Buerger Disease 1

138 CHAPTER
Thromboangiitis Obliterans
(Buerger Disease)
AHMET RÜÇHAN AKAR and BAHADIR INAN
INTRODUCTION 1809 Pharmacologic Treatment 1821

Definition 1809 Calcium Channel Blockers 1821
Brief Historical Review 1810 Prostacyclin Analogs 1821
EPIDEMIOLOGY 1810 Prostaglandin E1 Analogs 1822
Population Affected 1810 Phosphodiesterase Inhibitors 1822
Risk Factors 1811 Endothelin Receptor Antagonists 1822
Etiology 1811 Thrombolytics 1822
Immune-Mediated Injury 1811 Folate Supplementation 1822
Genetic Predisposition 1812 Statins 1822
Hypercoagulability 1812 Analgesia 1823
Oral Infection-Inflammatory Pathway 1812 Surgery 1823
Vascular Endothelium and Circulating Progenitor Lumbar or Thoracic Sympathectomy 1823
Cells 1812 Distal Surgical Revascularization 1823
Pathology 1812 Pedicled Omental Graft 1823
CLINICAL PRESENTATION 1813 Distal Venous Arterialization 1824
DIAGNOSIS 1816 Local Wound Care 1824
Vascular Evaluation 1816 Endovascular Treatment 1824
Noninvasive Testing 1816 Other Interventional Procedures 1824
Laboratory Testing 1818 Immunoadsorption 1824
Angiography 1818 Growth Factors 1825
Biopsy 1819 Stem Cell-Based Therapeutic Angiogenesis 1825
Differential Diagnosis 1819
Natural History 1820
TREATMENT 1821
Lifestyle Changes 1821
Smoking Cessation 1821
Exercise Training 1821
Foot, Hand, and Dental Care 1821
primarily involving infrapopliteal and infrabrachial medium and

INTRODUCTION small-sized arteries and veins.1-5 It is predominantly a disease of
young men, with onset typically before the age of 45 to 50
Definition years.1,4-6 The prevalence in women, however, has been increasing
Thromboangiitis obliterans (TAO), also known as Buerger disease likely related to increased tobacco use.1,7,8 The disease is more
(BD) or von Winiwarter-Buerger syndrome, is a chronic, non- common among people of Middle East, Asia, Mediterranean
atherosclerotic, segmental, obliterative, inflammatory vasculopathy region, and Eastern Europe but is rare in Africa, central Europe,
1809
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CHAPTER 138 Thromboangiitis Obliterans (Buerger Disease) 1809.e1
Abstract Keywords
Buerger disease (BD) is a chronic, inflammatory vasculopathy Buerger disease
primarily involving infrapopliteal or infrabrachial medium and Thromboangiitis Obliterans
small-sized arteries and veins typically detected in men before Vasculitis
the age of 50 years. Features of advanced BD include ischemic Critical Limb Ischemia
ulcerations and digital gangrene as a result of critical limb Ischemic ulcers
ischema. Smoking cessation is the first line therapy for BD, Revascularization
and revascularization is often not feasible. Intravenous iloprost Stem Cells
is an effective treatment option for patients with critical limb Intravenous prostanoids
ischemia. Endothelin receptor antagonists, immunoadsorption, Endothelin receptor antagonists
growth factors, and gene and stem cell-based therapies may
have a role for the treatment of patients with BD and critical
limb ischemia.
1810 SECTION 21 Nonatherosclerotic Arterial Diseases
and America. TAO is typically manifested by distal extremity

ischemia involving the feet, legs, or hands as a result of infrapopliteal TABLE 138.1 Proportion of Thromboangiitis Obliterans
or infrabrachial occlusive disease leading to critical limb ischemia Patients Within Peripheral Vascular
(CLI). Advanced TAO features are rest pain, ischemic ulcerations, Disease Throughout the World
and digital gangrene. Region/Country % Reference
TAO develops as response to environmental factors primarily
North America 0.75 42, 48-51
with smoking resulting in major and minor amputations with
high degree of morbidity and disability resulting in unemployment, Western Europe 0.5-5.6 42, 48-51
psychological, behavioral, social, and financial costs. Pathologically, Eastern Europe 3-39 45, 50, 52
TAO is characterized by a highly cellular arterial thrombus, Poland 3.3 32
extensive intimal inflammation, and preserved all layers of the Turkey 6.6 154
arterial wall including internal elastic lamina.9 The disease fre- Mediterranean 3-39 35, 304, 370
quently involves adjacent or superficial veins and nerves. TAO
Israel (Jews of Ashkenazi ancestry) 80 62
is classified under nonnecrotizing, nongranulomatous medium
and small vessel vasculitis.7 However, TAO has not been included Japan 16 138, 371, 372
in the revised 2012 Chapel Hill consensus conference nomen- Korea 66 1
clature of vasculitides.10,11 Absence of markers of inflammation India 45-63 1
and autoantibodies is unique for TAO in comparison to other
types of vasculitis.1,12 Patients experience periods of acute exacerba-
tion leading to CLI associated with smoking. Remissions follow
abstinence from tobacco or occur in the fifth to sixth decades
of life. Rare reports of cerebral, coronary, visceral, ophthalmic, EPIDEMIOLOGY
and multiorgan involvements have also been described. Reduction
in extremity amputation rate can be achieved by smoking cessation.
Population Affected
For optimal outcome, multidisciplinary approach is required TAO is found worldwide, and it affects both sexes and all
for the management of TAO patients including vascular surgery, races.1,7,12,29,31 However, the incidence varies by geographic
rheumatology, hematology, dermatology, smoking cessation location (Table 138.1) and with uneven gender distribution.1,32-35
counseling, dental care, rehabilitation medicine, analgesia, and Buerger’s view of the disease as being largely restricted to the
wound care specialists. Jewish race is no longer valid.18,36 TAO is more common
among people of the Middle East, Asia, the Mediterranean,
and Eastern Europe but is rare in Africa, central Europe,
Brief Historical Review and America. TAO has a striking predominance in men,
Reports resembling TAO have appeared in medical writings especially in series reported before 1960. The reported incidence
since the mid-1800s, but the cases were labeled arteriosclerosis of TAO in women was less than 1% in most published
obliterans (ASO) or frostbite because of the lack of pathologic series in that era.37 Indeed, only 2 of Buerger’s 500 reported
confirmation.13 In 1879, Felix von Winiwarter described a cases were women.18 However, TAO is no longer exclusively
57-year-old man with a prolonged history of foot pain that seen in male population.7,38-41 Over the last three decades,
eventually progressed to gangrene and limb loss, which is now this apparent gender discrimination for TAO is disappearing,
recognized as the first published case of a patient with CLI.1,13,14 probably as a result of the rising use of tobacco products by
In 1898, Haga reported similar clinical features resulting in young women.3,39,42 In recent series, 9.8% to 23% of patients
spontaneous gangrene.15 In 1908, Leo Buerger described a new were women.3,8,33,43,44 Currently, TAO affects men at a 5-fold
and unusual form of progressive vaso-occlusion in Polish and to 10-fold higher rate than women.3,29,33,38,44,45 A limited number
Russian immigrants with who underwent amputation for of pregnancies among patients with active TAO have also been
“Spontan-gangrän.”16 Based on his findings, Buerger called the reported.46-49
disease “thromboangiitis obliterans” to distinguish it from ASO. There was an eightfold decrease in the annual incidence of
Subsequently, Buerger emphasized the association of migrating TAO at the Mayo Clinic, which has steadily declined from 104
thrombophlebitis with thromboangeitis.17 Buerger’s 32-chapter, per 100,000 patient registrations in 1947 to 12.6 per 100,000
628-page monograph entitled “The Circulatory Disturbances patient registrations in 1986.8,50 The number of new
of the Extremities” was published in 1924.18 Allen and Brown patients with TAO in Japan has also been decreasing,51 the ratio
reviewed 200 patients diagnosed with TAO who were evaluated of TAO to ASO patients has declined from 1 : 3 in 1990s to
at the Mayo clinic from 1922 to 1926.19 However, between 1 : 10 after 2000 in Japan.51 Currently, TAO affects approxi-
the 1930s and 1960s, numerous investigators expressed skepti- mately 10 in 100,000 people in the European Union (estimated
cism concerning the identity of TAO.20-22 In the early 1960s, from the applications to the Committee for Orphan Medicinal
several authorities considered TAO a distinct diagnosis that Products). The number of patients affected by TAO is estimated
should be separated from ASO.23-27 Today, TAO is accepted as about 51,000 in European Union, and 4000 in Japan.52
a definite medium and small vessel vasculitis with a typical Pooled characteristics of patients with TAO are listed
clinical picture, natural history, and histopathology.1,4,8,28-30 in Table 138.2.
