Basic Data Underlying Clinical Decision-Making in

Endovascular Therapy
Buerger’s Disease
Phong T. Dargon,1 and Gregory J. Landry,2 Portland, Oregon

Buerger’s disease (thromboangiitis obliterans) is a nonatherosclerotic segmental inflammatory

disease of small- and medium-sized arteries of the distal extremities of predominantly young
male tobacco users. Early symptoms may include episodic pain and coldness in fingers, and
late findings may present as intermittent claudication, skin ulcers, or gangrene requiring eventual
amputation. Tobacco cessation is the cornerstone of treatment. Other modalities of reducing
pain or avoiding amputation have not been as successful. This review summarizes in tabular
form the types of treatment that have been used, including therapeutic angiogenesis.

INTRODUCTION Table I. Criteria for diagnosis of Buerger’s

disease4
Buerger’s disease (thromboangiitis obliterans) is
a nonatherosclerotic segmental inflammatory Major criteria
disease of small- and medium-sized arteries of the Onset of distal extremity ischemic symptoms before
distal extremities of male tobacco users.1 It was first age 45 years
Tobacco use
described by Felix Von Winiwarter in 1879. In 1908,
Exclusion of:
Leo Buerger published a detailed pathologic descrip- Proximal embolic source (cardiac,
tion of 11 amputated limbs.2 Buerger’s disease typi- TOS, ASO, aneurysms)
cally affects young male smokers; however, there is Trauma and local lesions (entrapment,
an increasing prevalence in women. It is more prev- adventitial cyst)
alent in the Middle East and Far East than in North Autoimmune disease
America and Western Europe. Hypercoagulable states
Patients may present with early findings of pain Atherosclerosis
or coldness in the fingers. Later findings include Atherosclerotic risk factors (diabetes, hypertension,
rest pain, skin ulcers, gangrene, and eventual ampu- hyperlipidemia)
tation. The Shionoya clinical diagnostic criteria are No evidence of arterial disease proximal to popliteal or
distal brachial arteries
as follows: (1) smoking history, (2) onset before
Objective documentation of distal occlusive disease
the age of 50 years, (3) infrapopliteal arterial occlu- by either:
sions, (4) either upper limb involvement or phlebitis Plethysmography
migrans, and (5) absence of atherosclerotic risk Histopathology
Arteriography
1
Department of Surgery, Oregon Health and Science University, Minor criteria
Portland, OR.
2
Migratory superficial phlebitis
Division of Vascular Surgery, Oregon Health and Science Univer- Raynaud’s syndrome
sity, Portland, OR.
Upper extremity involvement
Correspondence to: Gregory J. Landry, MD, MCR, Division of
Instep claudication
Vascular Surgery, Oregon Health and Science University, 3181 South
West Sam Jackson Park Road, OP-11, Portland, OR 97239, USA;
TOS, thoracic outlet syndrome; ASO, arteriosclerosis obliterans.
E-mail: landryg@ohsu.edu
Ann Vasc Surg 2012; 26: 871–880 factors other than smoking.3 A wider subset of major
DOI: 10.1016/j.avsg.2011.11.005
Ó Annals of Vascular Surgery Inc. and minor criteria for the diagnosis of Buerger’s
Published online: January 27, 2012 disease, described by Mills and Porter, is listed in

871
Table II. Surgical bypass in Buerger’s disease

872 Dargon and Landry

Single
Total number Number of Number of Number Mean saphenous % Limb
Reference Year Lead author Study type Description of patients bypasses graft failure of restored follow-up vein % Patency salvage

