Arterial thrombosis in the nephrotic syndrome

Abstract

Thrombosis is a frequent cause of morbidity and mortality in patients with the nephrotic syndrome. Venous thrombotic complications are well recognized but arterial complications are rare. Thrombosis is multifactorial, and has been attributed to a hypercoaguable state due to alterations in blood levels of the various factors involved in the coagulation and fibrinolytic systems, alterations in platelet function, venous stasis, haemoconcentration, increased blood viscosity and possibly the administration of steroids. Thrombosis in general and arterial thrombosis in particular is a significant and potentially serious problem in nephrotic patients. Awareness of the condition and its pathogenesis is needed. Assessment for the risk factors is required to allow appropriate prophylactic measures to be taken.

Full text

Postgrad
Med
J
(1994)
70,
905
-
909
i)
The
Fellowship
of
Postgraduate
Medicine,
1994
Clinical
Review
Arterial
thrombosis
in
the
nephrotic
syndrome
Ibrahim
H.
Fahal,
Peter
McClelland,
Charles
R.M.
Hay'
and
Gordon
M.
Bell
The
Regional
Renal
Unit
and
'Department
of
Haematology,
Royal
Liverpool
University
Hospital,
Prescot
Street,
Liverpool
L7
8XP,
UK
Summary:
Thrombosis
is
a
frequent
cause
of
morbidity
and
mortality
in
patients
with
the
nephrotic
syndrome.
Venous
thrombotic
complications
are
well
recognized
but
arterial
complications
are
rare.
Thrombosis
is
multifactorial,
and
has
been
attributed
to
a
hypercoaguable
state
due
to
alterations
in
blood
levels
of
the
various
factors
involved
in
the
coagulation
and
fibrinolytic
systems,
alterations
in
platelet
function,
venous
stasis,
haemoconcentration,
increased
blood
viscosity
and
possibly
the
administration
of
steroids.
Thrombosis
in
general
and
arterial
thrombosis
in
particular
is
a
significant
and
potentially
serious
problem
in
nephrotic
patients.
Awareness
of
the
condition
and
its
pathogenesis
is
needed.
Assessment
for
the
risk
factors
is
required
to
allow
appropriate
prophylactic
measures
to
be
taken.
Introduction
Thrombotic
complications
are
common
in
the
nephrotic
syndrome.
These
have been
attributed
to
a
hypercoagulable
state."2
Venous
thrombosis
is
well
recognized,
but
arterial
thrombosis
occurs
less
frequently
and
is
seen
primarily
in
children.3
We
report
two
patients
with
the
nephrotic
synd-
rome
who
developed
arterial
thrombosis,
and
discuss
the
pathogenesis,
management
and
the
prophylaxis
of
this
potentially
serious
condition.
Case
1
A
27
year
old
man
with
an
18-month
history
of
mesangioproliferative
glomerulonephritis
and
nephrotic
syndrome
presented
with
excruciating
pain
in
both
lower
legs
and
inability
to
walk,
which
began
after
a
long
train
journey.
He
smoked
about
15-20
cigarettes
a
day.
His
only
medication
was
frusemide.
Examination
revealed
that
both
calves
were
tender
and
swollen,
and
both
feet
were
cold
and
pale.
The
pedal
pulses
were
absent.
Bilateral
leg
venography
were
negative,
but
bilateral
femoral
arteriography
showed
thrombus
in
both
profunda
femoralis
and
distal
popliteal
arteries.
Investigations
showed
a
protein
C
antigen
activity
of
138%
(75-155).
Protein
S
antigen
activity
of
82%
(50-150),
plasminogen
activity
of
135%
(75-125),
fibrinogen
13.1
g/l
(1.5-4
g/l)
and
antithrombin
III
antigen
activity
of
55%
(80-155).
Haemoglobin
was
16.5
g/dl,
haematocrit
48.6%,
leucocyte
count
21.2
x
109/1,
neutrophils
14.8
x
109/1
and
platelet
count
318
x
109/l.
Plasma
viscosity
was
2.14
cp
(1.5-
1.72)
and
ESR
1
5
mm/
1
hour.