CHAPTER 138 Thromboangiitis Obliterans (Buerger Disease) 1811
induced by cocaine, amphetamines, and cannabis addiction

TABLE 138.2 Pooled Characteristics of Patients With can closely mimic TAO symptoms68-73 or may accelerate TAO
Thromboangiitis Obliterans From onset and presentation.73 Furthermore, a close relation between
Different Regions Globally long-term arsenic exposure from artesian well water and endemic
Prevalence Uncommon blackfoot disease has been reported in Taiwan.74,75 In fact, arsenic
Prevalence in woman Increasing
adulteration of tobacco as a causative agent for TAO has been
suggested in populations smoking bidis or kawung.66,76-78
Incidence Declining
Involved arterial size Small and medium
Age at diagnosis (years) 29-42
Etiology
Age at hospital admission (years) 42.5 ± 8.4 The etiology of BD is unknown; however, the close association
Male, % 77-98 between disease activity and use of tobacco in any form is
Female, % 2-23
beyond any debate.1,8,34,55,79-81 Genetic predisposition, immune-
mediated mechanisms, hypercoagulable states, endothelial
History of smoking, % 93-94
dysfunction, and an oral infection-inflammatory pathway have
Intermittent claudication, % 17-62 been implicated as potential etiologic factors.44,82-84
Rest pain, % 13-89
Ischemic ulcers and gangrene, % 38-85 Immune-Mediated Injury
Upper extremity 2-28 Several observations implicate an immunologic phenomenon
Lower extremity 35-100 and hypersensitivity to tobacco antigens in the etiology of TAO.85
Both 16-20
It is clearly demonstrated that there is a close relationship between
Migratory superficial phlebitis, % 34-62 active smoking (high levels of urinary cotinine) and the aggrava-
Deep vein thrombosis Unusual tion of TAO.86,87 Increased cellular sensitivity to collagen type
Raynaud’s phenomenon, % 10-45 I,88-90 type III,89 and type IV91 has been reported in patients
Sensory findings, % 69 with TAO compared to ASO patients and healthy male controls.
Abnormal Allen’s test, % 63
Circulating immune complexes have been reported in the
peripheral arteries of some patients with TAO.92-94 It has been
Joint manifestations, % 12.5
suggested that an unidentified antigen possibly related to a
Modified from Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl constituent of tobacco smoke triggers immunologic damage to
J Med. 2000;343:864–869; Puechal X, Fiessinger JN. Thromboangiitis obliterans the arterial intima.95 Recent research has shown that T-cell–medi-
or Buerger’s disease: challenges for the rheumatologist. Rheumatology
(Oxford). 2007;46:192–199; Mills JL, Sr. Buerger’s disease in the 21st century:
ated cellular and B-cell–mediated humoral immunity associated
diagnosis, clinical features, and therapy. Semin Vasc Surg. 2003; 16:179–189; with the activation of macrophages or dendritic cells in the
Ates A, Yekeler I, Ceviz M, et al. One of the most frequent vascular diseases intima play a key role in TAO.9
in northeastern of Turkey: thromboangiitis obliterans or Buerger’s disease Previous studies showed activation of endothelial cells associ-
(experience with 344 cases). Int J Cardiol. 2006;111:147–153; and Igari K, Inoue ated with TNF-alpha secretion by tissue-infiltrating mononuclear
Y, Iwai T. The epidemiologic and clinical findings of patients with Buerger
disease. Ann Vasc Surg. 2016;30:263–269.
inflammatory cells and expression of intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1
(VCAM-1), and E-selectin on endothelial cells in TAO patients.96
Increased levels of TNF-alpha, IL-1beta, IL-4, IL-6, IL-12,
Risk Factors IL-17, and IL-23 and reduced expression of IL-10 were reported
The only risk factor consistently reported is smoking. The strong in patients with TAO compared to the controls suggesting the
correlation between tobacco use and the pathogenesis, initiation, involvement of autoimmune pathology.97,98 An experimental
and progression of the disease is well established.3,6,28,29,31,53-55 study further reported the key role of high-mobility-group box
There is also a higher incidence of TAO among individuals protein 1 (HMGB1) which may contribute to the pathogenesis
with cigar and pipe smoking; habitual home-made cigarette of TAO by binding its receptor RAGE in sodium laurate-induced
smoking such as “bidi” smoking in India, Bangladesh, and TAO rats.99 HMGB1 not only induces the production of
Ceylon;56 “kawung” smoking in Indonesia;57,58 and chewed inflammatory mediators by mononuclear cells, but also activates
“miang” (steamed tea leaves) or “khiyo” (the home-made raw endothelial cells, leading to the upregulation of the adhesion
tobacco in handrolled banana leaves) smoking in Thailand, as molecules. rA box, the antagonist of HMGB1, improved the
well as in users of smokeless tobacco and marijuana.29,59-61 Higher pathologic condition by inhibiting the release and injury of
rate of tobacco consumption and higher carboxyhemoglobin inflammatory mediators and improving the hypercoagulable
levels were detected in patients with TAO than ASO patients state of blood.99 Furthermore, a recent clinical study confirmed
and control subjects.62 Lower socioeconomic status, poor oral significant increases in HMGB-1, MMP-9 and ICAM-1 levels
hygiene, nutritional deficits, a history of viral or fungal infection, compared with controls in patients with TAO.100 Thus, immu-
cold injury, abuse of sympathomimetic drugs, and arsenic nologically mediated inflammation of the vessels is thought to
intoxication are reported as other possible risk factors.9,57,62-67 be the cause of arterial or venous thrombosis and vascular
An emerging body of evidence demonstrates that ischemia occlusions in TAO.
The clinical picture of antiphospholipid syndrome in young force plays a role in the pathogenesis of TAO or simply serves
smokers may mimic TAO symptoms.101 The prevalence of as a marker of enhanced platelet function, endothelial dysfunc-
anticardiolipin antibodies was significantly higher in patients tion, or both remains to be elucidated.
