Thromboangiitis Obliterans and Smoking in Wome

Thromboangiitis obliterans
and smoking in women
Viera Stvrtinova,Svetoslav Stvrtina,Ivar Vacula
2ndClinic of Internal Medicine
and Department of Pathology,
Comenius University in Bratislava
Slovak republic
TAO –
thromboangiitis obliterans
a rare disease, but it beginns in young
persons, leads to disability, presents a
serious medical and social problem
 it was formerly traditionally considered to
be almost exclusively a disease of men

TAO – historical background
1878 - Felix von Winiwarter
Billroth´s assistant, described „a
peculiar form of endarteritis and
endophlebitis with gangrene of the
feet“
 1908 - Leo Buerger –
published a detailed
analysis of 11 pat.
thromboangiitis obliterans

1908 - Buerger´s original
criteria for clinical diagnosis
I.
Onset aged 20-40
 Early phase:
numbness, cold, indefinite pain with
associated blanching of forefoot,
absent ankle pulses
 Later developments:
Erytromelalgia and trophic (tissue
nutritional) changes

Buerger L.: Thromboangiitis obliterans: a study of the vascular lesions leading
to presenile spontaneous gangrene. Am. J. Med. Sci. 136: 567-580, 1908
1908 - Buerger´s original criteria
for clinical diagnosis
II.
Dependent rubor of toes and forefoot
 Blistering or ulceration near big toe nail
most often
 Cyanosis later around the above lesions
 Pain now so severe that amputation is
often sought before toe is necrotic

Buerger L.: Thromboangiitis obliterans: a study of the vascular lesions leading
to presenile spontaneous gangrene. Am. J. Med. Sci. 136: 567-580, 1908
TAO - fact or fancy?
1960 Wessler
TAO became a popular diagnosis for any
problem of gangrenous toes, quite
wrongly in diabetic and older people as
well
 In 1920-1930 TAO was twice as common
as all other arterial occlusive conditions
 During the 1940s the opinion began to
change

TAO - fact or fancy?
clinical presentation of 2-5% patients
with PAD in Central Europe differ from
atherocslerotic involvement
 PAD caused by primary systemic
vasculitis (TAO, GCA, TA, etc)
secondary vasculits (RA, SLE),
popliteal artery entrapment,
arterial thrombosis etc....

TAO – primary systemic
vasculitis
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This vasculitis is completely different
from every other type of vasculitis
Affects the small and medium-sized
arteries and veins in the lower and
upper extremities, but rarely also the
coronary, pulmonary, renal, visceral and
brain arteries
TAO - prevalence

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TAO – rare in Europe
The prevalence of the disease among all
patients with PAD varies
between 0.5 – 5.6% in Western Europe,
10% in Turkey, 43-63% in India,
16-66% in Korea and Japan
Arkilla PE. Thromboangiitis obliterans (Buerger´s disease), Orphanet J Rare Dis 2006, 271, 14
Bozkurt AK et al. Surgical treatment of Buerger´s disease, Vascular 2004, 12, 192-7
Grotenhermen F. Cannabis- associated arteritis, VASA 2010, 39, 43-53
TAO and women

