Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G.

Richter: TAO
© 2014 Hans Huber Publishers, Hogrefe AG, Bern DOI 10.1024/0301-1526/a000371

Review 337

Thromboangiitis obliterans (Buerger’s disease)

Peter F. Klein-Weigel1 and Jutta G. Richter2

1
HELIOS Klinikum Berlin-Buch, Klinik für Angiologie, Berlin, Germany
2
Poliklinik und Funktionsbereich Rheumatologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität,
Düsseldorf, Deutschland

Summary
Thromboangiitis obliterans (TAO, Buerger`s disease) is an in-
flammatory vascular disease affecting small and medium sized
arteries and veins. It is characterized by segmental throm-
botic occlusions by highly mononuclear cellular thrombi. Its
occurrence and re-occurrence is closely related to tobacco
use. Immunohistological examinations and the detections
of various autoantibodies led to the new paradigm of an im-
munopathogenesis of TAO. Clinically it is characterized by
distal ischemia syndromes in young people and high amputa-
tion rates. This article summarizes the disease characteristics,
clinical features, and diagnostic and therapeutic approaches
and focuses on new therapeutic options, i.e. stem cell derived
therapies, immunoadsorption, and the endothelin-receptor-
blocking agent bosentan.
Key words: Thromboangiitis obliterans, Buerger`s dis-
ease, critical limb ischemia, vasculitis, immunoadsorption,
stem cell therapy, progenitor cell therapy, bosentan
Zusammenfassung
Thrombangiitis obliterans
Die Thromboangiitis obliterans (Buerger`sche Erkrankung) ist
eine entzündliche Erkrankung der kleinen und mittelgroßen
Arterien und Venen, die durch segmentale thrombotische Ge-
fäßverschlüsse mit hohem mononukleären Zellanteil gekenn-
zeichnet ist. Das Auftreten und auch Rezidive sind eng mit
einem Tabakkonsum korreliert. Immunhistologische Unter-
suchungen und der Nachweis verschiedener Autoantikörper
führten zu dem neuen Paradigma einer Immunpathogenese.
Klinisch ist die Erkrankung durch distale Ischämiesyndrome
bei jungen Patienten und eine hohe Amputationsrate gekenn-
zeichnet. Der Artikel fasst die Krankheitscharakteristika, das
diagnostische Vorgehen und die therapeutischen Möglich-
keiten zusammen und fokussiert dabei auf neue therapeutische
Optionen wie die Stammzelltherapie, die Immunadsorption
und den Einsatz des Endothelin-Rezeptorblockers Bosentan.

Introduction leading to occlusion of the affected Europe to values as high as 45 to 63 %

In 1879 Felix von Winiwarter, a young
assistant physician of Theodor Billroth
in Vienna, published the result of his
pathologic examination of a lower
limb amputate of a 57 year old male
as „eine eigentümliche Form von En-
dangiitis und Endophlebitis mit Gan-
grän des Fußes“ [e1]. Although this is
considered to be the first case report of
thromboangiitis obliterans (TAO) the
disease is nowadays more exclusively
linked to the American surgeon Leo
Buerger, whose systematic work on
clinical and pathological aspects of
the disease built the fundaments of the
modern understanding of TAO [2].
Definition
TAO is characterized by a clinically
undulating multilocular segmental
inflammatory disease affecting small
and medium sized arteries and veins
vessels by the formation of a highly
cellular thrombus rich in mononu-
clear cells [2 – 4, e5].
In spite of its obviously inflamma-
tory character TAO is not listed in
the 2012 revised International Chapel
Hill Consensus Conference Nomen-
clature of vasculitides [e6].
Epidemiology
TAO occurs world-wide [3 – 4, e5].
It is relatively rare in North America
and Western Europe compared to
Eastern Europe and high prevalence
regions, which are located in the
Mediterranean, the Middle East, and
India. Among certain ethnical groups
Ashkenazi jews are predominantly af-
fected [3 – 4, e5, e7 – e9].
The prevalence rates among all pa-
tients with peripheral arterial disease
have been reported to range from val-
ues as low as 0.5 to 5.6 % in Western
in India, 16 to 66 % in Korea and Japan,
and 80 % among Ashkenazi Jews [7].
Nevertheless, in many countries
the reported prevalence of TAO has
declined during the past decades
[e10 – e12, 13]. There is conflicting
data about the reason for this obser-
vation. While some authors believe
the decline parallels the decrease in
tobacco use, others believe it is more
closely linked to changes in socioeco-
nomic conditions [13, 14].
TAO is more common in men, but
an increasing prevalence in women
has been reported [e10 – e11, 15].
Disease characteristics and prognosis
do not seem to differ between men
and women [15, e16].
Etiologic, pathologic, and
pathogenetic aspects
The etiology of TAO is still unknown.
Regional and ethnic differences in