7 1993 Sayin et al. Retrospective Bypass grafting 16 16 62.5, 7 yr

8 1997 Sasajima et al. Retrospective Crural/below 61 71 38 10 53 48.8, primary
ankle patency, 5 yr
62.5, secondary
patency, 5 yr
43, primary
patency, 10 yr
56.3, secondary
patency, 10 yr
9 1998 Bozkurt et al. Prospective All with PTFE 14 14 6 73 mo 100 (2/2) 93 (13/14)
2 aortofem + LS aortofem, late
3 iliofem + LS 66 (2/3) iliofem,
5 fem-pop + LS late
5 fem-crural 40 (2/5) fem-
+ LS pop, 8 yr
50 (2/4) fem-
crural, 8 yr
10 2002 Shindo et al. Retrospective 8 tibial 8 10 3 41.8 mo unknown
2 collateral
11 2002 Dilege et al. Prospective 9 fem-peron 24 24 6 4 36 mo 24 89 (8/9) fem- 92 (22/24)
7 fem-PT peron, early
5 fem-AT 71 (5/7) fem-PT,
3 fem-pop early
80 (4/5) fem-
AT, early
66 (2/3) fem-
pop, early
6 2004 Ohta et al. Retrospective 1 femoral 31 46 10.6 yr 33 41.3, primary 91.4, 1 yr
3 above-the- patency, 1 yr 88.6, 5 yr
knee pop 54.3, secondary 85.4, 10 yr

Annals of Vascular Surgery

8 below-the- patency, 1 yr
knee pop 32.2, primary
34 crural patency, 5 yr
47.4, secondary
patency, 5 yr
29.7, primary
patency, 10 yr
Vol. 26, No. 6, August 2012 Buerger’s disease 873

Table I.4 Angiography will show arterial occlusion

PTFE, polytetrafluoroethylene; aortofem, aortofemoral; LS, lumbar sympathectomy; iliofem, iliofemoral; fem-, femoro; -pop, popliteal; -crural, crural; -peron, peroneal; PT, posterior
and the development of ‘‘cork-screw’’ collateral
arteries.5
Total tobacco cessation (smoking, secondhand
smoke, and nicotine replacement therapy) is the
patency, 10 yr
39.4, secondary

only treatment that improves symptoms and

reduces the risk of amputation, if done before the
44.8, 1 yr
37, 5 yr

onset of gangrene or tissue loss. One study showed

that patients who required above-the-knee or
below-the-knee amputation were all active smokers
after diagnosis, and 85% of them became unem-
ployed secondary to amputation.6 Other forms of
treatment are not well established or have unfavor-
11.6 ± 7.1 yr 47

able results. Surgical revascularization is often inef-

fective because the distal target vessels are often
involved in this diffuse segmental disease. Calcium
channel blockers, anticoagulants, thrombolytics,
prostaglandin analogs, sympathectomy, adrenalec-
tomy, spinal cord stimulators, and omental transfers
have all been tried with limited effect in decreasing
rest pain and avoiding amputation. Therapeutic
5

angiogenesis through endothelial progenitor cells

(EPCs) has become an emerging area of interest in
the treatment of Buerger’s disease.
A Medline English-language literature search
17

was performed, focusing on keywords such as

‘‘Buerger’s disease,’’ ‘‘thromboangiitis obliterans,’’
‘‘bypass,’’ ‘‘thrombolytic therapy,’’ ‘‘spinal cord
stimulation,’’ ‘‘sympathectomy,’’ ‘‘omental trans-
47

fer,’’ ‘‘progenitor cell,’’ and ‘‘amputation.’’ A

tabular review of the treatments studied between
1990 and 2011 was created. Data that involved arte-
riosclerosis obliterans were excluded. Most studies
Retrospective 30 fem-pop/-tib 47

have cited a primary end point of pain relief and

17 fem-pop/-tib

limb salvage, defined as avoidance of below-the-

knee amputation, above-the-knee amputation, or
hand amputation. Secondary end points of complete
+ LS

ulcer healing, improved claudication distance, and

adverse events were also examined.
Table II summarizes the patency rates of surgical
revascularization in Buerger’s disease. Surgical
bypass is generally not successful owing to diseased
distal targets and progression of disease with
continued tobacco abuse.
tibial; AT, anterior tibial; -tib, tibial.

Table III summarizes publications that studied the

use of a prostacyclin analog for the treatment of
2006 Ates et al.