TAO was formerly traditionally considered
to be almost exclusively a disease of men,
but today still more and more women are
smoking
TAO and females
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male - to - female ratio is decreasing
now to 3.4 : 1, on contrary to Buerger´s
original ratio of 99 : 1 (Leu, 1985)
Olin et al (1990) reported 23 % of
women
Dehaine-Bamberger et al (1993) 14.5 %
of women
Stvrtinova et al (1999) 22.7 % of women
TAO - risk factors
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TOBACCO - SMOKING
Frostbite ???
Use of sympatomimetic drugs ???
Psychic stress ???
Personality disorders???
TAO - Etiopathogenesis
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The disease mechanism remains unclear
Several immunologic abnormalities
Patients with TAO show hypersensitivity to
intradermally injected tobacco extracts,
have increased cellular sensitivity to types I and
III collagen,
have elevated serum anti–endothelial cell antibody
titers,
have impaired peripheral vasculature endotheliumdependent vasorelaxation.
Increased prevalence of HLA-A9, HLA-A54, and
HLA-B5 is observed in these patients, which
suggests a genetic component to the disease.
Antiendothelial Cell Antibodies in TAO
EICHHORN, JENS MD*; SIMA, DAGMAR MD‡; LINDSCHAU, CARSTEN MS*; TUROWSKI, ANDREAS MD‡; SCHMIDT,
HEINER MD‡; SCHNEIDER, WOLFGANG MD†; HALLER, HERMANN MD*; LUFT, FRIEDRICH C. MD*
American Journal of the Medical Sciences:
January 1998 - Volume 315 - Issue 1 - pp 17-23
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The occurrence of autoimmune phenomena in 28 patients with
thromboangiitis obliterans (Buerger's disease) was determined. The
following were sought: antineutrophil cytoplasmic antibodies against
proteinase 3 (cANCA) and myeloperoxidase (pANCA), antinuclear
antibodies, anti-Ro antibodies, anticardiolipin antibodies, and
antiendothelial cell antibodies (AECA). For the last, an enzyme-linked
immunosorbent assay was developed which verified the presence of the
AECA phenomenon with immunofluorescence and confocal microscopy.
Seven patients with active disease had AECA titers of 1,857± 450
arbitrary units (AU) compared with 126 ± 15 AU in 30 normal control
subjects (P < 0.001) and 461 ± 41 AU in 21 patients in remission (P <
0.01). Antibodies from the sera of patients with active disease reacted
not only with surface epitopes but also with sites within the cytoplasm
of human endothelial cells.
AECA may be useful in following disease activity
and may play a role in the pathogenesis of
thromboangiitis obliterans.
Iwai T, Inoue Y, Umeda M, Huang Y, Kurihara N, Koike M, Ishikawa I.
Oral bacteria in the occluded arteries of
patients with Buerger disease.
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Nearly two thirds of patients with thromboangiitis
obliterans have severe periodontal disease, and
chronic anaerobic periodontal infection may represent
an additional risk factor for the development of the
disease.
Polymerase chain reaction analysis demonstrated
DNA fragments from anaerobic bacteria in both
arterial lesions and oral cavities of patients with
thromboangiitis obliterans but not in arterial samples
from healthy control subjects.
Trace elements and tocic heavy metals play
a role in Buerger´s disease
Arslan at al. Int Angiol 2010, 29:489, Fazelli B, Int Angiol 2011, 30:598
Possible role of lead (Pb) and copper (Cu) was
reported in northeastern Iran
Opium contamination (by lead) in opium consumers
might be the cause of TAO – like clinical
manifestation in passive smokers
TAO and tobacco
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The exact mechanism of tobacco´s
influence on TAO development is not
known
Tobacco seems to be a synergic factor
and not the cause of the disease (1)
(1) Lazarides MK et al. Diagnostic criteria and treatment of Buerger´s disease: a review. Int J
Low Extrem Wounds 2006, 5, 89-95
TAO 3 histologic phases acute, subacute, and chronic
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The acute phase is composed of an
occlusive, highly cellular, inflammatory
thrombus. Polymorphonuclear neutrophils,
microabcesses, and multinucleated giant
cells are often present.
The chronic phase is characterized by
organized thrombus and vascular fibrosis
that may mimic atherosclerotic disease.
G.Piazza, M.A. Creager: Thromboangiitis obliterans, Circulation 2010, 121:1858-61
Shigehiko Shionoya: Diagnostic clinical
criteria of Buerger's disease
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(1) smoking history; (2) onset before the age of
50 years; (3) infrapopliteal arterial occlusions; (4)
either upper limb involvement or phlebitis migrans;
and (5) absence of atherosclerotic risk factors
other than smoking.
Confident clinical diagnosis of Buerger's disease
may be made only when all five requirements have
been fulfilled.
A set of strict and well-defined clinical diagnostic
criteria is essential for any study of Buerger's
disease to ensure the homogeneity of the selected
patient population for valid comparisons.
TAO – laboratory testing

Laboratory testing in patients with suspected
thromboangiitis obliterans is used to
exclude alternative diagnoses (AS, DM
and other vasculitides).
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Initial laboratory studies should include a
complete blood count, metabolic panel, liver
function tests, fasting blood glucose,
inflammatory markers such as erythrocyte
sedimentation rate and C-reactive protein,
cold agglutinins, and cryoglobulins.
Serological markers of autoimmune disease,
including antinuclear antibody, anticentromere
antibody, and anti-SCL-70 antibody, should be
obtained and are typically negative in
thromboangiitis obliterans.
DSA
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Nonatherosclerotic, segmental occlusive lesions
of the small- and medium-sized vessels (eg,
digital, palmar, plantar, tibial, peroneal, radial, and
ulnar arteries)
Formation of distinctive small-vessel collaterals
around areas of occlusion known as "corkscrew
collaterals".