338 Review
the prevalence of the disease point
towards a genetic background de-
termining individual susceptibility.
HLA linked factors may play such a
role, like HLA A-9 und B-5, HLA-A,
HLA-BW, O, J-1-1 and the missing
of HLA A1 [e17], nevertheless, HLA
association studies have revealed
heterogeneous findings in different
populations including findings of no
correlation at all [e18 – e22]. Pub-
lished genetic polymorphisms consist
of CD14 T7T-Polymorphism, eNOS
gene 894 T/T -polymorphism as a
protective factor and MyD88 rrs7744
A-G polymorphismus, coding for a
Toll-like receptor signaling adaptor
[e23 – e25]. It must be stressed, that
methodological problems and the
immanent diagnostic uncertainties
may have substantially confounded
the results of the genetic studies as
the number of included patients has
been usually small.
There is a very tight correlation be-
tween the manifestation of TAO as
well as between flaring and re-occur-
rence of the disease and tobacco use,
leading to the well known aphorism
“no tobacco, no Buerger`s disease”
[3 – 4, e2,e5].
Pathohistologically, TAO-lesions
are classified in acute, subacute, and
chronic types, the latter being un-
distinguishable from other forms of
chronic arterial occlusive diseases [2,
e26]. Due to the undulating clinical
course normal vessel segments and
different stages of TAO-typical vascu-
lar lesions might be found simultane-
ously in the same patient [2].
Signs of endothelial activation and
proliferation as well as the presence
of immunocompetent cells are only
seen in the acute type-lesions. Im-
munoglobulin und complement de-
position as well as CD4+ and CD 8+
T-lymphocytes, CD 20+ B-lympho-
cytes, and S 100 positive- dentritic
cells are found alongside the lamina
elastica interna, which becomes
structurally altered but is typically
P. Klein-Weigel & J.G. Richter: TAO
preserved [e27, 30 – 31, e32]. Giant
cell formation and the appearance
of so called “microabcesses” within
the mononuclear cell rich thrombus
may occur [2].
Analysis of cytokine activation in
TAO patients has revealed a pattern
of elevated pro- and anti-inflamma-
tory cytokines with up-regulation of
tumor necrosis factor-α, Interleukin
(IL)-1ß, IL-4, IL-17, and IL-23 [33,
e34]. Nevertheless, one has to be
aware that this pattern might have
been influenced by the presence of
chronic wounds and gangrenes as
well as possible wound infections.
Various kinds of autoantibodies have
been identified in TAO-patients, in-
cluding anti-endothelial antibodies,
antibodies directed against vessel
wall structures like elastin and col-
lagen, anti-cardiolipin-antibodies,
and anti-neutrophil cytoplasmic
antibodies [e35 – e41]. None of
these have proved to be causative
or pathognomonic. Nevertheless,
autoantibodies may play an impor-
tant role in the pathogenesis of the
disease. More recently, a clustering
of agonistic autoantibodies directed
against α1-receptor loop 1 as well as
against endothelin-A-receptor loop
1 was identified potentially pro-
moting vasospasm, compromising
microcirculation, damaging vessel
structures, and inducing prolifera-
tive processes [42].
Alltogether, the findings are consis-
tent with the assumption of an immu-
nopathogenesis of TAO. A model of
this new paradigm has recently been
published by Ketha SS und Cooper
LT [43].
Although concomitant cannabis ex-
posure might influence the age of on-
set and the clinical presentation of
TAO, it does not seem to have a sig-
nificant influence on outcome [e44].
It is noteworthy that the clinical and
histological pattern of cannabis-as-
sociated angiopathy cannot be sepa-
rated from Buerger`s disease [e45].
