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Accelerated atherosclerosis
and digital clubbing in sickle cell diseases
Mehmet Rami
Helvaci (1)
Mustafa Sahan (2)
Agit Sulhan (1)
Abdullah Fatih Acik (1)
Adil Ocak (1)
Semih Salaz (1)
Lesley Pocock (3)
(1) Medical Faculty of Mustafa Kemal University,
Department of Internal Medicine, M.D.
(2) Medical Faculty of the Mustafa Kemal University,
Department of Emergency Medicine, M.D.
(3) medi+WORLD International
Correspondence:
Mehmet Rami Helvaci, M.D.
Medical Faculty of the Mustafa Kemal University,
31100, Serinyol, Antakya, Hatay, TURKEY
Phone: 00-90-326-2291000 (Internal 3399) Fax:
00-90-326-2455654
Email: mramihelvaci@hotmail.com
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Abstract
Background:
Sickle cell diseases (SCDs) are chronic
destructive processes mainly on the capillary
endothelium. We tried to understand the
significance of digital clubbing in severity
of SCDs.
Methods:
All patients with SCDs were taken into
the study.
Results: The
study included 397 patients (193 females).
There were 36 cases (9.0%) with digital
clubbing. Male ratio was significantly
higher in the digital clubbing group (66.6%
versus 49.8%, p<0.05). The mean age
was significantly higher in the digital
clubbing group, too (36.5 versus 29.0
years, p=0.000). Additionally, smoking
was also higher in the digital clubbing
group, significantly (30.5% versus 11.0%,
p<0.001). The mean white blood cell
counts of peripheric blood were similar
in both groups (p<0.05). On the other
hand, the mean hematocrit value and platelet
count of peripheric blood were lower in
the digital clubbing group, significantly
(p= 0.001 and p= 0.012, respectively).
Beside that, prevalence of leg ulcers,
pulmonary hypertension, chronic obstructive
pulmonary disease, coronary heart disease,
cirrhosis, and stroke were significantly
higher in the digital clubbing group (p<0.01
for all). There were 25 mortalities during
the period, and 13 of them were males.
The mean ages of mortality were 33.0 ±
9.6 (range 19-47) in females and 30.0
± 8.6 years (range 19-50) in males.
Conclusion: SCDs
are chronic destructive processes on endothelium
particularly at the capillary level, and
terminate with accelerated atherosclerosis
induced end-organ failures in early years
of life. Probably digital clubbing is
one of the terminal consequences of the
SCDs indicating significantly shortened
survival in such patients.
Key words:
Sickle cell diseases, digital clubbing,
chronic capillary damage, accelerated
atherosclerosis, metabolic syndrome
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Chronic endothelial damage induced atherosclerosis
may be the major cause of aging by inducing
prolonged cellular hypoxia all over the body.
For example, cardiac cirrhosis develops due
to the disseminated hepatic hypoxia in patients
with pulmonary and/or cardiac diseases. Probably
whole afferent vasculature including capillaries
are involved in the process. Some of the currently
known accelerator factors of the destructive
process are physical inactivity, overweight
and smoking, for the development of irreversible
consequences including obesity, hypertension,
diabetes mellitus (DM), peripheric artery disease
(PAD), chronic obstructive pulmonary disease
(COPD), chronic renal disease (CRD), coronary
heart disease (CHD), cirrhosis, mesenteric ischemia,
osteoporosis and stroke, all of which terminate
with early aging and death. They were researched
under the title of metabolic syndrome in the
literature, extensively (1-5). Similarly, sickle
cell diseases (SCDs) are chronic destructive
processes on endothelium mainly at the capillary
level. Hemoglobin S (HbS) causes loss of elastic
and biconcave disc shaped structures of red
blood cells (RBCs). Probably, loss of elasticity
instead of shapes of RBCs is the major problem,
since sickling is very rare in the peripheric
blood sample of the SCDs patients with associated
thalassemia minors, and human survival is not
so affected in hereditary elliptocytosis or
spherocytosis. Loss of elasticity is probably
present in the whole lifespan, but it is exaggerated
with increased metabolic rate of the body. The
hard cells induced prolonged endothelial inflammation,
edema, remodeling, and fibrosis mainly at the
capillary level and terminate with disseminated
tissue infarcts all over the body (6,7). On
the other hand, obvious vascular occlusions
may not develop in greater vasculature due to
the transport instead of distribution function
of them. We tried to understand significance
of digital clubbing in severity of SCDs in the
present study.
