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Review Article

Current Concepts CAUSE AND PATHOGENESIS


The cause of Buerger’s disease is unknown. How-
ever, use of or exposure to tobacco is central to the ini-
T HROMBOANGIITIS O BLITERANS tiation and progression of the disease.11 There is an ex-
(B UERGER ’ S D ISEASE ) tremely strong association between the heavy use of
tobacco and thromboangiitis obliterans.12,13 Throm-
boangiitis obliterans is more common in countries
JEFFREY W. OLIN, D.O.
with heavy use of tobacco. There is an extremely
high prevalence of thromboangiitis obliterans in In-
dia among people of low socioeconomic class who
smoke bidis (homemade cigarettes with raw tobac-

T
HROMBOANGIITIS obliterans (Buerger’s
co).14 There have been occasional cases of throm-
disease) is a nonatherosclerotic segmental in-
boangiitis obliterans in users of smokeless tobacco or
flammatory disease that most commonly affects
snuff.15,16 Although a few investigators believe that
the small and medium-sized arteries, veins, and nerves
Buerger’s disease can occur in nonsmokers,17 most
of the arms and legs.1 Von Winiwarter first described
view current or past smoking as a requirement for the
a patient with thromboangiitis obliterans in 1879.2
diagnosis.7,11,18-21
Twenty-nine years later, Leo Buerger provided a de-
Using an antigen-sensitive thymidine-incorporation
tailed and accurate description of the pathological
assay, Adar and colleagues 22 found an increased cellular
findings in 11 amputated limbs.3 Thromboangiitis ob-
sensitivity to types I and III collagen (normal con-
literans differs from other forms of vasculitis in some
stituents of human arteries) in patients with throm-
important ways. Pathologically, there is a highly cel-
boangiitis obliterans, as compared with patients with
lular and inflammatory thrombus with relative spar-
arteriosclerosis obliterans or normal men. In a study
ing of the blood-vessel wall. The acute-phase reactants
by Eichhorn et al.,23 7 patients with active thromboan-
(as assessed by the Westergren sedimentation rate and
giitis obliterans had mean serum anti–endothelial-cell
serum C-reactive protein level) are usually normal.
antibody titers of 1857 arbitrary units, as compared
Results of serologic tests for the immunologic mark-
with values of 126 in 30 normal subjects (P<0.001)
ers (circulating immune complexes, complement lev-
and 461 in 21 patients in remission (P<0.01). Al-
els, and cryoglobulins) and the commonly measured
though measuring anti–endothelial-cell antibody ti-
autoantibodies (antinuclear antibody and rheumatoid
ters appears to be a promising method of following
factor) are normal or negative, yet an immune reaction
disease activity in patients with Buerger’s disease, ad-
has been demonstrated in the arterial intima.4
ditional studies are required to delineate further the
Although Buerger’s disease has a worldwide distri-
sensitivity and specificity of this test.
bution, it is more prevalent in the Middle East and Far
There is impaired endothelium-dependent vasore-
East than in North America and western Europe,5,6 in
laxation in the peripheral vasculature of patients with
part because of differences in diagnostic criteria. At
Buerger’s disease.24 Forearm blood flow was measured
the Mayo Clinic, the proportion of patients with the
by plethysmography in the nondiseased limb after the
diagnosis of Buerger’s disease has steadily declined,
infusion of acetylcholine (an endothelium-dependent
from 104 per 100,000 patients in 1947 to 12.6 per
vasodilator) and sodium nitroprusside (an endothe-
100,000 in 1986.6,7 The prevalence of the disease
lium-independent vasodilator). The increase in fore-
among all patients with peripheral arterial disease var-
arm blood flow in response to intraarterial acetyl-
ies from as low as 0.5 to 5.6 percent in western Eu-
choline was lower in patients with thromboangiitis
rope to as high as 45 to 63 percent in India, 16 to
obliterans than in normal subjects (14.1 vs. 22.9 ml
66 percent in Korea and Japan, and 80 percent in Is-
per minute per deciliter of tissue volume, P<0.01),
rael among Jews of Ashkenazi ancestry.8-10
and endothelium-dependent vasodilatation is impaired
even in the nondiseased limbs of patients with throm-
boangiitis obliterans. There was no significant differ-
ence between patients and normal subjects in the in-
From the Heart and Vascular Institute of New Jersey, Morristown. Ad- crease in forearm blood flow in response to sodium
dress reprint requests to Dr. Olin at the Heart and Vascular Institute of nitroprusside (13.1 and 16.3 ml per minute per dec-
New Jersey, 111 Madison Ave., Morristown, NJ 07960, or at olinjw1@
aol.com. iliter, respectively), indicating that nonendothelial
©2000, Massachusetts Medical Society. mechanisms of vasodilatation are intact.