Blood
urea
was
8.3
mmol/l,
serum
creatinine
95
pmol/l,
serum
albumin
18
g/l
and
with
a
24
hours
protein
excretion
of
36
g.
Antinuclear
antibodies,
anti-DNA
antibody,
anti-
cardiolipin
antibodies
and
lupus
anticoagulant
were
negative.
He
was
treated
with
analgesia
and
anti-coagulation
with
reperfusion
of
the
lower
limbs
and
resolution
of
the
pain.
He
was
in
remission
18
months
later.
Case
2
A
47
year
old
female
with
a
6
month
history
of
mesangioproliferative
glomerulonephritis
and
the
nephrotic
syndrome
presented
with
a
painful
right
leg.
She
smoked
10
cigarettes
a
day.
Her
medica-
tions
were
frusemide
and
prednisolone.
On
examination
she
had
cold
and
blue
oedematous
feet
with
absent
right
femoral,
popliteal
and
pedal
pulses.
Arteriogram
revealed
a
thrombus
causing
a
complete
block
in
her
right
iliac
inflow
together
with
fairly
severe
femoro
distal
occlusive
disease.
Investigations
revealed
a
haemoglobin
of
15.9
g/
dl,
haematocrit
42%
and
a
leucocyte
count
22.4
x
10-9/l,
platelets
count
420
x
10-9/l.
Blood
urea
was
9.4
mmol/l,
serum
creatinine
134
jimol/l,
serum
albumin
27
g/dl
and
with
a
24
hour
protein
Correspondence:
I.H.
Fahal,
M.R.C.P.,
University
Department
of
Medicine,
University
of
Liverpool,
PO
Box
147,
Liverpool
L69
3BX,
UK.
Accepted:
18
July
1994
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906
I.H.
FAHAL
et
al.
excretion
of
18.4
g.
Serum
cholesterol
17
mmol/l
and
triglycerides
10.3
mmol/l.
Anti-nuclear
antibodies
were
positive
at
800
IU/ml,
but
anti-
DNA
antibody,
anticardiolipin
antibodies
and
lupus
anticoagulant
were
negative.
Total
protein
C
antigen
activity
was
57%,
total
protein
S
antigen
activity
of
120%,
plasminogen
activity
110%,
fibrinogen
7.42
g/dl
and
anti-thrombin
III
antigen
activity
70%.
She
underwent
a
femoro
femoral
crossover
graft
operation,
removal
of
the
thrombus
and
was
commenced
on
anti-coagulation
with
satisfactory
reperfusion
of
her
lower
limbs.
She
reached
end-stage
renal
disease
15
months
later
and
commenced
haemodialysis.
Discussion
Thrombosis,
a
frequent
cause
of
mortality
in
patients
with
the
nephrotic
syndrome,
was
first
reported
by
Addis
in
1948.4
Venous
thrombotic
complications
have
frequently
been
observed
but
arterial
complications
are
rare.5'6
In
contrast
to
venous
thrombi,
which
are
composed
predominantly
of
fibrin
and
red
cells,
arterial
thrombi
are
composed
predominantly
of
platelets.7
In
nephrotic
patients,
arterial
thrombosis
has
been
reported
in
the
aorta,
mesenteric,
axillary,
femoral,
ophthalmic,
carotid,
cerebral,
renal,
pulmonary
and
coronary
arteries.3
The
pulmonary8
and
femoral
arteries
are
particularly
susceptible,
the
latter
usually
as
a
complication
of
attempted
blood
sampling
from
the
femoral
vein.
Thrombosis
may
occur
at
any
stage
during
the
course
of
the
neph-
rotic
syndrome
but
it
is
most
frequent
in
the
early
months.
Factors
predisposing
to
thrombosis
The
tendency
of
nephrotic
patients
to
develop
thrombotic
episodes
has
been
attributed
to
a
hypercoagulable
state,
due
to
alterations
in
blood
levels
of
the
various
factors
involved
in
the
coagulation
and
fibrinolytic
systems,
alterations
in
platelet
function,
venous
stasis,
haemoconcentra-
tion,
increased
blood
visocity,
and
possibly
the
administration
of
steroids.