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
Reports on a possible causative as-
sociation between periodontal dis-
ease and TAO are not very convinc-
ing, as the prevalence of periodontal
infection is high in the typical risk
group and similar associations have
been reported for arteriosclerotic dis-
eases and even rheumatoid arthritis
[e46 – e49]. On the other hand, peri-
odontal infection might enhance
the inflammation level, endothelial
dysfunction, and hypercoagulability
[e50].
A prothrombotic state has been
discussed as an important patho-
genetical factor in TAO. Indeed,
some prothrombotic risk factors
and mutations like C 677 T meth-
ylentetrahydrofolate reductase
(MTHFR)-polymorphism, hyperho-
mocysteinaemia, and prothrombin
G 20210 A-polymorphism have been
described, but correlations might
be confounded by small numbers
[e51 – e53].
Social und psychosomatic
aspects
TAO typically occurs in patients
with a low social status [14]. Some
authors described a Buerger-type
personality with manipulative and
auto-aggressive tendencies often
matched with denial, negligence,
or tendencies to minimize their ill-
ness, while others even presumed
typical morphological character-
istics [e54 – e55]. Nevertheless, no
systematic work has been done in
this field and the preliminary results
do not allow differentiating between
premorbid traits and conditions and
psychological consequences of the
chronicity and/or severity of the dis-
ease or implications of chronic drug
intake like morphine or opioids.
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
Diagnostic criteria
TAO patients usually present with skin
discolorations including Raynaud`s
phenomenon, acute ischemic or infec-
tious acral lesions (ulcers, gangrenes,
subungual infections, phlegmone),
and/or thrombophlebitic nodules
(Tab. I and Fig. 1)[3 – 4, e5]. Rarely,
non-erosive arthritis precedes isch-
emia for month or years [56].
Diagnosis is usually based on clinical
and angiographic criteria published
by Olin et al. and Shinoya et al. [13,
e57]. Synoptically, it demands the
presentation of a more or less sym-
metrical distal ischemic syndrome
or the presence of an acral-crural/
antebrachial-acral type of arterial oc-
clusion in two or more extremities
in young patients (typically < 45 – 50
Figure 1: Typical clinical presentions of Thromboangiitis obliterans
P. Klein-Weigel & J.G. Richter: TAO
years of age) in which other vascular
diseases preferentially affecting the
same vascular beds (i.e. premature
atherosclerosis, thrombembolic dis-
ease, diabetic angiopathy) or other
distinct vasculitides are excluded [13,
e57]. Diagnosis can also be made by
scoring systems, nevertheless these
tools are not widely established in
clinical routine care [e58].
Upper extremity involvement was
reported to increase during the last
decades [13]. Combined upper and
lower extremity involvement is pres-
ent in about 20 – 25 % of the cases [13,
e59]. An isolated affection of only one
limb strongly argues against TAO.
Thrombophlebitis is often of migra-
tory type and precedes or parallels
arterial disease activity [60, e61].
Proximal arterial involvement is rare-
Review 339
ly present and usually argues more for
other entities such as atherosclerotic
disease [e62 – e63]. Nevertheless, case
reports of TAO-lesions in cerebral,
coronary, and visceral arteries as well
Table I: Common clinical presenta-
tions of TAO
Gangren
Acral ulcer
Ischemic rest pain
Subungual and skin infection,
phlegmone
(In-step-)claudication
Acral skin discoloration and
coldness, Raynaud’s phenomenon
Thrombophlebitic nodules or strings
(often migratory)