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CURR ENT CONC EP TS

PATHOLOGICAL FINDINGS
In thromboangiitis obliterans, inflammatory throm-
bi affect both the arteries and the veins. The histopath-
ological findings vary according to the duration of the
disease. The findings are most likely to be diagnostic
in the acute phase of the disease, most commonly
when a segment of a vessel with superficial throm-
bophlebitis undergoes biopsy. In the subacute (inter-
mediate) phase of the disease, the findings may be sug-
gestive, but in the chronic or end-stage phase of the
disease, all that remains is organized thrombus and
fibrosis of the blood vessels.25-30
The hallmark of the acute-phase lesion is an occlu-
sive, highly cellular, inflammatory thrombus, with less
Figure 1. Typical Acute Histologic Lesion of Buerger’s Disease
inflammation in the walls of the blood vessels. Poly- in a Vein with Intense Thromboangiitis, Showing a Microab-
morphonuclear leukocytes, microabscesses, and mul- scess in the Thrombus and Two Multinucleated Giant Cells (Ar-
tinucleated giant cells may be present (Fig. 1). rows) (Hematoxylin and Eosin, ¬400).
In the intermediate phase, there is progressive or- Adapted from Lie,5 with the permission of the publisher.
ganization of the thrombus in the arteries and veins.
In all three stages, the normal structure of the vessel
wall, including the internal elastic lamina, generally re-
chemic pain at rest and ischemic ulcerations on the
mains intact. This feature distinguishes thromboangi-
toes, feet, or fingers may develop (Fig. 2).
itis obliterans from arteriosclerosis and from other
At the Cleveland Clinic Foundation, 112 patients
types of systemic vasculitis, in which there is usually
with Buerger’s disease were evaluated and treated be-
striking disruption of the internal elastic lamina and
tween 1970 and 1987.11 Their demographic charac-
the media.13
teristics and presenting clinical symptoms and signs
Although Buerger’s disease most commonly affects
are shown in Table 1. Seventy-six percent of the pa-
the small and medium-sized arteries and veins in the
tients had ischemic ulcerations at the time of presen-
arms, hands, legs, and feet, it has been reported in
tation.11
many other vascular beds. There are case reports of
In Shionoya’s series, all patients with Buerger’s dis-
involvement of the cerebral arteries, coronary arter-
ease had more than one involved limb.19 Two limbs
ies, renal arteries, mesenteric arteries, aorta, pulmo-
were affected in 16 percent of patients, three limbs in
nary arteries, and iliac arteries.31-35 Multiple-organ in-
41 percent, and all four limbs in 43 percent. Because
volvement in thromboangiitis obliterans has also been
of the likelihood of involvement of more than one
observed.36,37 When thromboangiitis obliterans oc-
limb, it is advisable to obtain an arteriogram of both
curs in unusual locations, the diagnosis should be
arms, both legs, or all four limbs in patients who
made only when histopathological examination iden-
present with clinical involvement of only one limb. It
tifies the acute-phase lesion.
is not uncommon to see arteriographic abnormalities
CLINICAL FEATURES consistent with Buerger’s disease in limbs that are not
yet clinically involved.
Buerger’s disease typically occurs in young male In patients with leg ulceration in whom Buerger’s
smokers, with the onset of symptoms before the age disease is a possibility, the Allen test should be per-
of 40 to 45 years. Several published series have shown formed to assess the circulation in the hands and
an increasing prevalence of the disease in women, fingers40,41 (Fig. 3). An abnormal result on the Allen
ranging from 11 percent to 23 percent.7,11,18 Howev- test in a young smoker with leg ulcerations is highly
er, the prevalence among women in Japan and other suggestive of thromboangiitis obliterans, since it dem-
Asian countries remains low, despite increased smok- onstrates small-vessel involvement in both the arms
ing by Asian women.19,38 and the legs. An abnormal result can also be present
Buerger’s disease usually begins with ischemia of in other types of small-vessel occlusive disease of the
the distal small arteries and veins. As the disease pro- hands, such as scleroderma, the CREST syndrome
gresses, it may involve more proximal arteries. Involve- (calcinosis cutis, Raynaud’s phenomenon, esophageal
ment of the large arteries is unusual and rarely oc- dysfunction, sclerodactyly, and telangiectasia), repet-
curs in the absence of small-vessel occlusive disease.39 itive trauma (vibratory-tool use or hypothenar ham-
Patients may present with claudication of the feet, mer syndrome), emboli, hypercoagulable states, and
legs, hands, or arms. Foot or arch claudication may be vasculitis. The distal nature of thromboangiitis oblit-
mistaken for an orthopedic problem. As the disease erans and the involvement of the legs and arms help
progresses, typical calf claudication and eventually is- to differentiate it from atherosclerosis.