Buerger’s disease. Prostacyclin is a by-product of

arachidonic acid metabolism. It is a potent vasodi-
lator and inhibitor of platelet aggregation. Iloprost
is a prostacyclin analog available in the United States
in inhalation form for the treatment of pulmonary
hypertension. It is available in Europe in parenteral
form. Treprostinil is available in the United States in
parenteral form and also used to treat pulmonary
12

hypertension.
Table III. Prostacyclin analogs to treat Buerger’s disease

874 Dargon and Landry

Total % Complete % Complete % Complete % Complete % Limb % Limb
number relief of pain relief of pain healing healing salvage salvage
Reference Year Lead author Study type Description of patients Follow-up (study) (control) (study) (control) (study) (control)

13 1990 Fiessinger Prospective, IV iloprost versus 152 28 d 63 (43/68) 28 (18/65) 35 (18/52) 13 (6/46)
and Schafer randomized, ASA
double-blind
14 1998 European Prospective, Oral iloprost (low) 319 8 wk 30 (41/105) 34 (35/102) 19 (12/63) 17 (12/70)
TAO Study randomized, versus placebo
Group double-blind Oral iloprost (high) 8 wk 38 (41/108) 49 (50/102) 15 (10/65)
versus placebo
Oral iloprost (low) 6 mo 63a (66/105) 49 (31/63) 41 (29/70) 95% 91%
versus placebo
Oral iloprost (high) 6 mo 49 (53/108) 42 (27/65) 96%
versus placebo
15 2006 Fernandez Case report Treprostinil 1 10 mo Some 100 (1/1)
and
Strootman
16 2006 Bozkurt et al. Prospective, IV iloprost versus 84 4 wk 61.9a
randomized lumbar 6 mo 85.3a
sympathectomy

IV, intravenous; ASA, acetylsalicylic acid.

a
P < 0.05.

Table IV. The use of thrombolytics in Buerger’s disease

Time

Annals of Vascular Surgery

Total Number complete Time % Improved
Lead number of limbs Mean relief % Complete complete % Complete walking % Limb Bleeding
Reference Year author Study type Description of patients studied follow-up of pain relief of pain healing healing distance salvage complications

17 1993 Hussein Prospective Streptokinase 11 12 33 (4/12) 17 (2/12)

and el
Dorri
18 1997 Kubota Case report Urokinase 1 4 yr 2 mo 100 (1/1) 100 (1/1)
et al.
 Vol. 26, No. 6, August 2012
Table V. Spinal cord stimulators and Buerger’s disease
Time % Improved
Total number Location Mean Time complete % Complete complete % Complete walking % Limb
Reference Year Lead author Study type of patients of lesion Patient follow-up relief of pain relief of pain healing healing distance salvage

19 1999 Swigris Case report 1 Right hand 1 mo 1 mo 100

et al.
20 2002 Chierichetti Case report 3 Left foot a 5d Few wks 100
et al. Right foot b 8 wk 3 mo 100
Right foot c 2d
21 2005 Donas Retrospective 29 4 ± 1.6 yr 72 (21/29) 54 (7/13) 100 (8/8) 93.1 (27/29)
et al.

Table VI. Pedicled omental graft in Buerger’s disease

Total number Mean % Complete % Complete % Improved
Reference Year Lead author Study type Description of patients follow-up relief of pain healing walking distance % Limb salvage

22 1996 Singh and Retrospective Pedicled omental graft 50 4 yr 89 (32/36) 96 (48/50) 100 (50/50)
Ramteke
23 2000 Talwar Retrospective Pedicled omental graft 62 3.5 yr 94 (29/31) 83 (24/29) 92 (29/31) 100 (29/29)
et al.

Buerger’s disease 875

 876 Dargon and Landry
Table VII. Lumbar sympathectomy in Buerger’s disease
Lead Total number Mean % Complete % Complete % Improved
Reference Year author Study type Description of patients follow-up relief of pain healing walking distance % Limb salvage

16 2006 Bozkurt Prospective, Lumbar 78 4 wk 41

et al. randomized sympathectomy 6 mo 52.3
versus IV iloprost

IV, intravenous.