with TAO (36%) than in those with premature atherosclerosis
(8%; P = .01) and in healthy individuals (2%; P = .001).102 Oral Infection-Inflammatory Pathway
Patients with TAO and high anticardiolipin antibodies tended Historically, Buerger and then Allen and Brown suspected that
to be younger and to have a significantly higher rate of major infectious foci, including oral and throat infections, might serve
amputations and poor prognosis than did those without the as contributory factors in TAO.19 Higher prevalence of severe
antibody.103,104 Antineutrophil cytoplasmic antibodies (ANCAs)105 periodontal disease in TAO patients is well documented,82,128,129
and anti-endothelial cell antibodies106 were also reported in suggesting oral infection-inflammatory pathway as a possible
small series of TAO; however, in another study from Germany, etiologic link in TAO.82 Elevated immunoglobulin G titers
ANCA was not detected in any of the active or inactive TAO against Treponema denticola, Porphyromonas gingivalis, and
patients.107 Actinobacillus actinomycetemcomitans were detected in patients
with TAO.128 Furthermore, several bacterial DNAs of periodontal
Genetic Predisposition pathogens were identified in the biopsies from the arterial samples
The importance of a genetic predisposition to tobacco sensitivity and samples of phlebitis migrans in patients with TAO.82,130,131
is debatable.89,95,108 One percent of TAO cases in Japan consisted
of members of the same family.109 Genes of the major histo- Vascular Endothelium and Circulating
compatibility complex, particularly HLA-A9 and HLA-B5, have Progenitor Cells
been linked to TAO in a study from England.110 In Israel, a Endothelium-dependent vasorelaxation was impaired even in
higher frequency of HLA-DR4 and a significantly lower fre- the nondiseased limbs of patients with TAO.132 TAO during
quency of HLA-DRW6 antigen were reported.95 However, in the exacerbation phase is associated with diffuse increase in
the Japanese population, haplotypes of various HLA groups vasomotor tone in the conduit arteries that aggravates ischemia.133
were associated with TAO.111,112 These haplotypes are rare among In another study, similar to ASO patients, flow-mediated
Caucasians. In North Indian patients, there was a strong positive vasodilation was impaired compared to normal control subjects;
association between HLA-DRB1*1501 and TAO.113 Current however, the number and function of circulating progenitor
concepts suggest that the arterial vasospasm of TAO may be cells (CPCs) were restored despite endothelial dysfunction in
caused by an interaction between smoking and several gene patients with TAO.134 Increased levels of plasma endothelin-1
polymorphisms that reduce endogenous nitric oxide, an were also reported during the exacerbation periods of TAO.135
endothelium-derived vasodilator. Recently, higher incidence of
mutations associated with arterial vasospasm; 5A/6A
stromelysin-1, also called matrix metalloproteinase-3; and
Pathology
homozygosity were reported in TAO cases compared to con- The specific pathologic mechanisms in TAO are still unknown.83
trols.114 Findings regarding genetic predisposition of TAO should BD is characterized by segmental inflammatory cell infiltration
be confirmed in larger studies. A recent case-control study from of the vessel wall and arterial or venous thrombotic occlu-
China reported three single-nucleotide polymorphisms, namely sions.9,31,136 Hypercellular thrombus formation and preserved
rs376511 (OR = 24.4, 95% CI: 8.68-68.62, P < .0001), architecture of vessel walls is well established in TAO.137 Earlier
rs7632505 (OR = 29.47, 95% CI: 7.16-121.3, P < .0001), studies suggested TAO as a thrombotic disorder complicated
and rs10178082 (OR = 18.09, 95% CI: 6.56-49.92, P < .0001), by vasculitis, namely transmural neutrophilic infiltration.36,138
are associated with TAO in the Uyghur population.115,116 Today, there are compelling reasons to believe that the primary
event is the activation of antigen-presenting cells following
Hypercoagulability endothelial cell damage induced by an unidentified antigen,
The role of thrombotic risk factors including factor V Leiden possibly tobacco glycoproteins.9,51,95,137 Cellular and humoral
and prothrombin 20210G/A mutations, antithrombin, protein inflammation, which leads to thrombotic occlusion of the blood
C and S deficiency, hyperhomocysteinemia, and platelet aggrega- vessels, is restricted to the intima of the artery, which defines
tion responses in the etiology of TAO remains controversial.117-126 TAO as an endarteritis.9,51 Intimal inflammation followed by
Most authorities have failed to identify a specific hypercoagulable T-cell infiltrations might result in early arterial occlusion, which
state in patients with TAO,29,117 while others have shown one is the pathognomonic finding in TAO.139 Regardless of the
or more abnormalities.117,118 In one study, the level of urokinase- pathologic stage, the internal elastic lamina and the architecture
plasminogen activator was twofold higher and the level of free of the vascular walls are well preserved in TAO, which is in
plasminogen activator inhibitor 1 was 40% lower in patients contrast with atherosclerosis and systemic vasculitis.1,9,36,54,137,140
with TAO than in healthy volunteers.127 Some authors suggest Inflammatory cell infiltration is found in the intimal layer and
that hyperhomocysteinemia may have a role in the pathogenesis the thrombus.9,141
of TAO.120-123 Elevated platelet contractile force values were The evolution of TAO is often categorized into three stages.36
reported in two patients with TAO despite the use of anticoagula- In the acute phase, inflammation affecting the small-caliber
tion drugs and the suppression of adenosine diphosphate– and medium-caliber (1- to 5-mm diameter) arteries and veins
mediated platelet aggregation.125 Whether high platelet contractile is observed (Fig. 138.1). The primary features of TAO during
the acute phase include an occlusive, highly cellular arterial

thrombus, polymorphonuclear cell infiltrate with leukocytoclasis,
giant cells, and microabscess formation; marked inflammation
of the entire vessel wall; and neurovascular bundle.24,50,54
However, most of the infiltrating cells are detected in the intima.51
The intense inflammatory infiltration and cellular proliferation
n seen in acute lesions are distinctive, especially when veins are
involved. Multinucleated giant cells can be seen, but fibrinoid
v necrosis and granuloma are not observed.9 During the intermedi-
ate or subacute phase, there is progressive organization of the
a
occlusive thrombus, with partial recanalization and disappearance
of the microabscesses.9 An inflammatory response, including
CD3+ pan–T cells, CD4+ T helper-inducer cells, and CD20+
pan–B cells, against the internal elastic lamina of the affected
A vessels has been shown in detail (Fig. 138.2).9,139,141 In addition,
CD68+ macrophages or S-100+ dendritic cells are found in
the intima during both the acute and subacute stages.51 IgG,
IgM, and IgA and complement factors 3d and 4c are deposited
i along the inner aspect of the internal elastic lamina.9 The chronic
phase or end-stage lesion is characterized by thrombus organiza-
tion followed by recanalization, prominent vascularization of
the media, and perivascular fibrosis.36,54,136 Regardless of
t the pathologic stage, the internal elastic lamina and the archi-
tecture of the vascular walls are well preserved in TAO, in
contrast with atherosclerosis and other types of systemic vasculitis
(Fig. 138.3).1,9,36,54,140
CLINICAL PRESENTATION
TAO usually presents with distal extremity ischemia in a smoker
B younger than 50 years old,4,142 and the median age at diagnosis
is 34 years.29,143 Characteristically, distal extremity ischemia
involves the feet, legs, hands, or arms (Fig. 138.4A and B); and
as the disease progresses, it may involve more proximal arteries.54
Frequently identified signs and symptoms of TAO are listed in
Table 138.2, and the most common symptoms are forefoot
arch or lower calf claudication as a manifestation of infrapopliteal
occlusive disease.54 Foot claudication is particularly character-
istic,144 but foot or arch claudication may be misattributed to
orthopedic problems. Early symptoms may include coldness
or burning pain in the feet and hands, associated findings of
dependent rubor,145 cyanosis, migratory superficial thrombo-
phlebitis (see Fig. 138.4C),130,146 and Raynaud phenome-
non.3,57,147,148 Patients with TAO commonly report cold sensitivity,
and sensory findings may be one of the earliest manifestations.
In the Cleveland Clinic series reported by Olin and colleagues,
C 69% of cases revealed sensory findings.3 Ischemic neuritis or
Figure 138.1 (A) Typical subacute thrombotic occlusion of the right digital superficial thrombophlebitis may also produce severe pain.149
artery in a 37-year-old male smoker with Buerger disease (H&E, ×64). (B) High- In addition, migrating phlebitis (phlebitis saltans) may occur
power view of area a in A demonstrating the digital artery with cellular arterial as an early sign and has been reported in 40% to 65% of TAO
thrombus (t) and remarkable inflammation in the intima (i) (H&E, ×400). (C) patients during the course of the disease.146,150,151 Ascending
High-power view of area v in A demonstrating the adjacent digital vein with
phlebitis (H&E, ×400). n, Nerve.
venography and histologic investigations suggest that 60% of
the cases have venous involvement.152 Occasionally, superficial
thrombophlebitis may extend into the deep venous system;
however, deep venous thrombosis in BD is unusual151 In the
acute phase of the disease, involved vessels are tender and
indurated and reflect the local inflammatory reaction.
i i
A B
t t
i
C D
i
i
E F
Figure 138.2 (A) Microphotograph of an acute-stage lesion with highly cellular thrombus (t) and inflammatory
infiltration along the vessel wall with increased anti-CD68+ (clone: KP1) histiocytes. (B) High-power view showing
highly cellular thrombus (arrows) and abundant histiocytes in the intimal layer (arrowheads). (C to E) Anti-CD3+
(rabbit polyclonal) stained T cells (C), anti-CD4+ (clone: 1F6) T-helper cells (D), and anti-CD8+ (clone: C8/144B)
cytotoxic T cells (E) in the intimal layer (arrowheads; brown membrane staining, ×400). (F) Deposition of immunoglobulin
G (brown, arrowheads) within the interstitial intimal tissue (×600). Immunohistochemistry was performed with a
Ventana iVIEW DAB detection system. i, Intima.