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 1. DEMOGRAPHIC CHARACTERISTICS AND


PRESENTING SYMPTOMS AND SIGNS OF 112 PATIENTS
WITH THROMBOANGIITIS OBLITERANS,
1970 THROUGH 1987.*

VARIABLE VALUE

Mean age — yr 42
Male sex — no. (%) 86 (77)
Intermittent claudication — no. (%) 70 (62)
Pain at rest — no. (%) 91 (81)
Ischemic ulcers — no. (%) 85 (76)
Arm 24 (21)
Leg 39 (35)
Both 22 (20)
Thrombophlebitis — no. (%) 43 (38)
Raynaud’s phenomenon — no. (%) 49 (44)
Sensory findings — no. (%) 77 (69)
Abnormal Allen-test result — no. (%) 71 (63)

*Data are from Olin et al.11

and Scl-70); and screening for hypercoagulability, in-


cluding tests for antiphospholipid antibodies.
A proximal source of emboli may be ruled out by
echocardiography (transthoracic, transesophageal, or
both) and arteriography. The angiographic features
of Buerger’s disease are involvement of the small and
medium-sized vessels, such as the palmar, plantar, tib-
ial, peroneal, radial, and ulnar arteries and the digital
arteries of the fingers and toes; segmental occlusive
Figure 2. Ischemic Ulcers on the Distal Portion of the Left Great lesions (diseased arteries interspersed with normal-
Toe and Second Toe in a Patient with Acute Buerger’s Disease. appearing arteries); more severe disease distally, and
There is superficial thrombophlebitis on the dorsum of the foot normal proximal arteries with no evidence of athero-
(arrows). sclerosis; collateralization around areas of occlusion
(corkscrew collaterals) (Fig. 4); and no apparent source
of emboli.42-45 The disease is usually confined to the
distal circulation and is almost always infrapopliteal
Superficial thrombophlebitis occurs in approxi- in the legs and distal to the brachial artery in the arms.
mately 40 percent of patients with thromboangiitis Arteriographic findings may be suggestive but are not
obliterans (Fig. 2).11 The thrombophlebitis may be mi- pathognomonic. The arteriographic findings in Buer-
gratory and may parallel disease activity.12 Raynaud’s ger’s disease may be identical to those in scleroderma,
phenomenon is present in approximately 40 percent the CREST syndrome, systemic lupus erythematosus,
of patients. rheumatoid vasculitis, mixed connective-tissue disease,
and the antiphospholipid-antibody syndrome. The
Laboratory and Arteriographic Findings presence of diabetes mellitus rules out the diagnosis
There are no specific laboratory tests to aid in the of thromboangiitis obliterans.
diagnosis of thromboangiitis obliterans. A complete
serologic profile should be obtained, including a com- Diagnostic Criteria
plete blood count with differential count; liver-func- Several different criteria have been proposed for the
tion tests; renal-function tests; urinalysis; measurement diagnosis of thromboangiitis obliterans. Papa et al.46
of blood sugar while the patient is fasting, acute-phase have proposed various clinical, angiographic, histo-
reactants (Westergren sedimentation rate and C-reac- pathological, and exclusionary criteria and have de-
tive protein), antinuclear antibody, rheumatoid factor, vised a scoring system. Mills and Porter 47 have pro-
complement, and serologic markers for the CREST posed major and minor diagnostic criteria. The clinical
syndrome and scleroderma (anticentromere antibody criteria of Shionoya20,48 are a history of smoking, on-

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C URR ENT CONC EP TS

B
Figure 4. Angiogram of the Hand Showing Multiple Occlusions
of the Digital Arteries, with Collateralization (“Corkscrew Collat-
erals”) around the Areas of Occlusion (Arrows).
Reprinted from Olin and Lie,41 with the permission of the pub-
lisher.

set before the age of 50 years, infrapopliteal arterial


occlusions, either arm involvement or phlebitis mi-
grans, and the absence of risk factors for atheroscle-
rosis other than smoking. Our criteria are an age of
Figure 3. The Allen Test.
less than 45 years and current (or recent) history of
In the Allen test, the patient is instructed to make a fist, which
will empty the blood from the hand and fingers (Panel A). The
tobacco use; the presence of distal-extremity ischemia
examiner’s thumbs are then pressed down across the thenar (indicated by claudication, pain at rest, ischemic ul-
and hypothenar eminences to the wrist to occlude the radial cers, or gangrene) documented by noninvasive vascu-
and ulnar arteries. The patient then opens the hand, making lar testing; exclusion of autoimmune diseases, hyper-
sure not to overextend the fingers, since this can cause a false
positive result. The pressure on the ulnar artery is then re-
coagulable states, and diabetes mellitus by laboratory
leased while the radial artery is still compressed (Panel B). The tests; exclusion of a proximal source of emboli by
hand does not fill with blood. Note the paleness of the hand on echocardiography and arteriography; and consistent
the right compared with the hand on the left, indicating occlu- arteriographic findings in the clinically involved and
sion of the ulnar artery distal to the wrist (positive test result). noninvolved limbs.11,13 A biopsy is rarely needed un-
If there is prompt return of color to the hand (indicating a neg-
ative test result), the pressure on the radial artery is released
less the patient presents with unusual characteristics,
while the ulnar artery remains compressed. Reprinted from such as large-artery involvement or an age of more
Olin and Lie,41 with the permission of the publisher. than 45 years.