The study was performed in the Medical Faculty
of the Mustafa Kemal University between March
2007 and March 2015. All patients with SCDs
were taken into the study. The SCDs are diagnosed
with hemoglobin electrophoresis performed via
high performance liquid chromatography (HPLC)
method. Medical histories including smoking
habit, regular alcohol consumption, painful
crises per year, surgical operations, priapism,
leg ulcers, and stroke were learnt. Patients
with a history of one pack-year were accepted
as smokers, and one drink-year were accepted
as drinkers. A check up procedure including
serum iron, iron binding capacity, ferritin,
creatinine, liver function tests, markers of
hepatitis viruses A, B, and C and human immunodeficiency
virus, a posterior-anterior chest x-ray film,
an electrocardiogram, a Doppler echocardiogram
both to evaluate cardiac walls and valves and
to measure the systolic blood pressure (BP)
of pulmonary artery, an abdominal ultrasonography,
a computed tomography of brain, and a magnetic
resonance imaging (MRI) of hips, was performed.
Other bones for avascular necrosis were scanned
according to the patients' complaints. So avascular
necrosis of bones was diagnosed by means of
MRI (8). Cases with acute painful crises or
any other inflammatory event were treated at
first, and then the laboratory tests and clinical
measurements were performed on the silent phase.
Stroke is diagnosed by the computed tomography
of brain. Acute chest syndrome (ACS) is diagnosed
clinically with the presence of new infiltrates
on chest x-ray film, fever, cough, sputum production,
dyspnea, or hypoxia in the patients (9). An
x-ray film of abdomen in upright position was
taken just in patients with abdominal distention
and discomfort, vomiting, obstipation, and lack
of bowel movement. The criterion for diagnosis
of COPD is post-bronchodilator forced expiratory
volume in one second/forced vital capacity of
less than 70% (10). Systolic BP of the pulmonary
artery of 40 mmHg or higher during the silent
period is accepted as pulmonary hypertension
(11). CRD is diagnosed with a serum creatinine
level of 1.3 mg/dL or higher in males and 1.2
mg/dL or higher in females during the silent
period. Cirrhosis is diagnosed with liver function
tests, ultrasonographic findings, and histologic
procedure in case of indication. Digital clubbing
is diagnosed with the ratio of distal phalangeal
diameter to interphalangeal diameter which is
greater than 1.0 and with the presence of Schamroth's
sign (12,13). Associated thalassemia minors
are detected with serum iron, iron binding capacity,
ferritin, and hemoglobin electrophoresis performed
via HPLC method. Stress electrocardiography
is just performed in cases with an abnormal
electrocardiogram and/or angina pectoris. Coronary
angiography is taken just for the stress electrocardiography
positive cases. So CHD was diagnosed either
angiographically or with the Doppler echocardiographic
findings as the movement disorders in the cardiac
walls. Rheumatic heart disease is diagnosed
with the echocardiographic findings, too. Ileus
is diagnosed with gaseous distention of isolated
segments of bowel, vomiting, obstipation, cramps,
and with the absence of peristaltic activity
of the abdomen. Eventually, cases with digital
clubbing and without were collected into the
two groups, and they were compared in between.
Mann-Whitney U test, Independent-Samples t test,
and comparison of proportions were used as the
methods of statistical analyses.
The
study
included
397
patients
with
the
SCDs
(193
females
and
204
males).
There
were
36
cases
(9.0%)
with
digital
clubbing.