Late findings may present as trophic nail changes, ischemic amputation, and unemployment-related fears.162 No difference
ulcerations, and digital gangrene,29,35,54,150,153-155 and almost all in clinical presentation in women compared with men has been
ulcers occur in patients between 20 and 50 years of age.156 observed.3,163
Superinfection commonly develops, and the ischemic ulcerations TAO does not occur in only one limb.151 Multiple limb
progress toward necrosis and distal gangrene. At this stage, the involvement is a common feature of TAO.1,54,60,164,165 In the
pain is often excruciating. Ischemic ulcerations often appear series reported by Shionoya, two limbs were affected in 16%
dry and irregular with a pale base and various shapes.40,157 Joint of patients, three limbs in 41%, and all four limbs in 43% of
manifestations, mainly transient, migratory episodes of large patients.164 The Intractable Vasculitis Syndromes Research Group
joint arthritis involving wrist and knees, may occur in approxi- of Japan reported isolated lower extremity involvement in 75%,
mately 12.5% of patients before the onset of digital ische- only upper extremity involvement in 5%, and both upper and
mia.12,151,158,159 Subungual splinter hemorrhages may also be lower extremity involvement in 20% of patients with TAO
detected as an early sign.151,160,161 Coexisting psychological (Table 138.3).166 Therefore, it is recommended that noninvasive
conditions are also common and mainly are anxiety, depression, imaging of all extremities be performed in patients with suspected
A B
Figure 138.3 (A) Microphotograph of a chronic-stage lesion of Buerger disease, with recanalized arterial thrombus
and striking intimal thickening (H&E, ×200). The internal elastic lamina (arrowheads) and the architecture of the
vascular wall are well preserved. (B) The same vessel stained with elastic van Gieson (×200).
A B
C D
Figure 138.4 (A) Ischemic ulceration of the right second toe with a previously amputated great toe in a 42-year-old
man who smoked three packs of cigarettes a day for 15 years. (B) Necrosis of the ends of almost all fingers
led to autoamputation in the same patient after continued smoking. (C) One of the cardinal signs of thromboangiitis
obliterans is superficial thrombophlebitis, seen here on the left leg of a 28-year-old smoker. Note the hairless
skin distally. (D) Infected left metatarsal ulceration with osteomyelitis untreated for several weeks in a 32-year-old
male patient with previous great and 5th toe amputations.
TAO.1,167 It is common to see angiographic abnormalities mesenteric infarction, intestinal perforation, or liver
consistent with TAO in limbs that are not yet clinically involved. hypoxia.169-174,178,180,185-187 Involved vascular beds exhibit similar
Rarely, TAO has been associated with visceral,168-188 cerebral,189-193 pathologic characteristics as vessels in the extremities. Even
coronary,194-203 internal thoracic artery,196,197 and multiorgan rarer are instances of TAO in saphenous vein arterial grafts,207
involvement.204,205 Involvement of the cerebral vessels may result the temporal arteries,208 the ophthalmic circulation,209-211 and
in progressive cognitive decline and migraine,206 transient ischemic intrarenal arterial branches212 of smokers. Also uncommon is
attack, ischemic stroke, or schizophrenia-like symptoms.189-193 the occurrence of TAO in pudendal,213,214 testicular and spermatic
Coronary artery involvement may result in myocardial ischemia arteries and veins, as was originally described by Buerger.18 Rare
or infarction.194-202 Visceral vessel involvement may manifest as cases of nephropathy as a result of mesangial immunoglobulin
abdominal pain, nausea, vomiting, fever, diarrhea, melena, A deposition,215 or renal artery thrombosis; cutaneous manifesta-
weight loss, and anorexia and result in ileus, ischemic colitis, tions presenting as painful nodular erythema with livedo
rest, ischemic ulcers, or gangrene) documented by noninvasive

TABLE 138.3 Distribution of Arterial Involvement in vascular testing; (4) exclusion of autoimmune diseases, hyper-
825 Patients With Thromboangiitis coagulable states, and diabetes mellitus by laboratory tests; (5)
Obliterans (1650 Upper and 1650 exclusion of a proximal source of emboli by echocardiography
Lower Extremities) and arteriography; and (6) consistent arteriographic findings
Lower extremity involvement only 616 (74.7%) in the clinically involved and noninvolved limbs.1,3 All investiga-
Upper and lower extremity arteries 167 (20.2%)
tors accepted the exclusion of atherosclerotic risk factors other
than smoking. Therefore, TAO is a clinical diagnosis, and the
Upper extremity involvement only 42 (5.1%)
diagnosis requires investigations aimed at excluding other possible
Lower Extremity (n = 783) diagnoses.
Anterior tibial artery 683 (41.4%)
Posterior tibial artery 667 (40.4%) Vascular Evaluation
Dorsalis pedis artery 349 (21.2%)
A complete vascular examination is critical for the diagnosis.
Peroneal artery 304 (18.4%)
Physical examination reveals involvement of small and medium-
Popliteal artery 301 (18.2%) sized arteries with normal brachial and femoral pulses. The
Digital arteries 180 (10.9%) radial, ulnar, dorsalis pedis, or posterior tibial pulses may be
Plantar arteries 149 (9.0%) absent. Digital arteries may be occluded. An abnormal Allen
Other 296 (19.8%) test, which suggests ulnar artery occlusion in a young smoker
with lower extremity ulcerations, is highly suggestive of TAO,
Upper Extremity (n = 209)
since abnormal Allen tests occurred in 63% of cases in the
Ulnar artery 189 (11.5%) Cleveland Clinic series.3 Superficial phlebitis may be another
Digital arteries 133 (8.1%) clue to the diagnosis. Neurologic examination may document
Radial artery 115 (7.0%) peripheral nerve involvement, with sensory findings in up to
Superficial or deep palmar arch 75 (4.5%) 70% of patients.1 Calculation of the ankle-brachial index,
Brachial artery 13 (0.8%)
toe-brachial index, and wrist-brachial index at rest and after
exercise is recommended as the initial screening test. Seasonal
Other 26 (1.6%)
variation, with exacerbation of TAO occurring more frequently
Modified from Sasaki S, Sakuma M, Kunihara T, et al. Distribution of arterial in the winter, has been reported;223,224 this may be attributed
involvement in thromboangiitis obliterans (Buerger’s disease): results of a to cold weather and the stimulation of vasospasm and Raynaud
study conducted by the Intractable Vasculitis Syndromes Research Group in
Japan. Surg Today. 2000;30:600–605.
phenomenon.223
Noninvasive Testing
reticularis,216 and avascular necrosis of femoral heads217 have Four-limb segmental arterial pressure measurements and pulse
also been reported. TAO in unusual locations should be diagnosed volume recordings are usually normal above the knee and
only when the histopathologic findings are classic for the acute- markedly reduced distally.80 Abnormal digital plethysmographic
phase lesion and the clinical presentation is consistent with the patterns in both lower and upper extremities would objectively
diagnosis of BD.167 document distal occlusive disease in a patient meeting the clinical
criteria for TAO.29,55,65,79,225 Calcification of the involved arterial
wall is almost always absent on plain radiography,31 and arterial
DIAGNOSIS duplex scanning is used not only to exclude proximal athero-
A century after its first description, the major clinical challenge sclerotic lesions and to demonstrate distal arterial occlusive
in TAO is the absence of universally accepted diagnostic crite- disease, but also to visualize and functionally evaluate the
ria.1,28,218-220 Shionoya has identified five major criteria for the corkscrew shaped collaterals. Using continuous wave Doppler
diagnosis of TAO: (1) smoking history, (2) onset before age ultrasound monophasic waveform pattern within the corkscrew-
50, (3) infrapopliteal arterial occlusive lesions, (4) either upper shaped collaterals is also known as Martorell sign (“snake” or
limb involvement or phlebitis migrans, and (5) an absence of “dot” sign) (Fig. 138.5).226,227 In a recent study from Poland,
atherosclerotic risk factors other than smoking.28 In 1992, Papa Doppler spectral waveform analysis in 40 TAO patients and
and Adar proposed various clinical, angiographic, histopathologic 40 healthy subjects revealed a reduction of reversed diastolic
positive and negative criteria, and in a second report, they flow amplitude with no significant decrease in peak systolic
proposed a point-based scoring system to improve the diagnostic amplitude in patients with TAO.228 The authors concluded that
certainty.55,221 More stringent major and minor supportive criteria decreased vascular resistance may develop as a result of increased
were developed by Mills and Porter, based on a cohort of patients collateral blood flow and low-resistance cutaneous arteries; thus,
in Oregon.222 Olin’s criteria include (1) age less than 45 years; resistance index can be a useful Doppler parameter in the early
(2) current (or recent) history of tobacco use; (3) the presence diagnosis of TAO and probably in monitoring disease progres-
of distal-extremity ischemia (indicated by claudication, pain at sion. Another study confirmed augmented flow-mediated
R
L
ANT TIBIAL
ANT TIBIAL
35mm 60° 36mm 60°
A B
LEFT
DORSALIS
PEDIS
7mm 55° 6mm
C D
E
Figure 138.5 Color-flow Doppler studies demonstrating triphasic flow within the right (A) and left (B) anterior
tibial arteries, monophasic flow within the left dorsalis pedis artery (C), and the “dot” sign because of continuous
flow within corkscrew collaterals at the toe level (D and E).
