and Hb-A. Statistical analysis
shows that free fHb has a higher sensitivity and
specificity than any other suggested biomarker
for preeclampsia in early pregnancy. fHb
levels have been shown to be increased in the
mother’s blood in preeclampsia, in fact fHb is
increased eight-fold in preeclampsia compared
to controls. The prognostic value of free fHB
will be further evaluated by measuring samples
collected prospectively early in pregnancy
in combination with alpha-1 microglobulin
(A1M). In collaboration with Professor Baskaran
Thilaganathan from London, a prospective
cohort containing more than 60 preeclampsia
women and matched controls have been
followed from early pregnancy until delivery.
Free fHb and Hb-A and A1M have been
measured. Results from 96 cases show that
free fHb levels can be measured as early as
10-14 weeks of gestation (when the uteroplacental circulation is established), several
weeks before clinical manifestations are
present. The three markers, free fHb, free adult
Hb and A1M increased the sensitivity, specificity
and the predictive value for diagnosing
preeclampsia in the first trimester, when used in
combination.
Can you outline the methods taken to
analyse genes and proteins?
We have previously developed a preeclampsia
specific gene chip, this will be further used
to profile the gene expression in placentas
perfused with free fHb ±A1M and compare
to the gene expression profile obtained from
different high-risk pregnancies, in order to
better understand what placental genes that
are essential in preeclampsia. To strengthen
the analysis we have optimised our
methods to also undertake
protein profiling on placenta
tissue and maternal
plasma. We have
optimised protein
extraction
procedures for
placenta
tissue.
DR STEFAN HANSSON
New drugs for an old disease
A Swedish translational research team at Lund University is using
free haemoglobin to develop a new preeclampsia prognostic/
diagnostic method and effective therapies for this serious disease
PREECLAMPSIA IS A pregnancy disease that
knows no boundaries: it crosses geographic
and social borders, causes serious health
problems and can potentially lead to the
death of both the mother and child. Described
as early as the Egyptian era, this disease
has troubled scientists and medical experts
for thousands of years. It is still one of the
leading causes of death in unborn children
and pregnant women. Currently, only
symptomatic treatments are available, with
delivery often being the last viable option
for the most serious of cases. The disease is
believed to initiate in the placenta, and a group
of researchers are using the organ as a starting
point to investigate possible biomarkers. They
hope this work will help predict the onset
of preeclampsia, ultimately paving the way
towards new potential treatments.
This research team is led by Dr Stefan
Hansson, the Vice Dean for Research at the
Medical Faculty of Lund University, who is also
a professor and senior consultant in Obstetrics
and Gynecology at Skåne University Hospital
in southern Sweden. With preclinical training
in research, Hansson can apply his molecular
background to delve deeply into this clinically
puzzling disease often called ‘the disease
of theories’. Supported by a translational
research group, Hansson has been building on
findings from previous research into proteinand gene-array studies. These have highlighted
the possibility that free foetal haemoglobin
(fHb) may be an essential aetiological factor
of preeclampsia, thus also potentially an
ideal biomarker for prediction and diagnosis.
Their latest research aims to discover whether
a free haemoglobin scavenger, alpha-1microglobulin (A1M), might be used as a
potential therapeutic drug.
Currently, there are very few options
available for the prevention or treatment of
preeclampsia. Taking a low dose of aspirin has
shown to have some beneficial effects, but
falls short of offering a complete treatment
for the disease. Part of the reason that an
effective therapeutic option for the disease
still evades scientists to date is because its
clinical symptoms – which include high blood
pressure, headaches and visual disturbances
– only become evident once the disease has
taken hold.
A TWO STAGE DISEASE
It is recognised that this disease evolves in two
main stages. The first stage has been shown
to take place when a defect invasion of the
placental cells into the muscle layers of the
spiral arteries occurs, which can put the baby
at risk: “This may result in a reduced uteroplacental blood flow and afoetal intra-uterine
growth restriction, reduced oxygen delivery
and oxidative stress that further aggravate
placental vascular function,” Hansson
explains.
The second stage consists of the clinical signs
that occur later on during the pregnancy,
by definition after 20 weeks. At this point,
hypertension and proteinurea begin to
manifest. As the disease progresses, the
symptoms accelerate, with a generalised
endothelial dysfunction that eventually
affects all organs. When the disease moves
into this end stage – known as eclampsia
– severe epileptic seizures occur and if left
untreated, may be fatal for both the mother
and child.