Mean
age
of
patients
was
significantly
higher
in
the
digital
clubbing
group
(36.5
versus
29.0
years,
p=0.000).
The
male
ratio
was
significantly
higher
in
the
clubbing
group,
too
(66.6%
versus
49.8%,
p<0.05).
Parallel
to
the
male
ratio,
smoking
was
also
higher
in
the
digital
clubbing
group,
significantly
(30.5%
versus
11.0%,
p<0.001).
Prevalence
of
associated
thalassemia
minors
were
similar
in
both
groups
(58.3%
versus
66.2%
in
the
clubbing
group
and
other,
respectively,
p>0.05)
(Table
1).
The
mean
white
blood
cell
(WBC)
counts
of
the
peripheric
blood
were
similar
in
both
groups
(p<0.05).
The
mean
hematocrit
(Hct)
value
and
platelet
(PLT)
count
of
peripheric
blood
were
lower
in
the
digital
clubbing
group,
significantly
(p=
0.001
and
p=
0.012,
respectively)
(Table
2).
On
the
other
hand,
the
prevalence
of
leg
ulcers,
pulmonary
hypertension,
COPD,
CHD,
cirrhosis,
and
stroke
were
significantly
higher
in
the
clubbing
group
(p<0.01
for
all)
(Table
3).
Beside
that
there
were
25
mortalities
during
the
eight-year
follow
up
period,
and
13
of
them
were
males.
The
mean
ages
of
mortality
were
33.0
±
9.6
(range
19-47)
in
females
and
30.0
±
8.6
years
(range
19-50)
in
males
(p>0.05).
Additionally,
there
were
five
patients
with
regular
alcohol
consumption
who
are
not
cirrhotic
at
the
moment.
Although
antiHCV
was
positive
in
eight
of
the
cirrhotics,
HCV
RNA
was
detected
as
positive
just
in
two,
by
polymerase
chain
reaction
method.
Table
1:
Characteristic
features
of
the
study
cases
*Nonsignificant
(p>0.05)
Table
2:
Peripheric
blood
values
of
the
study
cases
*White
blood
cell
†Nonsignificant
(p>0.05)
‡Hematocrit
§Platelet
Table
3:
Associated
pathologies
of
the
study
cases
*Nonsignificant
(p>0.05)
†Chronic
obstructive
pulmonary
disease
‡Coronary
heart
disease
§Chronic
renal
disease
Acute
chest
syndrome
Chronic
endothelial
damage
induced
atherosclerosis
is
the
most
common
type
of
vasculitis,
and
it
is
the
leading
cause
of
morbidity
and
mortality
in
the
elderly.
Probably
whole
afferent
vasculature
including
capillaries
are
involved
in
the
body.
Much
higher
BP
of
the
afferent
vasculature
may
be
the
major
underlying
cause,
and
efferent
vessels
are
probably
protected
due
to
the
much
lower
BP
in
them.
Secondary
to
the
prolonged
endothelial
damage
and
fibrosis,
vascular
walls
become
thickened,
their
lumens
are
narrowed,
and
they
lose
their
elastic
natures
that
can
reduce
the
blood
flow
and
increase
BP
further.
Although
early
withdrawal
of
the
causative
factors
including
smoking,
physical
inactivity,
excess
weight,
increased
serum
glucose
and
lipids,
and
elevated
arterial
BP
may
prevent
terminal
consequences,
after
development
of
COPD,
cirrhosis,
CRD,
CHD,
PAD,
or
stroke,
the
endothelial
changes
may
not
be
reversed
completely
due
to
the
fibrotic
nature
of
them
(14).
SCDs
are
life-threatening
genetic
disorders
affecting
nearly
100,000
individuals
in
the
United
States
(15).
As
a
difference
from
other
causes
of
atherosclerosis,
the
SCDs
probably
keep
vascular
endothelium
mainly
at
the
capillary
level
(16),
since
the
capillary
system
is
the
main
distributor
of
the
hard
RBCs
to
tissues.