vasodilation in a corkscrew collateral artery but impaired rhythm monitoring, and echocardiography, are recommended
flow-mediated vasodilation in a native artery in patients with to rule out cardiac and thoracic aortic sources of emboli to the
TAO.229 These findings indicate selective impairment of vascular involved extremity.231 In addition, abdominal ultrasonography
endothelium, but not smooth muscle cells in native arteries in may be considered to rule out a proximal source of emboli
patients with BD.229 Laser Doppler flowmetry, transcutaneous from an abdominal aortic aneurysm or atherosclerotic aorta.
oxygen, and carbon dioxide pressures can help evaluate the Gadolinium-enhanced magnetic resonance angiography and
severity of ischemia and the effectiveness of treatment.230 multidetector computed tomographic angiography (Fig. 138.6)
Emboli as a cause of distal ischemia should be ruled out, as may be useful diagnostic alternatives in patients with TAO.
the signs and symptoms of embolic occlusions can mimic those Furthermore, ischemic ulcerations with signs and symptoms
of TAO. Cardiac investigations, including electrocardiography, of secondary infection should be evaluated using conventional
A B
Figure 138.6 (A and B) Abrupt right tibial vessel occlusion with corkscrew collaterals (arrows) in a 34-year-old
man detected with 64-slice multidetector computed tomographic angiography.
radiography and magnetic resonance imaging to determine the

Angiography
presence of osteomyelitis.232 Recently, 18F-flourodeoxyglucose
positron emission tomography has been investigated in TAO Thoracoabdominal digital subtraction angiography plays an
case series but have been found to be unsuitable investigative important role in both supporting the diagnosis of TAO and
procedure for the diagnosis of TAO.233 ruling out other causes of ischemia. Arteriographic findings in
TAO may be suggestive but not pathognomonic. Thus, this
method is not a “gold standard” for diagnosis. Segmental
Laboratory Testing occlusive lesions (diseased arteries interspersed with normal-
There are no specific laboratory tests for the diagnosis of TAO; appearing arteries), more severe disease distally, involvement of
however, serologic testing for autoimmune antibodies, throm- digital arteries,65 normal proximal arteries without evidence of
bophilia, and vasculitides should be included in the screening atherosclerosis, and collateralization around areas of occlusion
process. Acute-phase reactants, erythrocyte sedimentation rate with corkscrew shape (Martonell sign) also known as “tree root”
(ESR), and C-reactive protein (CRP) are typically normal or or “spider’s leg” collaterals are the common features of TAO
slightly elevated in the absence of extensive trophic lesions. (Fig. 138.7).44,234 The infrapopliteal or infrabrachial arteries are
Absence of immunologic markers including complement levels, the most common sites of occlusion. In addition, small corkscrew
rheumatoid factor (RF), antinuclear antibodies (ANA), anti- patterns (types III and IV) are associated with higher prevalence
centromere antibodies, anti–SCL-70 antibodies, ANCAs, and of ischemic ulcers compared to large corkscrew collaterals (types
cryoglobulins are characteristic for TAO. However, anticardiolipin I and II).235 Although corkscrew collaterals, which represent
antibodies may be present in patients with TAO, and the toxicol- widened vasa vasorum, suggest TAO to many clinicians,44 this
ogy panel should include cocaine, amphetamines, and cannabis. finding is not pathognomonic. In one study, 27% of 144 limbs
A suggested diagnostic algorithm for the diagnosis of TAO is affected by TAO had a corkscrew appearance.236 Corkscrew-
summarized in Table 138.4. shaped collaterals can also be seen in connective tissue diseases
TABLE 138.4 Suggested Diagnostic Algorithm for the Diagnosis of Thromboangiitis Obliterans
1. Young smoker (confirm tobacco, bidi, kawung, cannabis, or cocaine use)
2. Document distal lower or upper extremity ischemic symptoms and signs (claudication, ischemic rest pain, ulcerations, and gangrene)
3. Note the maximal pain-free walking distance, and pain scale (0-10 scale)
4. Document distal nature of disease
• Blood pressure measurements, ankle-brachial and/or ankle-toe pressure indices
• Transcutaneous oxygen tensions
• Arterial duplex scanning
• Intraarterial digital-subtraction angiography (IA-DSA)
• Computed tomographic angiography (CTA)
• Magnetic resonance angiography (MRA)
5. Laboratory tests to exclude connective tissue diseases and hypercoagulable states
• Routine complete blood count and biochemistry including fasting blood glucose, renal function, and liver enzymes
• Thyroid function tests
• Urinalysis
• Lipid profile
• Serum homocysteine, vitamin B12, red blood cell folate
• Coagulation profile: prothrombin time, activated partial thromboplastin time, protein C, protein S, antithrombin III, factor V Leiden,
prothrombin gene mutation 20210, antiphospholipid antibodies, anticardiolipin antibodies
• Autoimmune screen: erythrocyte sedimentation rate, C-reactive protein, complement measurements, antinuclear antibody, antineutrophil
cytoplasm antibody, rheumatoid factor, cryoglobulins, scleroderma-specific antibodies (antibodies SCL-70)
• Measurements of serologic markers for the CREST syndrome (calcinosis, Raynaud phenomenon, esophageal disease, sclerodactyly,
telangiectasia)—Anticentromere antibodies
• Hand radiographs (to exclude calcinosis)
• Hepatitis B, C serology
• Venereal Disease Research Laboratory test
6. Exclusion of proximal sources of emboli
• Electrocardiography, rhythm monitoring
• Echocardiography (transthoracic, transesophageal if necessary)
• Abdominal ultrasonography
• Arteriography (IA-DSA, CTA, MRA)
7. Nielsen digital hypothermic challenge test (Raynaud evaluation)
8. Toxicology screen for cocaine, amphetamine, and cannabis
9. Biopsy indicated only for unusual features
Age >45 years at onset
Documented disease in unusual locations (proximal disease, central nervous system disease)
Modified from Lazarides MK, Georgiadis GS, Papas TT, et al. Diagnostic criteria and treatment of Buerger’s disease: a review. Int J Low Extrem Wounds. 2006;
5:89–95; Mills JL, Sr. Buerger’s disease in the 21st century: diagnosis, clinical features, and therapy. Semin Vasc Surg. 2003;16:179–189; and Olin JW. Thromboangiitis
obliterans (Buerger’s disease). In: Rutherford RB, ed. Vascular Surgery. 6th ed. Philadelphia: Elsevier Saunders; 2005:404–419.