Table VIII. Immunomodulation in Buerger’s disease

Total number Mean % Complete % Complete % Improved
Reference Year Lead author Study type Description of patients follow-up relief of pain healing walking distance % Limb salvage

24 2001 Saha et al. Prospective Cyclophosphamide 12 1 yr 100 (6/6) 33 (3/9) Yes

Annals of Vascular Surgery

25 2011 Baumann et al. Prospective Immunoadsorption 10 6 mo 100 (10/10) 100 (10/10) 100 (10/10) 100 (10/10)
 Vol. 26, No. 6, August 2012
Table IX. Therapeutic angiogenesis in Buerger’s disease
Total Number % Improved %
number of limbs Mean % Complete % Complete walking % Limb Adverse
Reference Year Lead author Study type Description of patients studied follow-up relief of pain healing distance salvage event

26 1998 Isner Prospective, IM phVEGF165 6 7 14 mo 50 (3/6) 33 (2/6) 71 (5/7)

et al. nonrandomized gene transfer
27 2006 Miyamoto Prospective Bone marrow 8 11 23 ± 18 mo 36 (4/11) 88 (7/8) 100 (8/8) 50 (4/8)
et al. mononuclear
cell
28 2006 Kim et al. Prospective Fenestrated 27 34 19.1 ± 3.5 mo 3 (1/34) 76 (13/17)
bone marrow
mononuclear
cell
29 2006 Durdu Prospective Bone marrow 28 16.6 ± 7.8 mo 83 (15/18) 100 (28/28) 100 (28/28)
et al. mononuclear
cell
30 2006 Kim et al. Prospective Umbilical cord 4 16.5 mo 100 (4/4) 100 (2/2) 100 (4/4)
blood
31 2007 Saito et al. Prospective Bone marrow 14 24 wk 63 (12/19)
mononuclear
cell
32 2007 Saito et al. Prospective Bone marrow 7 16 wk 57 (4/7) 57 (4/7)
mononuclear
cell and
hyperbaric
oxygen
33 2008 Motukuru Prospective Bone marrow 33 6 mo 24 (8/33) Unknown 88 (22/25)
et al. mononuclear (7/)
cell
34 2009 Boda et al. Prospective Bone marrow 4 12 mo 100 (4/4) 50 (2/4) 100 (4/4) 100 (4/4)
mononuclear

Buerger’s disease 877

cell

IM, intramuscular.
Table X. Limb salvage rates of different treatment modalities in Buerger’s disease

878 Dargon and Landry

Number of
Total patients/
number limbs Mean % Minor % Major % Total % Limb
Reference Year Lead author Description of patients treated follow-up amputation amputation amputation salvage

8 1997 Sasajima et al. Crural/below ankle 61 71 39.2 (11/28)

9 1998 Bozkurt et al. Bypass with PTFE 258 14 73 mo 35.7 (5/14) 7 (1/14) 42.7 (6/14) 93 (13/14)
11 2002 Dilege et al. 9 fem-peron 36 24 36 mo 8.3 (2/24) 92 (22/24)
7 fem-PT
5 fem-AT
3 fem-pop
6 2004 Ohta et al. 1 femoral 110 31 10.6 yr 30.9 (34/110) 11.8 (13/110) 42.7 (47/110) 91.4, 1 yr
3 above-the-knee pop 88.6, 5 yr
8 below-the-knee pop 85.4, 10 yr
34 crural
12 2006 Ates et al. 30 fem-pop/-tib + LS 344 47 11.6 ± 7.1 yr 39.5 (136/344) 5.5 (19/344) 45 (155/344)
17 fem-pop/-tib
14 1998 European TAO Oral iloprost (low) 319 106 6 mo 4.7 (5/106) 95
Oral iloprost (high) 110 3.6 (4/110) 96
Placebo 103 8.7 (9/103) 91
17 1993 Hussein and Streptokinase 11 11 16.6 (2/12) 66.6 (8/12) 83.2 (10/12) 33 (4/12)
el Dorri
18 1997 Kubota et al. Urokinase 1 1 4 yr 100 (1/1)
21 2005 Donas et al. Spinal cord stimulator 29 29 4 ± 1.6 yr 13.8 (4/29) 6.9 (2/29) 20.7 (6/29) 93.1 (27/29)
22 1996 Singh and Pedicled omental graft 50 50 4 yr 2 (1/50) 100 (50/50)
Ramteke
23 2000 Talwar et al. Pedicled omental graft 62 62 3.5 yr 0 (0/29) 100 (29/29)
25 2011 Baumann et al. Immunoadsorption 10 10 6 mo 100 (10/10)
26 1998 Isner et al. IM phVEGF165 gene 6 7 14 mo 14.3 (1/7) 28.6 (2/7) 42.9 (3/7) 71 (5/7)
transfer
27 2006 Miyamoto et al. Bone marrow 8 8 23 ± 18 mo 25 (2/8) 0 (0/8) 25 (2/8) 100 (8/8)
mononuclear cell
29 2006 Durdu et al. Bone marrow 28 28 16.6 ± 7.8 mo 3.6 (1/28) 0 (0/28) 3.6 (1/28) 100 (28/28)
mononuclear cell