Blood
stasis
and
hypercoagulability
are
two
important
factors
for
the
development
of
venous
thrombosis
while
arterial
hypertension,
hyper-
lipidaemia,
tobacco,
diabetes
and
obesity
represent
further
risk
factors
for
arterial
thrombosis.9
Hypercoagulable
state.
a.
Alterations
in
zymogens
and
co-factors
Several
studies
showed
that
the
hypercoaguable
state
is
characterized
by
alterations
in
the
concentrations
and
activity
of
a
number
of
coagulation
factors.
Factors
IX,
XI
and
XII
are
decreased,
and
appear
to
be
due
to
their
urinary
losses
due
to
their
small
molecular
size.'0-14
In
contrast,
blood
levels
of
factors
II,
V,
VII,
VIII,
X
and
XIII
are
typically
increased.2"5
The
magnitude
of
these
increases,
especially
those
of
the
co-factors
(factors
V
and
VIII),
correlates
with
the
degree
of
reduction
in
serum
albumin
and
is
thought
to
result
from
increased
hepatic
synthesis
of
the
factors,
stimu-
lated
by
hypoalbuminemia.14
b.
Alterations
in
fibrinogen
concentrations
An
elevation
of
the
plasma
fibrinogen
levels
is
a
consistent
and
significant
abnormality
observed
in
the
nephrotic
patients,
which
is
attributed
to
an
increased
hepatic
synthesis
that
is
proportional
to
the
urinary
losses.'6
A
number
of
studies
have
observed
an
inverse
correlation
between
fibrinogen
concentrations
and
serum
albumin.'7
c.
Alterations
in
the
fibrinolytic
system
Altera-
tions
in
the
concentrations
of
several
of
the
com-
ponents
of
both
the
fibrinolytic
and
anti-thrombin
systems
have
been
documented.'8
Decreased
fibrinolytic
activity
has
been
associated
with
hyper-
triglyceridemia.'9
Decreased
concentrations
of
plasma
plaminogen
have
been
found
and
are
correlated
with
a
low
serum
albumin
and
the
magnitude
of
the
proteinuria.'8
Levels
of
plas-
minogen
activator
are
elevated.3
Levels
of
alpha
2-anti-plasmin3
and
alpha
2-macroglobulins
are
reported
to
be
increased.20
d.
Alterations
in
coagulation
inhibitors
(physio-
logical
anti-coagulants)
Plasma
concentrations
of
anti-thrombin
III
(ATIII)
are
decreased
in
the
nephrotic
syndrome2'
and
its
deficiency
plays
an
important
role
in
the
development
of
thrombosis.
It
is
likely
that
renal
losses
in
nephrotic
patients
Changes
in
coagulation
factors
and
fibrinolysis
system
in
patients
with
nephrotic
syndrome
Increased
Fibrinogen
antigen
and
activity
Factor
VIII
antigen
and
activity
Factor
XIII
antigen
Combined
factor
II,
VII,
X
activity
Cofactor
V
Alpha
2-macroglobulin
Alpha
2-anti-plasmin
Reduced
Anti-thrombin
III
Plasminogen
Factor
XI
Factor
XII
Areas
of
controversy
Protein
S
and
protein
C
(increased
in
some
studies,
decreased
in
others)
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ARTERIAL
THROMBOSIS
IN
THE
NEPHROTIC
SYNDROME
907
contribute
to
its
deficiency.22'23
However,
only
patients
with
plasma
albumin
levels
below
20
g/l
show
significant
reductions
in
plasma
AT
III
levels.'
A
low
serum
albumin
is
also
correlated
with
low
levels
of
plasma
AT
III!."'
Most
of
these
abnormalities
tend
to
normalize
with
clinical
remission
of
the
nephrotic
syndrome.24
Protein
C,
a
vitamin
K-dependent
protein,
is
an
anticoagulant
that
inactivates
the
coagulation
factors
V
and
VIII.