such as scleroderma, CREST syndrome (calcinosis, Raynaud TABLE 138.5 Angiographic Findings in Thromboangiitis
phenomenon, esophageal disease, sclerodactyly, telangiectasia), Obliterans
systemic lupus erythematosus, rheumatoid vasculitis, and the
antiphospholipid-antibody syndrome.1 Furthermore, cocaine, • Involvement of small and medium-sized arteries
amphetamine, or cannabis addiction can cause BD-like clinical Digital arteries of fingers and toes
and angiographic signs.69-72,77,151,237 The angiographic features Palmar, plantar, tibial, peroneal, radial, and ulnar arteries
• Segmental occlusive lesions: diseased arterial segments
that support a diagnosis of TAO are listed in Table 138.5, and interspersed with normal-appearing segments
a study from Japan determined the distribution of arterial • More severe disease distally
involvement in TAO on the basis of a nationwide survey in • Tapering or abrupt arterial occlusions with collateralization
1993 by the Intractable Vasculitis Syndromes Research Group around areas of occlusion: described as “corkscrew collaterals,”
(see Table 138.3).166 “spider leg” or “tree root appearance” (not pathognomonic)
• Normal proximal arteries free of atherosclerosis, aneurysms, or
other sources of emboli
Biopsy
A biopsy is rarely needed unless the patient presents with atypical Differential Diagnosis
features, such as large-artery involvement or age older than 50
years.1 Biopsy of an acute superficial thrombophlebitis often Differential diagnosis of TAO includes a broad range of disorders,
demonstrates the typical histopathologic lesions of acute TAO.50 and diagnostic evaluations should exclude ASO, thromboem-
Kroger suggested that the possibility of arteriosclerosis should bolism, and other vasculitides.7,54,220 TAO differs from ASO
be discounted only in young patients aged 20 to 30 years.220 with infrapopliteal or infrabrachial arterial involvement and
A B C
Figure 138.7 Digital subtraction angiography reveals left popliteal and tibial vessel occlusions with corkscrew
collaterals (arrows) proximally (A) and distally (B) and right radial and ulnar artery involvement (C) in a 32-year-old
man with a nonhealing left toe ulceration.
associated migratory thrombophlebitis. TAO differs from most important features that are distinguishable from other forms
other types of vasculitis with nonnecrotizing, nongranulomatous of vasculitis,167 such as a highly inflammatory thrombus with
inflammation of medium and small size arteries; preserved relative sparing of the blood vessel wall. Preservation of the
internal elastic lamina; and media; and serologic markers (elevated internal elastic lamina distinguishes TAO from the true necrotiz-
acute phase reactants such as ESR and CRP, presence of circulating forms of vasculitis.238-240 Kimura disease presenting with
ing immune complexes, and presence of autoantibodies such Raynaud phenomenon and digital infarcts, and marked
as antinuclear antibody, RF, and complement levels) are usually eosinophilia may mimic TAO symptoms.241
normal or negative.12,54 Causes of distal arterial ischemia,
including scleroderma, CREST syndrome, systemic lupus
erythematosus, Takayasu arteritis, polyarteritis nodosa, giant
Natural History
cell arteritis, rheumatoid vasculitis, mixed connective-tissue Exacerbations and remissions are characteristic features of TAO.
disorders, antiphospholipid syndrome, vascular compression In one study, at a mean follow-up of 10.7 (range: 2-30) years,
syndromes (thoracic outlet syndrome, hypothenar hammer patients experienced an average of 5.4 (range: 1-20) acute
syndrome, repetitive vibratory injury, popliteal artery entrapment, episodes with severe symptoms.143 Patients have a significantly
carpal tunnel syndrome), malignancies, hematologic thrombo- diminished quality of life compared with age- and sex-matched
philia disorders (lupus anticoagulant, anticardiolipin antibody controls.242,243 TAO population and a matched coronary artery
syndrome), drug-induced hypersensitivity, ergot abuse, cannabis disease population had similar degrees of tobacco dependence
arteritis, and microbial infection, should also be considered in and Fagerström scores.244 In one study, the life expectancy of
the differential diagnosis. If TAO and ASO or other vasculitides patients with TAO was comparable to that of the normal
cannot be differentiated, the diagnosis can be confirmed by population.25 In contrast, Cooper and colleagues reported that
biopsy of a subcutaneous nodule or involved vein, which may survival among the TAO cohort was significantly lower than
show the characteristic acute-phase lesion.54,151 TAO has that in the matched US population in the TAO group, and the
average age at death was 52.2 ± 8.9 years.242 The risk of any extremity should be treated promptly. Adequate oral hygiene,
amputation during mean follow-up of 15.6 years was 25% at controlling the bacterial biofilm, and periodontal treatment
5 years, 38% at 10 years, and 46% at 20 years.242 The risk of might be useful measures preventing the recurrence of the
major amputation, defined as above-knee, below-knee, or hand disease.130,253
amputation, was 11% at 5 years, 21% at 10 years, and 23%
at 20 years.242 In this analysis, the amputation rate was signifi-
cantly reduced in those who discontinued tobacco use. The
Pharmacologic Treatment
authors concluded that the risk of amputation in previous Treatment must be tailored to the individual and is often based
smokers is eliminated 8 years after smoking cessation.242 Cumula- on the patient’s clinical presentation. TAO has conventionally
tive survival rates in the series reported by Ohta and colleagues been treated with antiplatelet agents including oral anticoagu-
were 97.0% at 5 years, 94.4% at 10 years, 92.4% at 20 years, lants, clopidogrel, dextran, pentoxifylline, phenylbutazone,
and 83.8% at 25 years (mean follow-up, 10.6 years).243 These pyridinolcarbamate, inositol niacinate, nonsteroidal antiinflam-
investigators also demonstrated that the occurrence or recurrence matory agents, and immunosuppressive drugs including
of necrotic lesions was usually arrested in patients older than cyclophosphamide254 and corticosteroids.255 However, no
60 years. There was a strong correlation between continued randomized controlled trials have been reported assessing the
smoking and limb amputation leading to poor quality of life efficacy of previously mentioned agents in TAO.256,257 Reported
and job loss.243 Another study from Turkey reported similar two cases of steroid-responsive TAO255 with remarkable eosino-
survival rates: 95.0% at 2 years, 92.4% at 5 years, and 88.4% philia is controversial.241 Appropriate antibiotics and nonsteroidal
at 10 years (mean follow-up, 11.6 years).154 A study from Japan antiinflammatory agents should be used in patients with
confirmed that failure to cease smoking was the most significant complicated phlebitis, cellulitis, or osteomyelitis.