340 Review
Table II: Angiographic signs of TAO
Segmental distally located
multisegemtal vessel occlusions
Smooth vessels in non-affected
regions, no calcifications
Cut-off-occlusions
Corkscrew-, tree-root-, and
spider-leg collaterals
Martorell-sign (i. e. formation of
collateral vessels within the occluded
lumen of the affected vessel)
No-refill phenomenon of the
original vessel
Standing wave phenomenon
Vasospasm
Figure 2: Typical angiographic
feature of TAO
as even with multiple organ involve-
ment and failure have been published
[e64 – e68].
P. Klein-Weigel & J.G. Richter: TAO
Diagnostic measures
Distal pulses are usually absent or
diminished, but can be normal in
case of distal disease manifestations.
Allen-Test often reveals an upper ex-
tremity involvement.
Ankle brachial index or forearm-
brachial-index is usually reduced,
but might be normal in cases with
very distal disease. Digital pulse re-
cordings are characterized by low
amplitudes and delayed slopes, anar-
chic or silent pulse curves. Repeated
examination after thermal or phar-
macological provocation should be
performed as vasospasm is usually
present.
Angiographically a typical but not
pathognomonic pattern has been
described that substantiates the di-
agnosis [e55]. This pattern might
also be identified by careful duplex
ultrasound examination, although at
least in cases of critical ischemia angi-
ography should always be performed.
Table II summarizes the angiographic
signs of TAO, while Figure 2 demon-
strates a typical angiographic feature.
Embolic disease has to be ruled out
by electrocardiography, transesopha-
geal echocardiography, computer to-
mography angiography, and duplex
ultrasound of the aorta and proximal
extremity arteries.
Capillary video microscopy is often
limited by hornification. It often re-
veals unspecific morphologic chang-
es, bleedings, and a diminished capil-
lary density [e69 – e70]. Elongation of
capillary loops as presumably more
typical alterations have also been de-
scribed [e70].
There are no specific laboratory (bio-)
markers for TAO [3 – 4, e5]. Never-
theless, laboratory tests are important
to exclude other entities such as dia-
betes, connective tissue disease, vas-
culitides, or congenital or acquired
thrombophilia [3 – 4, e5].
If a biopsy can be performed without
endangering the limb or if an amputa-
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
tion is performed diagnosis should
be confirmed by histopathologic ex-
amination. Besides arterial segments
thrombophlebitic nodules are suit-
able for this purpose (Figure 3).
Due to often long-time and heavy
smoking features of arteriosclerotic
disease might be seen to some degree.
They do not per se exclude the diag-
nosis of Buerger`s disease. Differen-
tial diagnosis is outlined in Table III.
Markers of disease
activity
There are no commonly accepted
criteria defining disease activity in
TAO hampering direct comparisons
of clinical studies. Systemic inflam-
matory laboratory markers are usu-
ally absent or only slightly elevated
and are therefore unsuitable for as-
sessment of disease activity. If pres-
ent, they point towards concomitant
infections or argue for other enti-
ties. Clinical disease activity criteria
proposed by the authors is shown in
Table IV.
Therapy
Smoking cessation
The most important therapeutic in-
tervention in TAO is smoking ces-
sation [3 – 4, e5]. Its overwhelming
effect for the prevention of limb am-
putation has been impressively shown
[13]. TAO patients should not only
be prevented from active smoking
but also from alternative consump-
tion modi, as passive smoking as well
as chewing of tobacco, and snuffing
have been identified as causes of
disease flare-up and re-occurrences
[e71 – e73].
Tobacco dependency usually is con-
sidered to be exceptionally strong
in TAO patients, but in a prospec-
tive study addressing this question
the degree of tobacco dependence
Vasa 2014; 43: 337 – 350 P. Klein-Weigel & J.G. Richter: TAO
© 2014 Hans Huber Publishers, Hogrefe AG, Bern