Protein
S
is
a
cofactor
of
activated
protein
C.
The
levels
of
antigenic
and
functional
activity
of
protein
C
have
been
reported
as
normal25
or
raised26
in
nephrotic
patients.
On
the
other
hand,
raised27,
normal28
and
reduced29'30
levels
of
protein
S
have
been
reported
in
nephrotic
patients.
Major
altera-
tions
in
fluid-phase
coagulation
proteins
and
their
regulators
(such
as
AT
III)
seem
to
be
almost
confined
to
severe
nephrotic
syndromes,
with
a
serum
albumin
concentration
below
20
g/dl.
e.
Alterations
in
platelet
function
Thrombocyto-
sis,
increased
platelets
aggregation
and
adhesive-
ness,24
and
an
increase
in
the
levels
of
the
platelet-
release
substance
B-thromboglobulin31'32
have
been
observed
in
patients
with
the
nephrotic
syndrome
and
may
play
a
role
in
promoting
the
hyper-
coagulable
state,
and
hence
the
thrombotic
compli-
cations.33
Platelet
hyperaggregability
correlated
with
the
degree
of
proteinuria
as
well
as
with
plasma
cholesterol
levels.
These
findings
suggest
that
urinary
albumin
losses
or
hyperlipidaemia
may
be
responsible
for
this
platelet
hyperaggreg-
ability.
Platelet
aggregability
is
increased
in
type
II
hyperlipoproteinemia
to
a
degree
that
is
com-
parable
to
that
seen
in
the
nephrotic
syndrome.34
f
Increased
blood
viscosity
Increased
blood
vis-
cosity
contributes
to
generation
of
thromboembo-
lic
complications
and
is
due
to
the
haemoconcen-
tration
(with
elevated
values
of
both
haematocrit
and
haemoglobin
concentration),
which
is
often
present
and
aggravated
by
the
therapeutic
use
of
diuretics
in
these
patients.
Whole
blood
viscosity
is
increased
by
both
the
diuretic-related
increase
in
haematocrit
and
the
increased
plasma
viscosity
related
to
high
fibrinogen
concentration.35'36
When
plasma
fibrinogen
levels
increase,
especially
to
values
as
high
as
1
g/dl,
as
may
be
seen
in
nephrotic
syndromes,
they
cause
increased
erythrocyte
aggre-
gation
and
marked
increases
in
plasma
viscosity.35
g.
Endothelium
and
atherosclerosis
The
loss
of
functional,
if
not
structural,
integrity
of
the
vas-
cular
endothelium
is
closely
related
to
the
initiation
of
atherosclerosis.
Normal
endothelial
cells
are
thrombo-resistant
and
arterial
thrombi
character-
istically
result
from
elevated
shear
stress
at
sites
of
vascular
injury.
Shear-induced
platelet
aggregation
is
important
in
physiological
haematosis
and
in
the
pathogenesis
of
arterial
thrombosis.
Badimon
et
al.37
studied
the
effect
of
damaged
endothelium
on
the
development
of
atherosclerotic
disease.
They
investigated
the
function
of
normal
and
damaged
endothelium
in
pigs,
following
super-
ficial
balloon
injury,
which
produces
a
significant
alteration
in
endothelium-dependent
coronary
vasoreactivity.
As
vasoconstriction
in
arteries
can
reduce
blood
flow
and
increase
arterial
wall-shear
forces,
which
increase
platelet
deposition
in
injured
arteries,
they
concluded
that
the
intact
endothe-
lium
is
one
of
the
greatest
sources
of
protection
from
arterial
thrombosis,
atherosclerosis
and
vaso-
constriction.
h.
Drugs
administration
Drugs,
particularly
diur-
tics'7
and
steroids
aggravate
the
hypercoagulable
state
in
the
nephrotic
syndrome.
Diuretics
may
enhance
volume
depletion
and
thus
contribute
to
the
thrombotic
phenomena.