factor affecting the risk of ulcer formation (OR: 1.71) and risk
for amputation (OR: 2.73; 95% CI: 1.86-4.01).150 Calcium Channel Blockers
Calcium channel blockers have been used for TAO patients
associated with the Raynaud phenomenon. Nifedipine, nicar-
TREATMENT dipine, or amlodipine may similarly be used in patients with
Lifestyle Changes significant vasospasm.1
Smoking Cessation Prostacyclin Analogs
The first step in management of TAO is complete and permanent Prostaglandin I2 (Prostacyclin), a main product of arachidonic
discontinuation of smoking in any form,29,54,81,167,245 including acid metabolism by endothelial cells, is a potent vasodilator
passive smoking.87 The hazards of continued smoking in patients through vascular smooth cell relaxation, and it inhibits platelet
with TAO seems to be independent of factors such as the number aggregation, chemotaxis, and cell proliferation.258,259 Epoprostenol
of cigarettes smoked per day167; whether the tobacco product is a freeze-dried preparation of prostacyclin for intravenous
is in the form of cigarettes, bidis, cigars, chewing tobacco, or administration.260 Iloprost is a stable and synthetic analogue of
snuff;56,60,246 cigarette characteristics; and smoking behavior, epoprostenol with a plasma half-life of 20 to 30 minutes. It is
including degree of inhalation. Counseling, smoking-cessation commonly used in the treatment of peripheral vascular disease
programs, pharmacotherapy using bupropion or varenicline, because of its vasodilating and platelet inhibitory effects. Iloprost
and exercise training form the cornerstone of treatment.45 also downregulates the expression of intercellular adhesion
Nicotine replacement therapy may result in disease progression, molecule-1 and endothelial leukocyte adhesion molecule-1 on
thus this should be avoided;1,247 however, in terms of limb interleukin-1β–stimulated endothelial cells and inhibits lym-
salvage in a stage of CLI in patients with TAO, smoking cessation phocyte adhesion to endothelial cells.261
may not be sufficient.248
Iloprost Infusion
Exercise Training Moderate quality of evidence exists with limited number of
Benefits of exercise training in claudication are well established.249 randomized trials in pharmacologic treatment of TAO with
Regular exercise training (sessions lasted more than 30 minutes CLI.257 In a European multicenter, randomized, double-blinded
and 3-5 times per week) improves pain-free walking time by trial involving patients with TAO and CLI, Fiessinger and Schafer
an average of 180% and maximal walking time by an average compared 6-hour infusion of iloprost (0.5-2.0 ng/kg per minute)
of 120% in patients with claudication.250 Randomized trials and oral aspirin (100 mg/day) for a 28-day trial period.262 Among
confirmed that ischemic exercise training triggers the release of 152 patients, 133 patients fulfilled the entry criteria of rest
CPCs from the bone marrow and promotes homing of CPCs pain, ischemic ulceration, or gangrane.262 At 28 days of treatment,
into vascular networks.251 iloprost was superior to aspirin at achieving ulcer healing or
relief of ischemic pain; 85% of patients in the iloprost group
Foot, Hand, and Dental Care improved versus 17% in the aspirin group. Furthermore, at 6
Daily foot and hand hygiene as well as avoidance of trauma, months, the response rate was 45 of 51 (88%) patients treated
thermal injury, vibration, chemicals, and cold are easily applied with iloprost compared with 12 of 44 (21%) patients treated
measures to prevent ischemic ulcers.252 Any injury to the involved with aspirin. Only 6% of patients in the iloprost group ultimately
required amputation compared with 18% in the aspirin group.262

In a randomized, multicenter study, the Turkish Buerger’s Disease Phosphodiesterase 5 Inhibitors (Sildenafil, Tadalafil)
Research Group compared the results of lumbar sympathectomy PDE5 isoenzyme is found in the corpus cavernosum of the
(n = 78) to 28 days of intravenous iloprost (n = 84) in 162 penis and vascular smooth muscle. Inhibition of PDE5, a cyclic
patients with CLI and TAO.263 The primary endpoint of the guanosine monophosphate (cGMP)-dependent phosphodiesterase
study was complete healing without pain or major amputation increase intracellular cGMP, results in decreased intracellular
at 4 and 24 weeks. Complete healing was achieved in 61.9% calcium and increased nitric oxide leading to vascular smooth
of the iloprost group and 41% of the lumbar sympathectomy muscle relaxation and vasodilation. There are few reported cases
group at 4 weeks (P = .012) and in 85.3% versus 52.3%, of TAO with digital symptoms successfully treated with off-label
respectively, at 24 weeks (P < .001).263 The risk of amputation use of PDE5 inhibitors, namely sildefanil (20 mg tid) or tadalafil
is also reduced with combination of iv iloprost infusion and (40 mg every other day).266-268
supervised smoking cessation in TAO patients with CLI.264
Thus, reported evidence suggests that intravenous iloprost is Endothelin Receptor Antagonists
effective pharmacologic treatment option in healing ulcers and Bosentan, an oral dual endothelin-1 receptor antagonist targeting
relieving rest pain in patients with TAO and CLI.257 Iloprost two transmembrane receptors, namely ETA and ETB, has been
has been authorized in some European Union Member States useful in patients with TAO and ischemic lesions.268-271 Bosentan
for the treatment of TAO. has selective vasodilatory, antiinflammatory, and antifibrotic
properties. Previous case series showed clinical and angiographic
Oral Iloprost improvement in 10 out of 12 patients with ulcers and/or pain
The European TAO Study Group conducted a double-blinded, at rest.272 De Haro et al. reported that Bosentan therapy
randomized, placebo-controlled trial comparing oral iloprost (125 mg/12 h) maintained for four months resulted in clinical
(100 or 200 mcg) with placebo for 8 weeks among 319 patients improvement and complete healing of the ulcers in a single-center
with ischemic rest pain or ulcerations recruited from 22 centers prospective study with 48 months follow-up data in patients
in six countries in Europe,258 and the duration of treatment with TAO and ischemic ulcers unresponsive to conventional
was 6 weeks. The primary endpoint was total healing of the therapies.273 Only 2 out of 22 extremities (9%) underwent
most important lesion, and the secondary endpoint was major amputation. Well-conducted randomized clinical trials
total relief of pain at rest without the need for analgesics are, however, still needed, especially in patients with pain at
at six months. The combined endpoint consisted of the patient’s rest and ischemic ulcers.
being alive with no major amputation, no lesions, no rest pain,
and no analgesic use. After 6 months of therapy, low-dose Thrombolytics
iloprost was significantly better than placebo at relieving rest Selective intraarterial infusion of urokinase and streptokinase
pain without the use of analgesics, and for achieving the as a treatment option for TAO has been reported.274-278 However,
combined endpoint.258 However, neither dose of oral iloprost in the series of Hussein et al., limb salvage rate was 33%,
showed a significant effect on the total healing of lesions and bleeding complications occurred in 17% of the patients
compared with placebo. treated with intraarterial streptokinase.275 Matsushita and
associates administered a continuous intraarterial infusion of
Prostaglandin E1 Analogs urokinase (20,000 U/h) and heparin (800 U/h) in a 19-year-old
Limaprost alfadex, a prostaglandin E1 analogue, was developed woman with CLI and TAO.39 Although her symptoms
in Japan to treat ischemic symptoms of TAO also has strong improved temporarily, thrombolytic therapy did not enable
vasodilatory and antiplatelet activity similar to Prostacyclin. recanalization of the occluded popliteal artery. High-quality
In a randomized, double-blinded trial in 136 Japanese trials assessing the effectiveness of thrombolytics in patients
patients primarily with TAO, there was no significant difference with TAO are needed.
in the improvement of ischemic symptoms between patients
receiving limaprost 30 µg/day and those receiving oral ticlopidine Folate Supplementation
500 µg/day.265 Folate therapy in TAO patients with increased homocysteine
levels has been investigated in one randomized trial from Iran.279
Phosphodiesterase Inhibitors Single dose of folic acid (5 mg) and placebo were compared in
30 patients with TAO.279 The authors concluded that single
Phosphodiesterase 3 Inhibitors (Cilastazol) dose folic acid has homocysteine lowering effect but did not
Phosphodiesterase 3 (PDE3) isoenzyme is found in vascular inhibit the risk of minor or major amputation rate.279 Further
smooth muscle and platelets. Inhibition of PDE3 isoenzyme clinical evidence about folate therapy for TAO patients is
increases intracellular cyclic adenosine monophosphate required.
(cAMP) results in smooth muscle relaxation and decreases platelet
aggregation. In one small study, cilastazol was effective at Statins
improving ischemic ulcerations in patients with refractory There is increasing experimental evidence that the pleiotropic
digital ischemia.239 The role of cilostazol in TAO is, however, effects of statins may improve or restore endothelial function
still not clear. and decrease oxidative stress and vascular inflammation.280-282
However, the therapeutic role of statins in inflammation-induced handicaps. The arterial circulation of the lower extremity gener-
thrombosis is still an unresolved issue.283 ally cannot serve as the distal anastomotic site for bypass surgery,
resulting in suboptimal patency rates. However, if the patient
Analgesia has CLI and a distal target vessel is present, bypass surgery
Analgesia is often required in patients with rest pain and ischemic using autologous vein should be considered.298,299 Arterial bypass
ulcers. Opioids, nonsteroidal antiinflammatory drugs, antidepres- of the larger vessels may be used in selected cases. In 1974,
sants, and neuronal block may relieve symptoms. Inada and associates demonstrated that of their 236 patients
with TAO, only 11 (4.6%) had lesions that were amenable to
Regional Sympathetic Blockade surgical revascularization,300 whereas a vasculitis database from
Guanethidine, an adrenergic neuron blocker that inhibits the Japan revealed that 15.5% of TAO patients underwent surgical
presynaptic release and subsequent reuptake of noradrenaline revascularization.150 Dilege and associates reported that 36 of
from postganglionic sympathetic nerve endings, has been their 94 patients with TAO (38.3%) were deemed eligible for
proposed for the treatment of TAO.284-287 Intravenous regional revascularization, but only 27 patients (28.7%) actually under-
sympathetic blockade with guanethidine has been described by went revascularization procedures.301 In this study, any crural
Hannington-Kiff.288 This “chemical sympathectomy” is based vessel with at least 10 cm of patency, preferably in continuation
on multiple sessions of intravenous regional sympathetic blockage with the pedal arch or draining with a good collateral network,
with lidocaine and guanethidine using Bier’s arterial arrest.289,290 was considered appropriate for revascularization. The patency
However, despite promising case reports in patients with ischemic rates at 12, 24, and 36 months were 59.2%, 48%, and 33.3%,
rest pain and nonhealing ulcerations, limitations regarding the respectively. The limb salvage rate was, however, 92.5%. Bypass
use of this therapy still exist.284 surgery was most frequently required below the trifurcation
segment of the knee joint, with a cumulative patency rate of
Spinal Cord Stimulation 54.6% at 5 years.302 In a retrospective review of 216 patients
There are increasing reports in the literature regarding the use with TAO over a 10-year period, Sayin and colleagues reported
of implantable spinal cord stimulators in patients with TAO.291-296 that lumbar sympathectomy was performed in 85% and thoracic
Electrical spinal cord stimulation relieves pain through several sympathectomy in 9.3% of TAO patients.303 Twenty-one patients
mechanisms, including preventing transmission of painful stimuli (9.7%) underwent direct arterial reconstruction of varying types.