THE IMPORTANCE OF ‘NOTCHING’
One way to clinically elevate increased
vascular resistance in the placenta is to use
Doppler ultrasound techniques. By employing
this tool, the occurrence of early diastolic
notches as a sign of increased resistance
in the utero-placental blood flow, high
risk pregnancies can be identified, patients
who have a significantly elevated risk of
developing preeclampsia. Investigations have
shown that the plasma level of serotonin and
norepinephrine are significantly increased
in preeclamptic patients. Hansson has been
able to provide evidence, by demonstrated
decreased expression of the norepinephrine
and a steroid sensitive monoamine
transporter in placentas in preeclamptic
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FREE HEMOGLOBIN IN PREECLAMPSIA
ENABLE NEW DIAGNOSTIC AND
TREATMENT OF PREECLAMPSIA
OBJECTIVES
This translational project intends to develop
and validate fHb as a new potential marker for
prediction and diagnosis of PE. Furthermore,
the injury mechanism of fHb in PE will be
examined and the therapeutic effect of alpha1-microglobulin as a scavenger evaluated as a
new therapy.
KEY COLLABORATOR
Professor Bo Åkerström, Lund University
FUNDING
Preelumina Diagnostics AB • A1M Pharma AB
• Torsten Söderbergs Foundation • Marianne
and Marcus Wallenberg Foundation for Clinical
Research • Maggie Stephens Foundation •
Swedish Society for Medical Research • Region
Skåne • ALF • Swedish Research Council •
MENA/SIDA
CONTACT
Professor Stefan Hansson
Project Leader
Women’s Clinic, Prenatal Unit
Skåne University Hospital (SUS)
205 02 Malmo
Sweden
T +46 40 332 976
Biomedical Center
Institute Clinical Sciences Lund
Department Obstetrics and Gynecology
Lund University
Sweden
T +46 46 222 3011
E [email protected]
STEFAN HANSSON works as Professor and
Senior Consultant in Obstetrics and Gynecology
at Lund University and Skåne University
Hospital in southern Sweden. He is currently
funded by the Marianne and Marcus Wallenberg
foundation for clinical research, combining
research and clinical work in equal proportions.
As of March 2012, he is vice Dean for research
at the medical faculty, Lund university. He
is co-founder of two biotech companies,
Preelumina Diagnostics and A1M Pharma, in
which a new diagnostic kit and a new therapy
for preeclampsia are being developed.
The possibility of a treatment for preeclampsia is an exciting prospect for
both researchers and patients
pregnancies. This is an important discovery,
since it emphasises that by inhibiting their
uptake, the extracellular levels of the signal
substances are increased, which ultimately
affects the strength of the transmitted signal.
The monoamine transporters in the placenta
may protect the foetus from maternal stress
hormones occurring in preeclampsia.
Although this is an interesting finding in terms
of building understanding of this disease,
there is still much work to be done within this
area of research. For example, cocaine abuse
during pregnancy has been linked to triggering
a preeclampsia-like state, which suggests that
a monoaminergic imbalance might be central
in the development of preeclampsia. “The reuptake of monoamines by the transporters
is by far the most important mechanism by
which the extra cellular concentrations of
these substances are regulated, but their role
in the placenta during pregnancy is not yet
fully understood,” elucidates Hansson.
THE VALUE OF BIOMARKERS
Research undertaken on women with
preeclampsia has illustrated that the levels
of the free haemoglobin scavenger A1M
are also elevated in maternal plasma and
placenta tissue. This implies that the protein
is involved in a defence-like reaction against
the Hb-insult. By hypothesising that A1M,
and other defence systems, are literally being
overwhelmed when a patient suffers from
preeclampsia, the research team consider
that they can then treat this disease by adding
an exogenously administrated recombinant
A1M. Measuring biomarkers, such as free fHb
and endogenous A1M, has allowed them to
previously reveal that these can be used to
predict preeclampsia at very early stages, in
fact several weeks before the manifestations
of this disease are seen on a clinical level.
This in itself is a profound discovery, but from
Hansson’s perspective, there are a number
of other benefits that come from using free
fHb and A1M as biomarkers. For instance,
free fHb and A1M have higher sensitivity
and specificity than any other generally
used biomarker, and both these biomarkers
provide the opportunity to develop a more
personalised therapy.
The new therapy could potentially be
administered in two different ways. Firstly,
in early pregnancy when increased levels
of free fHb and A1M are detected, the A1M
based drug can be offered to help inhibit the
development of preeclampsia. Secondly, the
levels of Hb correlate with the severity of
the disease, therefore the dose of the A1M
based drug can potentially be adjusted to the
plasma levels of free Hb when preeclampsia
has manifested.
The possibility of a treatment for preeclampsia
is an exciting prospect for both researchers
and patients. Not only would it offer hope
for women suffering from the disease, but
it would also have a tremendous impact on
women’s health all over the world.
PHOTOGRAPHER
CHARLOTTE CARLBERG BÄRG
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