Review 341

Table III: Differential diagnosis of TAO

Disease Exclusion predominantly by

Diabetic angiopathy HbA1c, fasting glucose, glucose tolerance test
Embolic disease Electrocardiogram, transesophageal echocardiography,
computed tomography angiography, duplex ultrasound,
angiographic pattern
(Premature) Atherosclerosis Presence of classic cardiovascular risk factors, duplex
ultrasound, angiographic pattern
Hypercoagulability/thrombophilia Blood count, markers of thrombophilia
Vasculitis/connective tissue disease Blood sedimentation rate, C-reactive protein, antinuclear
antibodies, antineutrophil antibodies, cryoglobulin,
eosinophiles, immunoglobulines, capillary microscopy,
duplex ultrasound, biopsy
Drug-associated vaculitis (cocaine, amphetamine) History, drug screening
Ergotamine, lead, or drug poisoning History, biochemical/drug screening
Occupational diseases (chronic vibration syndrome, Occupation, angiographic or duplex ultrasound pattern
hypothenar-hammer-syndrome)

in subjects with TAO was similar to

that in subjects with coronary artery
disease [74].
Individual strategies for smoking
withdrawal have to be discussed, in-
cluding in- and outpatient-treatment
in specialized institutions [e75 – e76].
Unfortunately, the percentage of
those who maintain smoking cessa-
tion is low [e75 – e76]. In one study,
the continuous abstinence rate de-
creased from 29 % at the end of treat-
ment to 18.5% at 12-month follow up
[e76]. Overall, best results might be
achieved by structured and guided
peer group programs starting already
during hospital stay or shortly there-
after [e77 – e78].