Such arteriographic findings suggest Buerger
disease but are not pathognomonic because similar
lesions can be observed in patients with
scleroderma, SLE, rheumatoid vasculitis, MCTD,
antiphospholipid syndrome
TAO
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Echocardiography may be indicated in certain
cases when acute arterial occlusion caused by
thromboembolism is suspected to detect a
cardiac source of embolism.
Biopsy is rarely needed unless the patient
presents with unusual characteristics, such as
large-artery involvement, or age older than 45
years.
A point-scoring system has been proposed by
Papa to support or contest the diagnosis of
TAO using the following criteria.
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More than 80% percent of pat. present with involvement of 3-4 limbs.
Distal (feet, toes, hands, fingers) involvement
Onset before age 45
Tobacco use
Exclusion of atherosclerosis or proximal source of emboli
Lack of hypercoagulable state
Lack of definable arteritis - vasculitis
Classic arteriographic findings
Involvement of digital arteries of finger or toes
Segmental involvement (ie, "skip areas")
Corkscrew collaterals
No atherosclerotic changes
Classic histopathologic findings
Inflammatory cellular infiltrate within thrombus
 Intact internal elastic lamina
 Involvement of surrounding venous tissues
Scoring system for TAO
Positive points
Age at onset
Less than 30 (+2)/30-40 years (+1)
Foot intermittent claudication
Present (+2)/ by history (+1)
Upper extremity
Symptomatic (+2)/ asymptomatic (+1)
Migrating superficial vein thrombosis
Present (+2)/ by history only (+1)
Raynaud
Present (+2)/ by history only (+1)
Angiography; biopsy
If typical both (+2)/ either(+1)
Negative points
Age at onset
45-50 (-1)/more than 50 years (-2)
Sex, smoking
Female (-1)/ nonsmoker (-2)
Location
Single limb (-1)/no LE involved (-2)
Absent pulses
Brachial (-1)/femoral (-2)
Arteriosclerosis, diabetes, hypertension,
hyperlipidemia
Discovered after diagnosis 5.1-10 years (-1)
/2.1- 5 years later (-2)
Scoring system for TAO
Number of points
Probability of diagnosis
0-1
Diagnostic excluded
2-3
Suspected, low probability
4-5
Probable, medium probability
6 or more
Definite, high probability
TAO - treatment

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Except for absolute tobacco avoidance, no forms
of therapy are definitive. Smoking as few as 1 or 2
cigarettes daily (weekly), using chewing tobacco,
or even using nicotine replacements may keep the
disease active
Treatment with intravenous iloprost or
prostavasine, an expensive therapy, has been
shown to be somewhat effective in improving
symptoms, accelerating resolution of distal
extremity trophic changes, and reducing the
amputation rate among patients with Buerger
disease.
TAO - therapy
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Use of well-fitting protective footwear to
prevent foot trauma and chemical injury
Early and aggressive treatment of
extremity injuries to protect against
infections
Avoidance of cold environments
Avoidance of drugs that lead to
vasoconstriction
New therapeutic possibilities

Improved healing of ischemic ulcers and
relief of rest pain in a small series of
patients with Buerger disease using
intramuscular gene transfer of vascular
endothelial growth factor.
TAO – our group of patients
Bratislava Medical Journal, 1999, 100 (3):123-128
24 patients - 18 men, 6 women (men to
women ratio 3:1)
 mean age 42.4 + 10.5 years
 mean age at the time of disease onset in the
subgroup of 6 women 40.8 + 7.04 years
(26 - 48 years)

Clinical signs and symptoms in
the group of 6 women.
I.
age of onset before 50 years
 claudications in feet or calves
 ischemic finger ulcers or gangrene
 smoking

- 6
- 6
-6
- 5
Clinical signs and symptoms in the
group of 6 women
II.
migrating superficial thrombophlebitis - 2
 Raynaud´s phenomenon
-3

upper extremities involvement
 normal blood pressure
 normal cholesterol
 normal blood sugar

-3
-6
-6
-6
TAO - first clinical sign in the
group of 6 women
necrosis or gangrene of the finger - 4
 claudicatio intermittens (LL)
- 1
 superficial thrombophlebitis
- 1

Woman E.M., born 1956, smoker
1990 - Dg of TAO, index finger
amputation at 34 years of age
Woman E.M., born 1956
In 2002 began to smoke again
In 2003 – CLI, In 2004 – amputation
of the second toe of her right leg
Woman E.M., born 1956
In January 2008 began to smoke again
April 21, 2008
Before treatment
with Prostavasin
May 28, 2008
After treatment
with Prostavasin
In 2010 suddenly died on MI
TAO – the role of
smoking in women
.
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Tobacco is central to the initiation and
continuance of Buerger´s disease activity
To cease the smoking is still the most
important therapeutic procedure
 If the pat. is able to discontinue tobacco
use completely, amputation will not occur if
critical limb ischemia is not already present

Smoking and TAO
Pat. M.K., 1948
Woman
TAO - the spectrum of
patients is changing
women are still more and more
frequently affected
 upper limb involvement is more common
 more older patients are beeing diagnosed
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In conclusion
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The main and only proved risk factor, known
from Buerger´s time, is smoking.
But how cigarette smoking causes arterial
occlusion is not yet precisely known.
There is no curative medication or surgery
for this disease.
Despite the extensive literature which has
accumulated around this disease its etiology
remains unknown, the clinical course is
individual and in spite of the treatment is still
unpredictable.
Conclusion
It is very difficult to study rare
diseases such as thromboangiitis
obliterans (not enough patients, not
enough research money)
 Therefore there is only a little
progress in understanding the
etiology and pathogenesis of the
disease as well as treatment
possibilities

TAO – like a storm – unpredictable