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International Journal of Stem Cells Vol. 3, No. 1, 2010
SPECIAL ISSUE
1
Accepted for publication February 25, 2010
Correspondence to Dong-Ik Kim
Division of Vascular Surgery, Samsung Medical Center, 50 Irwon-
dong, Kangnam-gu, Seoul 135-710, Korea
Tel: +82-2-3410-3467, Fax: +82-2-3410-0040
E-mail: dikim@skku.edu
Thromoboagiitis Obliterans (TAO)
Ui-Jun Park, Dong-Ik Kim
Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Thromboangiitis obliterans (TAO) is nonatherosclerotic inflammatory disease of the peripheral blood vessels, and TAO
affects the small and medium sized vessels of the extremities. TAO is mainly seen in young males who smoke, and
smoking is strongly associated with the disease course and progression. The diagnosis is made on the basis of the
history, the physical examination and the clinical diagnostic criteria. As the bedrock for treating patients with TAO,
absolute abstinence from tobacco is most important factor, and patients with TAO are usually managed conservatively.
Surgical bypass or endovascular therapy is usually not possible for patients with TAO because of the diffuse segmental
involvement and the distal nature of the disease. Therefore, stem cell therapy is considered to be a novel therapeutic
modality for treating patients with TAO and who are not eligible for conventional revascularization therapies. In this
paper, I have summarized the recent knowledge about TAO and I have reviewed the recent studies that have focused
on the treatment of TAO.
Keywords: Stem cells, Thromboangiitis obliterans, Angiogenesis
Introduction
Thromboangiitis obliterans (TAO, Buerger’s disease) is
nonatherosclerotic inflammatory disease of the peripheral
blood vessels, and it affects the small and medium sized
vessels of the extremities (1). Felix von Winiwarter, as a
student of Billroth at the University Clinic in Vienna, first
described TAO in 1879 and Leo Buerger described in ex-
quisite detail the clinical and histopathological features of
the disease in 1908 (2), yet the etiology of TAO is still
largely unknown. TAO predominantly occurs in young
males who habitually use tobacco (3). TAO intensifies
usually at the 4th decade and then the symptoms diminish.
TAO is almost never observed in persons over the age of
60 years.
TAO is clinically and pathologically distinguishable
from other forms of vasculitis according to some points.
For the pathology, there is a highly cellular and in-
flammatory thrombus with relative sparing of the blood
vessel wall. An immune reaction has been demonstrated in
the arterial intima, yet the acute phase reactants and sero-
logic tests for the immunologic markers and the commonly
measured autoantibodies are normal or negative (4).
Epidemiology
TAO has a worldwide, but quite uneven distribution. It
has more prevalent in the Middle East and Far East than
in North America and Western Europe. It appears that
TAO occurs with the least frequency in Western Europe
(TAO makes up 0.5∼5.6% of the patients with peripheral
arterial disease, PAD) and the most commonly afflicted
are the people of India, Japan, Korea, Bangladesh and the
Ashkenazi Jews in Israel (1, 5). High morbidity is ob-
served in India (45∼63%), Korea and Japan (16∼66%)
(1, 6). The reasons for this pattern are unclear. The high
prevalence in some areas has been attributed to the use
of specific types of tobacco (7). The question of a genetic
predisposition has been raised by several investigators (8
∼10).
A decline in the number of patients who are diagnosed
2 International Journal of Stem Cells 2010;3:1-7
Fig. 1. Ischemic toe ulcer of the thromboangiitis obliterans patient.
with TAO has been observed in the developed countries.
A literature has reported that the prevalence rate of diag-
nosing TAO in North America has declined steadily from
104/100,000 in 1947 to 13/100,000 in 1986 (an 8 fold de-
crease), and the clinical and pathological criteria for the
diagnosis of TAO have remained unchanged (3). In Japan,
the prevalence of diagnosing TAO has decreased (6).
However, a dramatic increase in the incidence of female
TAO has been observed. A marked increase of female
TAO was reported by several studies and the increased
prevalence of TAO in women may be attributed to the in-
crease rate of smoking by young women (3, 11).