Prostanoid therapy
The effectiveness of prostanoid ther-
apy was elucidated in two older ran-
domized trials and in two more re-
cently published trials prospectively
assessing clinical outcome in addition
to smoking cessation or compared to Figure 3: Histologic feature of thrombophlebitic nodule in TAO
sympathectomy [79 – 82]. Iloprost, a
prostacyclin analogon, is the drug of
choice. Although often used in clini-
cal routine effectiveness of iloprost re- randomly allocated 152 patients with disease) and pain from critical leg
mains controversial. Fiessinger et al. thromboangiitis obliterans (Buerger’s ischemia (98 patients suffered from

342 Review
Table IV: Disease activity criteria in TAO (proposed by the authors)
(Re-)appearance or worsening of preexisting distal ischemic syndromes i. e. rest
pain or trophic lesions (ulcers, necrosis, and gangrene)
(Re-)appearance of new thrombophlebitic nodules or strings
Persistence or relaps of tobacco-use or passive exposure
leg ulcers) to intravenously applicat-
ed iloprost or low-dose aspirin for
28 days in a double-blind trial. After
exclusion of 19 patients not meeting
the inclusion criteria, retrospectively,
58 (85 %) of 68 iloprost-treated pa-
tients showed ulcer healing or relief
of ischaemic pain versus 11 (17 %)
of 65 in the aspirin-treated group.
43 (63 %) on iloprost treatment had
complete relief of pain, compared
with 18 (28 %) on aspirin [79]. These
striking results could not be repro-
duced in the largest trial including
319 patients when iloprost was ad-
ministered orally in two dose regimes
and compared to placebo. The pri-
mary end point, which was defined
as total healing of dominant ischemic
lesions was not significantly differ-
ent between the treatment groups.
Only relief of rest pain without need
of analgesics as well as a combined
secondary endpoint defined as alive
without major amputation, lesions,
rest pain, and no intake of analge-
sics was significantly more preva-
lent in the treatment group [80].
In the first study published by the
Turkish Buerger’s Disease Research
Group, complete ulcer healing rate
was 61.9 % in the iloprost group and
41 % in the lumbal sympathectomy
group (LS) at 4 weeks and 85.3 %
versus 52.3 % at 24 weeks. Intake of
analgestics was lower in the iloprost
group and decrease in ulcer-size was
significantly more pronounced [81].
More recently, the same group pub-
lished their results of a prospective
multicenter observational trial con-
ducted to clarify the role of intrave-
nous iloprost therapy for 28 days in
P. Klein-Weigel & J.G. Richter: TAO
the acute phase of Buerger`s disease
in 158 patients with rest pain and/
or ischemic ulcers [82]. Treatment
started with 0.5 ng / kg / min and was
aimed to reach 1 ng/kg/min if toler-
ated. Aspirin was given, but any drugs
with vasodilating or hemorheologic
properties as well as epidural anaes-
thesia were prohibited throughout
the observational period of 6 months.
After exclusion of 8 cases with an in-
sufficient data set the primary end
point defined as complete ulcer heal-
ing without pain or major amputation
was met by 60 % of the patients. Pain-
Scale values decreased from 7.07 ±
2.12 to 2.12 ± 2.18 and 1.72 ± 2.33
after 4 and 24 weeks. Ulcer size-re-
duction at 4 and 24 weeks, as well as
standardized clinical status scaling,
investigator, and observer grading
was also significantly improved at
both time points. Reported side ef-
fects consisted of headache in 39 %,
flushing in 32 %, nausea in 24 %, and
abdominal discomfort in 8.5 % of the
patients [82].
Iloprost is nowadays exclusively applied
intravenously in either body-weighted
dose regimes (0,5 – 2 ng/kg/min) or in
a fixed daily dose regime with 20 μg
dissolved in 0.9% saline over 5 – 6 h
per day for 2 – 4 weeks as intravenous
application seems to be more effective
and oral applications did not enter the
market. If necessary, infusions might
be repeated.
Antiplatelet drugs and oral
antigoaculants
Although widely used, there is no
proven evidence for platelet func-
tion inhibitors such as aspirin or
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© 2014 Hans Huber Publishers, Hogrefe AG, Bern
clopidogrel in TAO [3 – 4, e5, 79]. The
same is true for oral anticoagulants
[3 – 4,e5,79].
Vasodilatating drugs
Some reports including TAO-patients
have been published addressing the
use of calcium-channel-blockers to
reduce vasospasm and improve walk-
ing distance [e83 – e84]. In the older
literature pentoxifyllin was often rec-
ommended, but evidence of clinical
improvement in TAO is missing [for
overview see e9, e55]. Cilostazol is ad-
vocated in one review, again without
proven evidence in Buerger`s disease
[e85].
Analgesia
Effective analgesia is crucial as isch-
emic and neuropathic pain in TAO
is usually severe. Combinations of
morphine or opioids and NSAR are
often required in high doses for pain
control. Antidepressants might be of
additional value. Epidural anaesthe-
sia, neuronal block, or local analgetics
are often applied in inpatients [e86-
e88]. In selected cases with preserved
microvascular reserve capacity, i.e.
increase of tcpO2 of at least 10 – 15
mmHg in a postural test or during
trial spinal cord stimulation is in-
dicated as it does not only improve
pain-control, but also improves per-
fusion by sympathicolysis and anti-
drome mechanisms [89, e90].
Revascularisation procedures
Due to the distal localization of ar-
terial occlusions and the absence of
recipient vessels interventional or
surgical revascularization is impos-
sible in the majority of cases.