The
hard
RBCs
induced
chronic
endothelial
damage,
inflammation,
edema,
and
fibrosis
mainly
at
the
capillary
level
and
build
up
an
advanced
atherosclerosis
in
much
younger
ages
of
the
patients.
In
other
words,
SCDs
are
mainly
chronic
inflammatory
disorders,
and
probably
the
main
problem
is
endothelial
damage,
inflammation,
edema,
and
fibrosis
induced
occlusions
in
the
vascular
walls
rather
than
the
vascular
lumens
all
over
the
body.
As
a
result,
the
lifespans
of
patients
with
the
SCDs
were
48
years
in
females
and
42
years
in
males
in
the
literature
(17),
whereas
they
were
33.0
and
30.0
years
in
the
present
study,
respectively.
The
great
differences
may
be
secondary
to
delayed
initiation
of
hydroxyurea
therapy
and
inadequate
RBC
transfusions
in
emergencies
in
our
country.
On
the
other
hand,
longer
lifespan
of
females
with
the
SCDs
and
longer
overall
survival
of
females
in
the
world
cannot
be
explained
by
the
atherosclerotic
effects
of
smoking
alone,
instead
it
may
be
explained
by
more
physical
power
requiring
role
of
male
sex
in
life
(18,19),
since
physical
power
induced
increased
metabolic
rate
may
terminate
with
an
exaggerated
sickling
and
atherosclerosis
in
human
body.
Digital
clubbing
is
probably
an
indicator
of
disseminated
atherosclerosis
even
at
the
capillary
level,
and
it
is
characterized
by
bulbous
enlargement
of
distal
phalanges
because
of
the
increased
soft
tissue.
Digital
clubbing
develops
in
the
following
steps;
fluctuation
and
softening
of
the
nailbed,
loss
of
normal
<165°
angle
between
the
nailbed
and
fold,
increased
convexity
of
the
nail
fold,
thickening
of
the
whole
distal
finger,
and
shiny
aspect
and
striation
of
the
nail
and
skin
(20).
Schamroth's
window
test
is
a
well-known
test
for
the
diagnosis
of
clubbing
(13).
When
the
distal
phalanges
of
corresponding
fingers
of
opposite
hands
are
directly
opposed,
a
diamond-shaped
'window'
is
normally
apparent
between
the
nailbeds.
If
this
window
is
obliterated,
the
test
is
positive.
Digital
clubbing
is
seen
with
pulmonary,
cardiac,
and
hepatic
disorders
that
are
featuring
with
chronic
tissue
hypoxia
(12,14),
since
lungs,
heart,
and
liver
are
closely
related
organs
that
affect
their
functions
in
a
short
period
of
time.
Similarly,
hematologic
disorders
that
are
featuring
with
chronic
tissue
hypoxia
may
also
terminate
with
digital
clubbing.
For
example,
we
observed
digital
clubbing
in
9.0%
of
patients
with
the
SCDs
in
the
present
study
and
leg
ulcers,
pulmonary
hypertension,
COPD,
CHD,
cirrhosis,
and
stroke
like
other
atherosclerotic
disorders
were
significantly
higher
among
them
(p<0.01
for
all).
Similar
to
some
other
studies,
there
was
a
male
predominance
in
the
digital
clubbing
cases
(66.6%
versus
49.8%,
p<0.05)
that
may
also
indicate
roles
of
smoking
on
digital
clubbing
(12,14).
Smoking
has
a
major
role
in
systemic
atherosclerotic
processes
such
as
COPD,
cirrhosis,
CRD,
PAD,
CHD,
stroke,
and
cancers,
too
(21,22).
Its
atherosclerotic
effects
are
the
most
obvious
in
Buerger's
disease
and
COPD.
Buerger's
disease
is
an
inflammatory
process
terminating
with
obliterative
changes
in
small
and
medium-sized
vessels
and
capillaries,
and
it
has
never
been
reported
without
smoking.