Pathophysiology
Although the cause of TAO is still unknown, there is
an extremely strong association between the heavy use of
tobacco and TAO, and what precipitates the disease and
determinates its course is smoking (12, 13). It mainly af-
fects young male smokers, although a few cases have been
reported in ex-smokers and users of smokeless tobacco (14,
15). TAO is more common in countries whose people
heavily use tobacco or they use unprocessed low-grade to-
bacco called “bidi” (a homemade surrogate for cigarettes
without filters) (7, 16). Some author believe that TAO can
occur in nonsmokers (17); however, most authors believe
current smoking or a past smoking history is required for
making the diagnosis (16, 18, 19). It has long been recog-
nized that persistent tobacco use, and most commonly cig-
arette smoking, is a major risk factor for disease persis-
tence, progression and recurrence. Clinical recurrence is
almost always associated with resumption of tobacco use.
Endothelial cells play a key role in the initiation of the
inflammatory response. Eichhorn et al. suggested an in-
creased serum antiendothelial-cell antibody titer was re-
lated with the disease activity and pathogenesis of TAO
(20). Halacheva et al. described an increased expression
of adhesive molecules such as VCAM-1, ICAM-1 and se-
lectin on the surface of endothelial cell from patients with
TAO (21). In TAO patients, the cellular sensitivity to
types I and III collagen were increased on an anti-
gen-sensitive thymidine-incorporation assay (22). Endo-
thelial dysfunction is reflected by impaired endothelium
dependent vasorelaxation in the peripheral vasculature of
patients with TAO, as was observed in studies that focused
on the forearm blood flow (23).
Several studies have been conducted to determine the
immunologic and genetic factors related with TAO. A
multifactorial etiology of TAO may involve the interplay
between hereditary susceptibility, tobacco exposure and
the immune and coagulation responses.
Clinical features
Chronic ischemia in the lower extremities is mainly
caused by arterial obstruction or stenosis in the leg. TAO
usually begins with ischemia of the distal small arteries
and veins of the extremities. The first clinical manifes-
tation the patients notices is coldness, skin color changes,
intermittent claudication, pain or ulceration (Fig. 1).
Claudication is a much less common complaint for pa-
tients with TAO than for patients with atherosclerosis.
Whereas the clinical features show staged progression in
the arterial insufficiency of atherosclerosis, in that of
TAO, rest pain or ulceration does not always follow clau-
dication (13). Ischemic rest pain and ulceration of the
forefoot are the most frequently encountered clinical
presentations. Superficial thrombophlebitis can be ob-
served in the patients with TAO and it is a distinguishing
clinical feature (1, 24). The frequent upper extremity in-
volvement, which is characterized by the development of
Raynaud’s syndrome or digital ischemia, differs from the
patients with atherosclerosis (25). Skin color change is
characteristic of TAO. The affected peripheral extremity
is abnormally red and cyanotic particularly on depen-
dency. The cause of the stagnation of the peripheral circu-
lation might be poor inflow, multiple occlusion of periph-
eral arteries and veins, or atony of the microcirculatory
vessels.
The disease rarely affects the vessels proximal to the
popliteal artery. However, the aortoiliac region is sporadi-
Ui-Jun Park, Dong-Ik Kim: Thromoboagiitis Obliterans (TAO) 3
Fig. 2. Typical angiographic findings in thromoboangiitis obliteran
s
patient; abrupt occlusion and corkscrew appearance of collateral
vessels.
cally affected and involvement of the mesenteric artery,
cerebral artery, coronary artery and renal artery during
the course of the TAO has been described in the literature
(26-30).
Diagnosis
The diagnosis can often be made on the basis of a care-
ful history and physical examination, together with the
ancillary laboratory studies. Several diagnostic criateria
have been suggested, but any commonly accepted diag-
nostic criteria are still unavailable. Mills and Poster (31)
proposed major and minor diagnostic criteria and Papa et
al. (32) proposed a scoring system based on the negative
and positive criteria. The clinical criteria suggested by
Shionoya in 1998 are some of the most recently used
criteria. Shionoya’s criteria for making the diagnosis of
TAO is based on 5 criteria (a smoking history, an onset
before the age of 50 years, infrapopliteal arterial occlusive
disease, either upper limb involvement or phlebitis mi-
grans, and the absence of atherosclerotic risk factors other
than smoking). As there is no specific diagnostic test and
an absence of positive serologic markers, a confident clin-
ical diagnosis should be made only when all these 5 cri-
teria have been fulfilled, although this is not universally
accepted (13, 19).
Because of the likelihood of involvement of more than
one limb, it is advisable to evaluate all four limbs in pa-
tients who present with clinical involvement of only one
limb. Noninvasive vascular testing, laboratory tests to ex-
clude hypercoagulable states autoimmune disease and dia-
betes mellitus, and echocardiography and arteriography
for exclusion of the proximal source of emboli are
mandatory.