Steroids
administra-
tion
increases
the
concentrations
of
several
clotting
factors
and
modifies
the
coagulation
mechanisms.3
They
raise
the
concentration
of
factor
VIII,38
and
shorten
prothrombin
and
activated
partial
throm-
boplastin
times.39
Management
and
thromboprophylaxis
Thrombosis,
a
potentially
serious
problem
in
nephrotic
patients,
is
multifactorial.
A
number
of
predisposing
factors
has
been
identified.
Anti-
coagulation
therapy
should
be
commenced
as
soon
as
the
condition
is
diagnosed.
It
must
be
remembered
that
anti-coagulation
in
hypoal-
buminemic
patients
is
hazardous,
higher
doses
of
heparin
may
be
required
to
achieve
a
satisfactory
anticoagulation,
and
changes
of
serum
albumin
levels
may
interfere
with
the
anticoagulant
effect
of
warfarin.
If
the
disease
remits
then
anti-
coagulation
can
be
discontinued
after
6
months,
otherwise
it
should
be
continued
until
the
serum
albumin
exceeds
20
g/dl.
Prophylactic
anti-coagulation
Despite
the
seriousness
of
this
condition,
there
is
no
consensus
about
the
need
for
prophylactic
anti-
Changes
in
platelets
in
patients
with
the
nephrotic
syndrome
Thrombocytosis
Increased
adhesiveness
Increased
ADP-induced
rate
and
percentage
of
aggregation
Increased
collagen-induced
rat
and
percentage
of
aggregation
Shorter
time
for
collagen-induced
aggregation
Increase
in
beta-thromboglobulin
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908
I.H.
FAHAL
et
al.
coagulation.
Bellomo
and
Atkins'
argued
the
case
for
prophylactic
anti-coagulation
in
membranous
nephropathy
and
concluded
that
all
nephrotic
patients
with
membranous
nephropathy
should
receive
prophylactic
anticoagulation
therapy
unless
it
is
contraindicated.
Aspirin
There
is
growing
evidence
that
aspirin
may
be
useful
in
reducing
the
risks
of
thromboembolic
disease
in
the
nephrotic
syndrome.
In
a
model
of
arterial
thrombosis
induced
by
laser,
a
partial
occlusion
was
induced
in
small
mesenteric
arteri-
oles.
Thrombus
formed
within
seconds
after
the
laser
lesion
and
grew
rapidly.
Embolization
began
within
the
minute
following
the
laser
flash.
The
administration
of
aspirin
at
three
doses
(50,
100
and
200
mg/kg)
by
intramuscular
injection,
15
min
before
the
laser
injury,
induced
three
different
phenomena:
(1)
an
increase
of
the
number
of
laser
injuries
required
for
the
thrombus
formation;
(2)
a
dose-dependent
decrease
in
the
duration
of
emboli-
zation;
and
(3)
a
dose-dependent
decrease
in
the
number
of
emboli.4'
In
another
aspirin-sensitive
model
of
arterial
thrombosis
in
anaesthetized
rats,
carotid
artery
thrombi
were
formed
in
response
to
electrical
stimulation
and
were
occlusive
in
84%
of
vehicle-treated
rats.
Among
other
anti-thrombotic
drugs,
intravenous
administration
of
aspirin
(10
mg/kg)
decreased
average
thrombus
weight
by
35%
and
also
reduced
the
frequency
of
occlusion
to
less
than
25%.42
Reduction
ofproteinuria
Serum
albumin
below
25
g/l
is
a
statistically
signi-
ficant
risk
factor
for
venous
(40.0
versus
2.7%;
P<0.01)
and
for
combined
arterial
and
venous
(28.6
versus
5.5%;
P
<
0.01)
episodes
of
thrombo-
embolism.'
A
low
serum
albumin
is
inversely
correlated
with
fibrinogen'7
and
correlated
with
anti-thrombin
111,1,17
and
increased
platelet
aggre-
gability.
These
abnormalities
can
be
reduced
by
the
normalization
of
serum
albumin.24
An
attempt
to
reduce
the
degree
of
proteinuria
should
be
made
in
these
patients.