In an older series published in 1977
by Inada et al. only 11 (4.6 %) out of
236 patients were eligible for bypass
procedures. Primary and secondary
patency during a mean follow-up of
2.8 years (4 month to 7 years) was
reported to be 49.0 % resp. 62.5 %,
respectively. [91]. Sayin et al. in 1993
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
published a revascularization-rate of
10 % [e92]. Shionoya and coworkers
reported in their series of 266 patients
a surgical reconstruction rate of 17.7 %
with 38 bypass procedures, 7 thromb-
endarterectomies, and two replace-
ments with an overall patency rate of
24 %, 0 %, and 100 % (only 2 cases) after
a follow-up period of 6 to 102 months
also stressing the importance of smok-
ing cessation for a favorable outcome
[93]. Sasajima et coworkers described
primary and secondary patency rates
of 48.8 % and 62.5 % at 5 years, and
43.0 % and 56.3 % at 10 years, respec-
tively, in their series of 71 autogenous
vein bypasses in 61 TAO-patients. The
amputation rate in this series was 18 %
[94]. In highly selected cases, collateral
artery bypass might be an option when
the main arteries are affected by the
disease [e95].
Omentum-transfer, another surgi-
cal procedure in non-bypass candi-
dates, is almost unknown in Europe
or North America, but is commonly
performed for limb salvage in some
centers in India [e96 – e97].
Endovascular therapy might also be
effective even in extended femoro-
tibial occlusions [e98]. Good out-
come results have been published in
a recent series of 20 patients interven-
tionally treated in Italy, nevertheless
the reported numbers are small and
the role of endovascular therapy in
Buerger`s disease has yet to be de-
fined [99, e100].
There are some reports about effec-
tive local thrombolysis without or
in combination with angioplasty in
TAO, but controlled trials are missing
[e101 – e103].
Sympathectomy
In a cohort of 216 Turkish patients
sympathectomy, although unproven
by controlled trials in TAO, was pre-
ferred over open surgical reconstruc-
tion or bypass procedures (81 % ver-
sus 19 %). Clinical outcome following
sympathectomy was considered im-
P. Klein-Weigel & J.G. Richter: TAO
proved in 52.3 %, stable in 27.8 %,
and worse in 19.8 % of the patients,
while 7 major and 36 minor ampu-
tations were performed [e104]. On
the other hand, lumbar sympathec-
tomy was reported to be inferior to
intravenous iloprost applications by
the same group [81]. Thus, currently
there is no proven indication for sym-
pathectomy in TAO.
Immunsuppressive drugs
Although widely used in former times
there is no proven evidence for the
use of steroids in TAO [for overview
see e9, e55]. A small (n = 12) nonran-
domized Indian trial of cyclophos-
phamide in the treatment of patients
with advanced TAO has been pub-
lished with non-conclusive results us-
ing 400 mg intravenously for 7 days
followed by daily oral administration
of 100 mg for another 7 weeks [e105].
Furthermore, a Russian group com-
pared a single three day glucocorti-
coid and cyclophosphamide pulse-
therapy in 16 patients to 12 controls
under standard medical care and
reported positive results, but out-
come parameters focused mainly on
inflammatory markers and the num-
ber of patients was far too small to
draw any reliable conclusions about
limb salvage rates [e106]. Thus, out-
side RCTs there are no indications for
immunosuppressive drugs in TAO.
Wound management and
infection
Local wound management in isch-
emic lesions in TAO is based on mod-
ern wound care standards. Intermit-
tent pneumatic compression might be
of additional value, although there is
very limited published experience in
TAO [e107]. Wound-, soft tissue, and
bone infections cause serious clinical
problems as they occur in often highly
ischemic states. Bacterial species and
resistance spectra vary widely with
gram-positive species dominating
our own series [unpublished data].
Review 343
Starting calculated antibiotic therapy,
one has to take anaerobic species and
multiple resistances into account.
Outcome and social
consequences
According to a literature survey con-
ducted by Börner et al. amputations
are being performed in 6.9 to 75 %
of TAO patients within 3 to 10 years
of follow-up. Minor amputations are
predominant; nevertheless, the major
amputation-rate was as high as 31 %
[108]. The high amputation rates in
the relatively young patients signifi-
cantly contributes to the financial and
social burden of the disease, which
additionally includes job loss, early
retirement, divorces, severence, and
subsequent social isolation [108].
New treatment
opportunities
Progenitor cell therapy
In order to improve outcome, new
experimental treatment approaches
have been published. In the last de-
cade cell-based therapies with au-
tologous progenitor cells harvested
from bone marrow or peripheral
blood have been advocated for critical
limb ischemia, including TAO. The
cell suspensions are usually applied
by intramuscular injections alongside
the vascular bed of the limbs or by
intraarterial injection [e109 – e111,
112, 113, e114, 115].
Metaanalyses have confirmed practi-
cability and safety as well as positive
therapeutic effects (including pain-
control, ulcer healing, pain-free walk-
ing ability, amputations-free survival)
of cell-derived therapies in critical
limb ischemia [e109, 112, 115]. Prob-
ably caused by higher progenitor-cell
crop and better cell quality (younger)
TAO patients have responded better
than (older) PAD-patients in some,
but not all studies [e116 – e118].