Computed tomographic angiography or conventional ar-
teriography is useful for evaluating the clinically involved
and noninvolved limbs. The angiographic findings in pa-
tients with TAO typically involve the medium and small
sized arteries that are localized distal to the elbow and/or
the knee. An abrupt occlusion, skip lesions and segmental
lesions can be noticed and the characteristic "corkscrew,"
"spider legs" or "tree roots" are helpful, but these are not
pathognomonic (33) (Fig. 2).
Treatment
Successful therapy is possible only with absolute ab-
stinence from tobacco. Tobacco consumption, in any form,
must be strictly prohibited. A wide spectrum of medical
or surgical therapeutic options have been proposed, yet to-
tal abstinence from tobacco use remains the most im-
portant mean of stopping disease progression (34). Conti-
nued tobacco use is associated with a multiplied rate of
amputation (35). The initial management of patients with
TAO should be conservative. Because several arteries may
be unaffected, patients with claudication should be en-
couraged to walk, whereas the patients with critical ische-
mia should be admitted to a hospital for bed rest. A mild
reverse Trendelenburg position may be helpful and ad-
ministration of narcotic analgesics may be required.
Infected lesions should be treated with appropriate anti-
biotics and limited debridement as required to control
infection. Administration of a prostacyclin analogue that has
vasodilatory and antiplatelet properties may be helpful to
relieve the ischemic symptoms in the TAO patients (36, 37).
The role of sympathectomy in preventing amputation
and for treating painful or nonhealing ischemic lesions re-
mains unclear (25, 38). Sympathectomy may occasionally
help the healing of superficial ischemic ulceration. It may
be employed in a patient with persistent severe pain and
minor ischemic lesions despite abstaining from tobacco.
A spinal cord stimulator showed benefit in the treatment
of the ischemic extremity lesions of TAO, and this re-
sulted in healing of ulcerations and a good limb survival
rate (39, 40). However, there is currently no prospective
randomized evidence that spinal cord stimulation is effec-
tive in healing ischemic lesions.
In TAO, concern should be focused on healing trophic
lesion and salvaging the affected limbs. Major amputation
4 International Journal of Stem Cells 2010;3:1-7
of the extremity must be avoided if possible, and necrot-
omy will be recommended after the boundary between the
living and necrotic tissue has been well defined.
Bypass grafting is seldom an option as the distal loca-
tion of the lesions leaves little to bypass because of the
lack of distal target vessels and the poor vein quality due
to previous phlebitis. Although direct arterial surgery is
usually not feasible, successful arterial revascularization is
most effective for healing trophic lesion. A literature re-
view revealed only a few series that reported on vascular
reconstruction (mainly femorodistal bypasses) in patients
with TAO (13). The bypass patency rates were suboptimal;
however, the corresponding limb salvage rates were
satisfactory. A possible explanation for this is that patent
grafts, even over a short period of time, are sufficient to
allow healing of ulcers in patients with TAO (41, 42). The
toe blood pressure did not return to normal after success-
ful femoraodistal bypass grafting because of multiple arte-
rial occlusions below the ankle, and improvement of in-
flow did not bring about a significant increase in the toe
blood pressure.
The prognosis for patients with TAO is significantly
worse with respect to limb loss than that for the patients
with atherosclerosis (24). It has been reported that TAO
is not associated with increased mortality and the prog-
nosis is considerably better than that for patients with
atherosclerosis (13, 24). Yet a recent study observed that
the survival of TAO patients was lower than that in the
general population and the risk of death was nearly identi-
cal for those TAO subjects who continued to use tobacco
and those who quit (34).
Application of stem cell therapy
Surgical bypass or endovascular (transluminal angio-
plasty or intravascular stent) therapy is currently believed
to be the best option for limbs salvage in the eligible
patients. However, these treatments are usually not possi-
ble for patients with TAO because of the diffuse segmental
involvement and the distal nature of the disease.
Therefore, novel therapeutic modalities are needed for
treating patients with TAO, and especially those patients
who are not eligible for conventional revascularization
therapies.