COPD
may
also
be
a
capillary
endothelial
inflammation
terminating
with
disseminated
pulmonary
destruction,
and
it
may
be
accepted
as
Buerger's
disease
of
the
lungs.
Although
it
has
strong
atherosclerotic
effects,
smoking
in
human
beings
and
nicotine
administration
in
animals
may
be
associated
with
weight
loss
(23).
There
may
be
an
increased
energy
expenditure
during
smoking
(24),
and
nicotine
may
decrease
caloric
intake
in
a
dose-related
manner
after
cessation
of
smoking
(25).
Nicotine
may
lengthen
inter-meal
time,
and
decrease
amount
of
meal
eaten
in
animals
(26).
Body
weight
seems
to
be
the
highest
in
former,
lowest
in
current,
and
medium
in
never
smokers
(27).
Since
smoking
may
also
show
the
weakness
of
volition
to
control
eating,
prevalences
of
HT,
DM,
and
smoking
were
the
highest
in
the
highest
triglyceride
having
group
as
a
significant
indicator
of
metabolic
syndrome
(28).
Additionally,
although
CHD
were
detected
with
a
similar
prevalence
in
both
sexes
(22),
smoking
and
COPD
were
higher
in
males
against
the
higher
prevalences
of
body
mass
index
and
its
consequences
including
dyslipidemia,
HT,
and
DM,
in
females.
COPD
is
an
inflammatory
disease
that
may
mainly
affect
the
pulmonary
vasculature,
and
aging,
smoking,
and
excess
weight
may
be
major
causes
of
the
inflammation.
The
inflammatory
process
of
endothelium
is
enhanced
by
release
of
various
chemical
factors
by
lymphocytes,
and
it
terminates
with
fibrosis
and
atherosclerosis.
Probably
the
accelerated
atheroscerotic
process
is
the
main
structural
background
of
the
functional
changes
characteristic
of
the
disease.
Although
COPD
may
mainly
be
an
accelerated
atherosclerotic
process
of
the
pulmonary
vasculature,
there
are
several
reports
about
existence
of
an
associated
endothelial
inflammation
all
over
the
body
(29-30).
For
example,
there
may
be
a
close
relationship
between
COPD
and
CHD,
PAD,
and
stroke
(31).
In
a
multi-center
study
performed
on
5.887
smokers
aged
between
35
and
60
years,
two-thirds
of
mortality
cases
were
caused
by
cardiovascular
diseases
and
lung
cancers,
and
CHD
was
the
most
common
cardiovascular
complication
among
them
(32).
When
the
hospitalizations
were
searched,
the
most
common
causes
were
the
cardiovascular
diseases
again
(32).
In
another
study,
27%
of
all
mortality
cases
were
due
to
the
cardiovascular
causes
in
the
moderate
and
severe
COPD
patients
(33).
Similarly,
beside
digital
clubbing,
pulmonary
hypertension,
leg
ulcers,
and
stroke,
COPD
may
be
one
of
the
final
consequences
of
the
SCDs
(34).
Leg
ulcers
are
seen
in
10
to
20%
of
patients
with
the
SCDs
(35),
and
the
ratio
was
13.8%
in
the
present
study.
The
incidence
increases
with
age
and
they
are
rare
under
the
age
of
10
years
(35).
Leg
ulcers
are
also
more
common
in
males
and
sickle
cell
anemia
(HbSS)
cases
(35).
They
have
an
intractable
nature,
and
around
97%
of
healed
ulcers
return
in
less
than
one
year
(36).
The
ulcers
occur
in
distal
areas
with
less
collateral
blood
flow
in
the
body
(36).
They
are
mostly
seen
just
above
the
medial
malleolus.
The
lateral
malleoli
are
involved,
secondly.
Venous
insufficiency
is
not
a
primary
cause,
but
chronic
endothelial
damage
at
the
microcirculation
of
the
skin
due
to
the
hard
RBCs
may
be
the
major
cause
in
the
SCDs
(35).
