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Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4.
[heparin-induced thrombocytopenia]
The
chemokine
platelet
factor
4
(
PF
4
)
undergoes
conformational
changes
when
complexing
with
polyanions
.
This
can
induce
the
antibody-mediated
adverse
drug
effect
of
heparin-induced
thrombocytopenia
(
HIT
)
.
Understanding
why
the
endogenous
protein
PF
4
becomes
immunogenic
when
complexing
with
heparin
is
important
for
the
development
of
other
negatively
charged
drugs
and
may
also
hint
toward
more
general
mechanisms
underlying
the
induction
of
autoantibodies
to
other
proteins
.
By
circular
dichroism
spectroscopy
,
atomic
force
microscopy
,
and
isothermal
titration
calorimetry
we
characterized
the
interaction
of
PF
4
with
unfractionated
heparin
(
UFH
)
,
its
16
-
,
8
-
,
and
6
-
mer
subfractions
,
low
-molecular-weight
heparin
(
LMWH
)
,
and
the
pentasaccharide
fondaparinux
.
To
bind
anti-
PF
4
/
heparin
antibodies
,
PF
4
/
heparin
complexes
require
(
1
)
an
increase
in
PF
4
antiparallel
β-sheets
exceeding
∼
30
%
(
achieved
by
UFH
,
LMWH
,
16
-
,
8
-
,
6
-
mer
)
,
(
2
)
formation
of
multimolecular
complexes
(
UFH
,
16
-
,
8
-
mer
)
,
and
(
3
)
energy
(
needed
for
a
conformational
change
)
,
which
is
released
by
binding
of
≥
11
-
mer
heparins
to
PF
4
,
but
not
by
smaller
heparins
.
These
findings
may
help
to
synthesize
safer
heparins
.
Beyond
PF
4
and
HIT
,
the
methods
applied
in
the
current
study
may
be
relevant
to
unravel
mechanisms
making
other
endogenous
proteins
more
vulnerable
to
undergo
conformational
changes
with
little
energy
requirement
(
eg
,
point
mutations
and
post-translational
modifications
)
and
thereby
predisposing
them
to
become
immunogenic
.
Diseases
Validation
Diseases presenting
"antibody-mediated adverse drug effect"
symptom
heparin-induced thrombocytopenia
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