The development of collateral vessels in an important
physiological adaptation to chronic ischemia that is due
to occlusive arterial disease, and the extent of collaterali-
zation in patients with peripheral artery disease can have
a major impact on the symptoms, distal blood flow and
lower limb outcomes (43). With the recent advances in
molecular biology, gene therapy and stem cell therapy for
the treatment of many diseases, a new and promising ap-
proach using stem cell therapy has recently been devel-
oped to treat the intractable symptoms related to ischemia
in the subjects with peripheral artery disease, including
TAO and atherosclerosis (44-46). New applications of bio-
technology can stimulate new vessel formation via the lo-
cal administration of proangiogenic growth factors in the
form of recombinant protein, gene therapy or by the im-
plantation of stem cells that will synthesize multiple an-
giogenic cytokines.
Formation of new vessels involves at least 3 distinct bio-
logical processes (47). Angiogenesis refers to a process in
which preexisting capillaries sprout and proliferate to
form networks that consist of vessels at the capillary level
and this is triggered by endothelial cell activation, migra-
tion and proliferation followed by remodeling and ex-
pansion of the extracellular matrix (48). Vasculogenesis is
in-situ formation of new blood vessels from circulating
bone marrow-derived endothelial progenitor cells. At last,
arteriogenesis refers to an increase in the wall thickness
and luminal diameter of existing arteriolar collateral ves-
sels via recruitment of perivascular cells and smooth mus-
cle cells. New vessel formation in the lower limbs of pa-
tients with peripheral artery disease is likely to involve a
combination of these three processes.
There are several methods of stem cell therapy such as
intramuscular injection of bone marrow derived mono-
nuclear cells, intramuscular injection of cytokine mobi-
lized peripheral blood mononuclear cells, intramuscular
injection of whole bone marrow and mobilization alone
(46).
Tateishi et al. first reported the significant clinical ben-
efits of injecting bone marrow mononuclear cells
(BMMNCs) in the calf muscle in terms of the walking
time, the ankle brachial index and the transcutaneous oxy-
gen concentration (49). Several small, nonrandomized stu-
dies have replicated these results. Higashi et al. suggested
that improvement of the endothelial dysfunction with
BMMNCs implantation was a potential mechanism for
improving limb ischemia (50).
Several authors have performed randomized trials to as-
sess implantation of peripheral blood mononuclear cells
(PBMNCs) that were mobilized by granulocyte colony
stimulating factor (G-CSF) and they reported significant
improvements in the ankle brachial index, the Doppler
flow and the angiographic scores (45, 51-53).
Kim et al. reported the favorable results of autologous
whole bone marrow transplantation in animal experiments
and in the clinical trials that included patients with TAO
Ui-Jun Park, Dong-Ik Kim: Thromoboagiitis Obliterans (TAO) 5
(54, 55). They suggested that transplantation of autologous
whole bone marrow is a simple, safe and effective means
of inducing therapeutic angiogenesis.
Arai et al. examined the effect of injecting G-CSF into
patients with intractable PAD symptoms. The patients
were randomly assigned into 3 groups: a group treated
with conventional drug therapy, a group treated with con-
ventional drug therapy plus bone marrow transplantation
(BMT) and a group treated with conventional drug ther-
apy plus subcutaneous injection of G-CSF once daily for
10 days. One month after treatment, the subjective symp-
toms significantly improved in the G-CSF and BMT
groups. The ankle-brachial pressure index and the trans-
cutaneous oxygen pressure significantly increased in the
BMT and G-CSF groups, but no such improvements were
seen in the group that received conventional therapy alone
(56). This is the least invasive mode of cell therapy for
treating PAD, yet advanced PAD make it less likely for
a large number of mobilized cells to be delivered to ische-
mic tissue due to the reduced blood flow.
The trials performed to date suggest that stem cell ther-
apy could serve as a much needed novel therapeutic mo-
dality for the treatment of PAD. But trials of stem cell
therapy for the PAD need to discriminate the etiologic
factors. Especially, the patients with PAD caused by TAO,
and these patients are rarely candidates for surgical treat-
ment, will be good candidate for treatment with stem cell
therapy. Several studies that are currently ongoing are fo-
cused on the treatment of PAD that is caused by TAO,
and the treatments involve stem cell therapy (55, 57-62).
So far, these studies have shown good treatment results
and the treatments were safe for the patients. However,
these studies have enrolled small numbers of subjects,
they are often non-randomized studies and they are large-
ly being performed to investigate the feasibility and safety
of these approaches. For the clinical application of stem
cell therapy to the TAO patient, more clinical evidence
has to be gathered from appropriately designed, adequa-
tely powered trials with robust endpoint measurement.
Potential Conflict of Interest
The authors have no conflicting financial interest.
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