Angiotensin-converting
enzyme
inhibitors
are
effective
in
reducing
proteinuria
by
decreasing
glomerular
filtration
pressure.43
Their
effect
is
increased
if
they
are
accompanied
by
a
salt-restricted
diet.
Non-steroidal
anti-inflamma-
tory
drugs
also
reduce
the
proteinuria
by
reducing
the
renal
blood
flow
and
glomerular
filtration
rate,44
therefore
they
must
not
be
used
in
patients
with
renal
impairment.
Drug
administration
Diuretics,
the
mainstay
of
therapy
in
nephrotic
oedema
should
be
used
with
caution
and
only
if
oedema
persists
in
spite
of
salt
restriction.
The
judicious
use
of
salt-poor
albumin
and
diuretic
infusion
in
severe
cases
reduces
the
risks
of
plasma
volume
depletion,
haemoconcentration
and
throm-
boembolic
complications.
Steroid
administration
increases
the
concentrations
of
several
clotting
factors
and
modifies
the
coagulation
mechanisms.3
Thus
these
agents
should
be
used
cautiously
in
the
treatment
of
the
nephrotic
syndrome.
Arterial
hypertension
Arterial
hypertension,
as
discussed
earlier,
consti-
tutes
a
risk
factor
for
arterial
thrombosis
and
should
be
treated
vigorously,
aiming
at
a
diastolic
pressure
of
less
than
90
mmHg.
Angiotensin-con-
verting
enzyme
inhibitors
are
useful
in
the
treat-
ment
of
hypertension
because
of
their
ability
to
reduce
proteinuria
and
retard
progressive
glome-
rular
sclerosis.
Hyperlipidaemia
There
is
a
suggestion
that
hyperlipidaemia
may
be
responsible
for
platelet
hyperaggregability
as
platelet
aggregability
is
increased
in
type
II
hyper-
lipoproteinemia
to
a
degree
that
is
comparable
to
that
seen
in
the
nephrotic
syndrome.34
Reduction
of
dietary
saturated
fats
and
cholesterol,
and
the
administration
of
the
newer
and
safer
anti-lipid-
aemia
drugs,
for
example,
hydroxy-methylglutaryl
coenzyme
A
(HMG
CoA)
can
reverse
the
nephrotic
hyperlipidaemia
and
thus
decrease
the
platelet
hyperaggregability,
reducing
the
risk
of
throm-
bosis.
Endothelium
and
atherosclerosis
Tobacco,
diabetes,
and
obesity
contribute
to
atherosclerosis.
Refraining
from
smoking,
control
of
weight
and
diabetes
mellitus,
if
present,
is
of
utmost
importance
in
reducing
the
risk
of
athero-
sclerosis,
thus
minimizing
endothelial
damage
and
possible
arterial
thrombosis.
Thrombosis
in
our
patients
was
multifactorial
and
related
partly
to
the
prothombotic
tendency
associated
with
a
nephrotic
syndrome
as
evident
by
the
low
level
of
anti-thrombin
III
and
the
raised
fibrinogen
level.
This
is
related
to
the
hypoalbum-
inaemia
and
the
massive
proteinuria,
particularly
in
the
first
patient.
Other
possible
contributing
factors
to
the
thrombosis
are
the
hyperlipidaemia
and
smoking
in
both
patients,
the
use
of
diuretics,
the
stasis
and
immobility
suffered
by
the
first
patient
during
the
long
train
journey,
and
the
use
of
diuretics
and
corticosteroids
in
the
second
patient.
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ARTERIAL
THROMBOSIS
IN
THE
NEPHROTIC
SYNDROME
909
Conclusion
Thrombosis
in
general
and
arterial
thrombosis
in
particular
is
a
significant
and
potentially
serious
problem
in
nephrotic
patients.
Awareness
of
the
condition
is
needed.
Assessment
for
the
risk
factors
is
required
to
allow
appropriate
prophylactic
measures
to
be
taken.
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doi: 10.1136/pgmj.70.830.905
1994 70: 905-909Postgrad Med J
I. H. Fahal, P. McClelland, C. R. Hay, et al.
nephrotic syndrome.
Arterial thrombosis in the
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