344 Review
Positive results of long-term effects
have been published for a limited
number of patients [113, e116 – e118].
Kinoshita and co-workers reporting
outcome data up to week 208 post
CD34+ cell therapy in 17 patients
including 12 with Buerger`s disease
published a critical limb ischemia-
free ratio of 88.2 % at week 52 and
104, 92.5 % at week 156, and 94.6 %
at week 208 as well as significant
improvement of toe-brachial pres-
sure index, tcpO2, pain rating scale
results, ulcer size, and exercise toler-
ance at various final evaluation time
points [e116]. In the TACT-trial out-
come data of 41 patients with TAO
and 74 patients with atherosclerotic
disease were reported for a median
follow-up-time of 25.2 month, rang-
ing from 0.8 to 69 months. There was
significant improvement of pain and
ulcer size as well as claudication-free
walking distance in both groups.
Patients with TAO had a better am-
putation-free survival [e117]. Mori-
ya J et al. retrospectively analyzed
the results of 42 patients including
14 patients with TAO at 1, 6, 12, 24,
and 36 months after treatment and
found improvement of rest pain in
72.2 % of patients with pain scale
values normalizing after 12 months.
Ulcer size decreased in 66.7 % of all
patients staying alive without ampu-
tation, but there was no significant
improvement in walking distance.
Patients with TAO and those with
non-dialysis atherosclerotic disease
experienced fewer amputations and
cardiovascular events, and had a
lower mortality-rate [e118]. Finally,
Lee et al. analyzed the outcome for
90 limbs in 67 patients exclusively
suffering from TAO. Clinical and
angiographic improvement was ob-
served in 55.6 % and 43.2 % whereas
amputation-free survival for all limbs
after 1, 3, and 5 years was reported to
be 91.9 %, 88.5 %, and 84.6 %, respec-
tively. In patients initially suffering
from critical limb ischemia amputa-
P. Klein-Weigel & J.G. Richter: TAO
tion-free survival was reported to be
8 – 14 % lower [113]. Results of ran-
domized double blinded studies are
being awaited.
There seems to be a significant time
lag of 4 – 8 weeks until an improve-
ment of microcirculation becomes
evident in responders after BM-cell
transplantation [e119]. This lag might
be problematic in case of severe isch-
emia demanding a more urgent im-
provement of perfusion.
Further research relates to the op-
timal cell type and dosage, the best
isolation methods, the role of colo-
ny-stimulating factors, administra-
tion routes, and supportive stimula-
tion methods. More recently, Teraa
et al. published diverging results of
placebo and non-placebo controlled
studies stressing the need of a pla-
cebo controlled arm in randomized
controlled trials assessing treatment
effects of BM-cell therapies in the
future [115].
Intramuscular or intraarterial pro-
genitor cell therapies compete against
surgical concepts of stimulating an-
giogenesis and arterialization in
TAO patients based on tibia bone
distraction or fenestration, or im-
plantation of a Kirschner-wire in a
medullary channel of the tibia [e120,
121 – 122]. These procedures were
also reported to result in improved
outcome regarding pain-scores, ulcer
healing, and walking distances [e120,
121 – 122]. Nevertheless, they might
be hampered by side effects as the
operation takes place in an ischemic
environment. Controlled and com-
parative studies are missing.
Immunadsorption (IA)
Based on the hypothesis, that TAO
is an immunmediated disease with
humoral factors playing a major role
in the pathogenesis IA was success-
fully introduced in a pilot study con-
ducted by Baumann and co-workers
and later introduced in a clinical
routine care setting [123, e124]. Im-
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
munoadsorption is an extracorporal
procedure clearing plasma from im-
munoglobulines and circulating im-
muncomplexes already successfully
applied in other immunmediated
diseases. It is being performed on 5
consecutive days for 5 – 6 hours per
session aiming for a clearance of ap-
proximately the 2.5 fold of patient`s
plasma volume [123, e124]. IA might
be followed by substitution of polyva-
lent immunoglobuline to ameliorate
infectious risks in patients with gan-
grene or ulcers.
The pilot study revealed a fast im-
provement of pain, a steep incline
of tcpO2-levels, a steep decrease of
tcCO2-levels, an improvement in
ulcer healing, and a high return-to-
work-rate of the patients [123]. Over
all, these positive results could be re-
produced in a clinical routine setting
[e124].
The rapid effects have suggested a
pivotal role of immune-mediated
vasospasm. More recently, a pos-
sible effective mechanism of IA was
elucidated as IA eliminates α- and
endothelin-receptor-agonistic au-
toantibodies that seem to cluster in
TAO [42].
Bosentan
Referring to a first positive case re-
port another Spanish group recent-
ly published their results of a pilot
study introducing the endothelin-
receptor blocking agent bosentan
in the treatment of digital ulcers in
TAO patients [e125, 126]. Dosing
was derived from the approved ap-
plication for prophylaxis of digital
ulcers in scleroderma patients. De-
spite the promising results about 1/6
of the patients had to undergo minor
digital amputations – a finding, not
necessarily arguing against the ef-
fectiveness of bosentan as minor am-
putations might have already been
inevitable at presentation or might
even have been made successfully
possible by the treatment – a find-
Vasa 2014; 43: 337 – 350
© 2014 Hans Huber Publishers, Hogrefe AG, Bern
ing that was also observed in our IA-
patients [e124]. Another explanation
is given by the relatively low smoking
cessation rates, as only 4 patients re-
frained from smoking. The reported
positive effects of bosentan might be
explained by the identification of re-
ceptor agonistic autoantibodies di-
rected against endothelin-receptors
in TAO patients, whose binding
might be blocked by the receptor
blocking drug [42].
Forecast and hopes for
future research
Although the incidence of TAO
seems to have declined worldwide
over the past decades Buerger`s dis-
ease remains an important health
issue not only in high prevalence
regions but also in our latitudes as
it affects young people and induces
high social and financial costs. De-
spite this fact, scientific interest in
Buerger`s disease obviously has de-
creased over the last decades as is
indicated by the number of publi-
cations dealing with TAO listed in
the results-by-year pubmed-chart.
Hopefully, the new paradigm of
an immunopathogenesis of TAO
might fuel the scientists` interest
in this still unrecognized condition.
It might not only enhance basic re-
search, but might also lead to new
treatment measures and meaning-
ful randomized controlled treatment
trials which are needed most urgent-
ly from the clinician`s point of view.
Conflicts of interest
There are no conflicts of interest
existing.
P. Klein-Weigel & J.G. Richter: TAO
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Correspondence address
Dr. med. Peter Franz Klein-Weigel,
MD
HELIOS Klinik Berlin-Buch
Klinik für Angiologie
Schwanebecker Chaussee 50
13125 Berlin
Germany
p.klein-weigel@web.de
Submitted: 12.01.2014
Accepted after revision: 12.05.2014