Prolonged
exposure
to
the
causative
factors
due
to
the
blood
pooling
in
the
lower
extremities
by
the
effect
of
gravity
may
also
explain
the
leg
but
not
arm
ulcers
in
the
SCDs.
Probably
the
same
mechanism
is
also
significant
for
the
diabetic
ulcers,
Buerger's
disease,
and
varicose
veins.
Smoking
may
also
have
an
additional
role
for
the
ulcers
(37),
since
both
of
them
are
more
common
in
males
(35),
and
atherosclerotic
effects
of
smoking
are
well-known
in
COPD,
CHD,
PAD,
and
Buerger's
disease
(21,22).
Probably
cirrhosis
is
also
a
systemic
atherosclerotic
process
prominently
affecting
the
hepatic
vasculature,
and
aging,
smoking,
regular
alcohol
consumption,
local
and
systemic
inflammatory
or
infectious
processes,
excess
weight,
elevated
BP,
dyslipidemia,
hyperglycemia,
and
insulin
resistance
may
be
the
major
causes
of
inflammation
(38).
The
inflammation
is
enhanced
by
the
release
of
various
chemical
factors
by
lymphocytes
to
repair
the
damaged
endothelium
of
hepatic
vasculature
(39),
and
the
chronic
inflammatory
process
terminates
with
an
advanced
atherosclerosis
and
tissue
hypoxia
and
infarcts.
Although
cirrhosis
is
mainly
an
accelerated
atherosclerotic
process
of
the
hepatic
vasculature,
there
may
be
a
close
relationship
between
cirrhosis
and
CHD,
COPD,
PAD,
CRD,
and
stroke
probably
due
to
the
underlying
systemic
atherosclerotic
process
(40).
For
example,
most
of
the
mortality
cases
in
cirrhosis
may
actually
be
caused
by
cardiovascular
diseases,
and
CHD
may
be
the
most
common
one
among
them
(41).
Similarly,
beside
digital
clubbing,
pulmonary
hypertension,
leg
ulcers,
stroke,
and
COPD
like
other
atherosclerotic
end-points,
cirrhosis
may
be
one
of
the
final
consequences
of
the
SCDs
(42).
Stroke
is
an
important
cause
of
death,
and
thromboembolism
in
the
background
of
atherosclerosis
is
the
most
common
cause
of
it.
Aging,
male
sex,
smoking,
increased
serum
glucose
and
lipids,
elevated
arterial
BP,
and
excess
weight
may
be
the
major
accelerator
factors
of
it.
Stroke
is
also
a
common
complication
of
the
SCDs
(43,44).
Similar
to
the
leg
ulcers,
stroke
is
higher
in
HbSS
cases
(45).
Additionally,
a
higher
WBC
count
is
associated
with
a
higher
incidence
of
stroke
(46).
Sickling
induced
endothelial
injury,
activations
of
WBC,
PLT,
and
coagulation
system,
and
hemolysis
may
terminate
with
chronic
endothelial
inflammation,
edema,
remodeling,
and
fibrosis
(47).
Probably,
stroke
is
a
complex
and
terminal
event
in
the
SCDs,
and
it
may
not
have
a
macrovascular
origin,
instead
disseminated
capillary
inflammation
induced
endothelial
edema
may
be
much
more
important.
Infections
and
other
stressful
conditions
may
precipitate
stroke,
since
increased
metabolic
rate
during
such
episodes
may
accelerate
sickling.
A
significant
reduction
of
stroke
with
hydroxyurea
may
also
suggest
that
a
significant
proportion
of
strokes
are
secondary
to
the
increased
WBC
and
PLT
counts
induced
disseminated
capillary
inflammation
and
edema
(16,48).
As
a
conclusion,
SCDs
are
chronic
destructive
processes
on
endothelium
particularly
at
the
capillary
level,
and
terminate
with
accelerated
atherosclerosis
induced
end-organ
failure
in
early
years
of
life.
Probably
digital
clubbing
is
one
of
the
terminal
consequences
of
the
SCDs
indicating
significantly
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