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TREATMENT There is little information on the use of intra-arte-


rial thrombolytic therapy57,58 in the treatment of Buer-
The only proven strategy to prevent progression ger’s disease. Hussein and el Dorri57 used selective
of the disease and avoid amputation is the complete low-dose intraarterial streptokinase (a 10,000-unit bo-
discontinuation of cigarette smoking or other use of lus followed by 5000 units per hour) in 11 patients
tobacco in any form.11,49-51 Even smoking one or two with long-standing Buerger’s disease who had gan-
cigarettes a day, using smokeless tobacco (chewing grene or pregangrenous lesions of the toes or feet.
tobacco or snuff ), or using nicotine replacement may They reported an overall success rate (defined as avoid-
keep the disease active.15,16 Among 120 patients with ance or alteration in the level of amputation) of 58
Buerger’s disease, 43 percent had discontinued cig- percent. Further study will be required to determine
arette smoking after an average of 7.6 years of fol- the role of thrombolytic therapy.
low-up.52 If there was no gangrene when the patient Surgical revascularization is usually not possible for
discontinued smoking, amputation did not occur. patients with Buerger’s disease, because of the diffuse
Overall, 94 percent of those who quit smoking avoid- segmental involvement and distal nature of the disease.
ed amputation, whereas 43 percent of those who con- Often no distal target vessel is available for bypass sur-
tinued smoking required one or more amputations. gery. However, if the patient has severe ischemia and
One patient had 18 different operations, resulting in there is a distal target vessel, bypass surgery with the
bilateral amputations above the knees and above the use of an autologous vein should be considered.59-61
elbows.37 Sasajima and colleagues61 reported a five-year rate of
There is a misconception that it is extremely diffi- primary patency of 49 percent and a rate of second-
cult to get patients with thromboangiitis obliterans to ary patency of 62 percent in 61 patients after infrain-
discontinue smoking. In fact, it may be easier to per- guinal bypass. The patency rates were 67 percent in
suade patients with Buerger’s disease to stop smok- those who discontinued smoking and 35 percent in
ing than patients with atherosclerosis.11,52 Physicians those who continued to smoke.61 Another surgical
must educate and counsel their patients repeatedly approach is omental transfer.62,63 Singh and Ramteke62
about the importance of discontinuing the use of all reported on 50 patients with thromboangiitis oblit-
tobacco products. Patients can be reassured that if erans who underwent omental transfer for pain at
they are able to discontinue tobacco use, the disease rest, nonhealing ischemic ulcers, or both. All patients
will remit and amputation can be avoided. The cor- had an improvement in skin temperature, and 36 pa-
relation between smoking and disease activity is so tients had decreased pain at rest. The ulcers healed in
strong that if the patient claims to have stopped us- 32 of 36 patients. Surgical therapy for thromboangi-
ing tobacco and the disease is still active, measure- itis obliterans is uncommon in the United States, both
ments of urinary nicotine and cotinine (a metabolic because a reasonable target vessel for bypass is usu-
byproduct of nicotine) should be performed. These ally not found and because most patients do very well
tests will help determine whether the patient is still if they are able to discontinue smoking.
smoking, using nicotine-replacement products, or be- The role of sympathectomy in preventing amputa-
ing exposed to large amounts of environmental to- tion or treating pain remains unclear.11,38 Occasionally,
bacco smoke.53,54 Patients may continue to have clau- sympathectomy may help the healing of superficial
dication or Raynaud’s phenomenon even after the ischemic ulcerations. We recently treated a patient with
complete discontinuation of tobacco use, however. a spinal cord stimulator, resulting in complete healing
Except for discontinuation of tobacco use, no forms of all arm ulcerations when all other conservative meas-
of therapy are definitive. Fiessinger and Schafer55 con- ures had failed.64 Isner and colleagues65 reported the
ducted a prospective, randomized, double-blind trial use of intramuscularly administered vascular endothe-
comparing the effects of a six-hour daily infusion of lial growth factor gene therapy in seven limbs of six
iloprost (a prostaglandin analogue) with those of as- patients with Buerger’s disease. Ischemic ulcers healed
pirin. Iloprost was superior to aspirin at 28 days, with in three of five limbs in four patients, and the other
total relief of pain at rest and complete healing of all two patients had relief of pain at rest.
trophic changes. At six months, 88 percent of the pa-
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C URR ENT CONC EP TS

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