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Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation.
[heparin-induced thrombocytopenia]
Platelets
are
essential
in
maintaining
hemostasis
following
inflammation
or
injury
to
the
vasculature
.
Dysregulated
platelet
activity
often
results
in
thrombotic
complications
leading
to
myocardial
infarction
and
stroke
.
Activation
of
the
FcγRIIa
receptor
leads
to
immune-mediated
thrombosis
,
which
is
often
life
threatening
in
patients
undergoing
heparin-induced
thrombocytopenia
or
sepsis
.
Inhibiting
FcγRIIa-mediated
activation
in
platelets
has
been
shown
to
limit
thrombosis
and
is
the
principal
target
for
prevention
of
immune-mediated
platelet
activation
.
In
this
study
,
we
show
for
the
first
time
that
platelet
12
(
S
)
-
lipoxygenase
(
12
-
LOX
)
,
a
highly
expressed
oxylipin-producing
enzyme
in
the
human
platelet
,
is
an
essential
component
of
FcγRIIa-mediated
thrombosis
.
Pharmacologic
inhibition
of
12
-
LOX
in
human
platelets
resulted
in
significant
attenuation
of
FcγRIIa-mediated
aggregation
.
Platelet
12
-
LOX
was
shown
to
be
essential
for
FcγRIIa-induced
phospholipase
Cγ
2
activity
leading
to
activation
of
calcium
mobilization
,
Rap
1
and
protein
kinase
C
activation
,
and
subsequent
activation
of
the
integrin
αIIbβ
3
.
Additionally
,
platelets
from
transgenic
mice
expressing
human
FcγRIIa
but
deficient
in
platelet
12
-
LOX
,
failed
to
form
normal
platelet
aggregates
and
exhibited
deficiencies
in
Rap
1
and
αIIbβ
3
activation
.
These
results
support
an
essential
role
for
12
-
LOX
in
regulating
FcγRIIa-mediated
platelet
function
and
identifies
12
-
LOX
as
a
potential
therapeutic
target
to
limit
immune-mediated
thrombosis
.
Diseases
Validation
Diseases presenting
"first time"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
adrenomyeloneuropathy
alpha-thalassemia
aniridia
aromatase deficiency
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dentin dysplasia
dentinogenesis imperfecta
dracunculiasis
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
fabry disease
familial mediterranean fever
gm1 gangliosidosis
harlequin ichthyosis
heparin-induced thrombocytopenia
hirschsprung disease
hodgkin lymphoma, classical
holt-oram syndrome
hydrocephalus with stenosis of the aqueduct of sylvius
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
malignant atrophic papulosis
megacystis-microcolon-intestinal hypoperistalsis syndrome
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
omenn syndrome
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
severe combined immunodeficiency
sneddon syndrome
triple a syndrome
trochlear dysplasia
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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