Annals of Vascular Surgery

30 2006 Kim et al. Umbilical cord blood 4 4 16.5 mo 100 (4/4)
32 2007 Saito et al. Bone marrow 7 7 16 wk 42.9 (3/7)
mononuclear cell and
hyperbaric oxygen
33 2008 Motukuru et al. Bone marrow 33 33 6 mo 12 (3/25) 88 (22/25)
mononuclear cell
34 2009 Boda et al. Bone marrow 4 4 12 mo 0 (0/4) 100 (4/4)
mononuclear cell
Vol. 26, No. 6, August 2012 Buerger’s disease 879

Table IV summarizes the use of thrombolytics in

Buerger’s disease. There have been very few studies

PTFE, polytetrafluoroethylene; fem-, femoro-; -peron, peroneal; PT, posterior tibial; AT, anterior tibial; -pop, popliteal; -tib, -tibial; LS, lumbar sympathectomy; IM, intramuscular.
on this modality of treatment in Buerger’s disease.
Table V summarizes the use of spinal cord stimu-
lators. The true mechanism behind their effect in
Buerger’s disease is still unknown. It is thought
that the electrical stimulation causes analgesia and
inhibits vasoconstriction mediated by the sympa-
thetic nerve.
10.4 (30/287) 27.1

25.2

Table VI summarizes the use of omental grafts in

27

23

India for treating leg ulcers and providing a vascular-

ized wound bed for healing.
Table VII summarizes a study that compared
intravenous iloprost versus sympathectomy. The
iloprost data are presented in Table I. The lumbar
10

23

sympathectomy data from the same study are pre-

sented here.
16.7 (48/287)

Table VIII summarizes the use of immune modu-

lation in treating Buerger’s disease. Cyclophospha-
mide was started parenterally and continued orally
to suppress autoantibodies. The mechanism of
17

action of immunoadsorption in treating Buerger’s

disease is not known, and it is thought to be due
to the removal of pathogenic immunoglobulin
15.6 yr

from the circulation.

7.6 yr
19 yr

Table IX summarizes the current focus of treating

Buerger’s disease with therapeutic angiogenesis.
Most studies have used autologous bone marrow
cells, which are rich in EPCs. EPCs are known to
secrete proangiogenic factors to drive angiogenesis.
One study in 1998 used gene therapy to promote
angiogenesis. Therapeutic angiogenesis appears to
be safe, and only one study in 2006 reported a single
287

850
111
89

death.
Table X summarizes the limb salvage rates of the
previously described treatment modalities. Major
amputation is described as above-the-knee or
below-the-knee amputation or hand amputation.
Limb salvage was defined as an intervention that
Epidemiology
Epidemiology

Epidemiology
Epidemiology

prevented a major amputation. The rates of minor

and major amputations are also summarized. One
study showed that at 11.6 years, the finger amputa-
tion rate was 39.5% and the total amputation rate
was 45%.12 Another study had a similar finger
1999 Shigematsu and

amputation rate, 35.7%, at 6.1 years.9 Finally, the

Shigematsu

2004 Cooper et al.

2000 Sasaki et al.

risk of major amputation was reported to be 11%

1990 Olin et al.

at 5 years and 23% at 20 years.38 The high rates of

amputation are due to continued smoking leading
to progression of disease.

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