through the corresponding dermatomes, stimulation of the The investigators noted that four of the five endarterectomized
production of inhibitory neurotransmitters in the spinal cord, segments had occluded by the 7-year follow-up.303 Sasajima
and inhibition of sympathetic vasoconstriction with consequent and associates showed that a strategy of aggressive distal bypass
improvement in peripheral microcirculation.291,294,296 Spinal cord surgery using autologous disease-free vein grafts for TAO may
stimulation successfully addresses the neurogenic, but not the provide acceptable primary and secondary patency rates.298 The
somatic, aspects of pain in patients with TAO.287 Spinal cord patency rates in the postoperative nonsmoking group were
stimulation can be attempted when other forms of therapy are significantly higher than in the smoking group (66.8% vs.
ineffective.167 34.7%; P < .05).298 Predictors of early graft failure were poor
quality vein, inadequate technique for anastomosis, inadequate
Surgery tunneling, anastomosis to a diseased artery, arterial spasm, and
vein graft intimal hyperplasia.298 Late failures were due to disease
Lumbar or Thoracic Sympathectomy progression, especially in smokers, vein graft intimal hyperplasia
In a randomized, multicenter study, the Turkish Buerger’s Disease or aneurysm, atherosclerosis, and competition with collateral
Research Group compared the results of lumbar sympathectomy flow.298 Bozkurt and colleagues reported cumulative secondary
(n = 78) to 28 days of intravenous iloprost (n = 84) in 162 patency rates of 57.9% for bypass grafts at a mean follow-up
patients with CLI and TAO.263 The primary endpoint of the of 5.4 years in 19 patients with BD.304 Cumulative patency
study was complete healing without major amputations or pain was 70% (7 of 10) for saphenous vein grafts, 50% (3 of 6) for
at 4 and 24 weeks. Complete healing was achieved in 61.9% polytetrafluoroethylene grafts, and 33.3% (1 of 3) for composite
of the iloprost group and 41% of the lumbar sympathectomy grafts. Different distal bypass techniques and routes have been
group at 4 weeks (P = .012) and in 85.3% versus 52.3%, described to obtain better anatomic orientation and patency
respectively, at 24 weeks (P < .001).263 Kothari et al. recently rates in patients with TAO.305-307 Collateral artery bypass is an
reported that thoracoscopic dorsal sympathectomy reduces pain option when the main arteries are affected by TAO,308 and
in patients with upper limb involvement in a recent case series successful local flap transfers after distal bypass surgeries
of 25 TAO patients from India.297 have been reported in selected cases.309-312 The prevalence of
amputation and the primary and secondary patency rates
Distal Surgical Revascularization after revascularization in patients with TAO are summarized
The role of surgical revascularization in TAO is not clear. in Table 138.6.
Revascularization is often not feasible because of the distribution
of diffuse, segmental arterial involvement, and the distal nature Pedicled Omental Graft
of the disease.54 Distal arterial spasm during dissection and For foot salvage, paramalleolar arterial bypass grafts may be
poor-quality veins owing to phlebitis are other disease-specific combined with microvascular free tissue transfer.309 Successful
TABLE 138.6 Prevalence of Amputations, Primary and Secondary Patency Rates After Arterial Revascularization in
Patients With Thromboangiitis Obliterans
Study Number Number of Primary Secondary
Authors Year Type of Patients Bypasses Patency Patency Limb Salvage Amputations
19 b a
Sayın 1993 R 21 21 62.5% at 5 years 4 Major
20
Sasajima 1997 R 61 71 49% at 5 years 63% at 5 years 59% 3 Major 8 minor
43% at 10 years 56% at 10 years
Nakajima21 1998 R 26 65% at 2 yearsb a a
22 b a
Bozkurt 1998 P 14 14 57% at 8 years 89%
23 a a a a
Shindo 2002 R 8 10
24
Dilege 2002 P 27 24 59% at 1 year 33% at 3 years 93% at 3 years 2 Major
48% at 2 years
Bozkurt4 2004 P 19 20 a
57.9% at 5.4 years 90% 2 Major
25
Ohta 2004 R 31 46 41% at 1 year 54% at 1 year 91% at 1 year 5 Major (14%)
32% at 5 years 48% at 5 years 89% at 5 years
30% at 10 years 39% at 10 years 85% at 10 years
Ateş26 2006 R 27 27 44.8% at 1 yearb a
12 (total)
37% at 5 years
a
Not mentioned.
b
Not stated primary or secondary.
P, Prospective; R, retrospective.
Modified from references 5 and 238.
Lazarides MK, Georgiadis GS, Papas TT et al. Diagnostic criteria and treatment of Buerger’s disease: a review. Int J Low Extrem Wounds. 2006;5:89–95; Dargon PT,
Landry GJ. Buerger’s disease. Ann Vasc Surg. 2012;26:871–880.
local flap transfers after distal bypass surgery has been reported considered only in selected patients with ischemic ulcers,
in selected cases,309-312 and omental transfer to areas not amenable osteomyelitis, or necrotizing fasciitis who have not responded
to arterial reconstruction has been proposed as a therapeutic to other forms of treatment.40,72,326-331 Negative-pressure wound
option in TAO.313-319 In two retrospective series from India, therapy may be helpful, as continuous or intermittent vacuum-
complete healing was achieved in more than 80% of the patients, assisted settings may have a role in the treatment of debilitating
and limb salvage was 100% with pedicled omental graft.314,317 complex chronic ulcers in patients with TAO.332-334
This surgical technique, however, has not been used in Europe
or the United States.
Endovascular Treatment
Distal Venous Arterialization Percutaneous subintimal angioplasty for limb salvage in patients
Distal venous arterialization may be offered as a last surgical with nonhealing ulcers has been proposed,335-338 but it would
resort for limb salvage in the absence of graftable distal be premature to claim that this method might provide new
arteries.320-324 Distal venous arterialization can successfully salvage opportunities for patients with TAO. However, extended
the critically ischemic lower limb with few serious complications. endovascular management for tibial or foot artery obstruction
A recent meta-analysis showed that overall 1-year foot preserva- was recently achieved in 17 patients with TAO and CLI with
tion was 71% (95% CI: 64%-77%), and 1-year secondary a technical success rate of 95%.339 Successful use of Silver-Hawk
patency was 46% (95% CI: 39%-53%) after distal venous directional atherectomy in two TAO patients with popliteal
arterialization.321 occlusions was recently reported; however, this endovascular
procedure requires further validation by larger studies.340
Local Wound Care
In clinical practice, wound toilette, including limited surgical Other Interventional Procedures
or ultrasound debridement and appropriate antibiotics, is often
useful in the treatment of infected ischemic ulcerations.29 Caution Immunoadsorption
is advised for excessive local debridement, which may widen Recent pilot studies demonstrated near complete pain relief,
ulcers.325 Topical agents for elimination of necrotic tissue and increased maximum walking distance, and tissue perfusion after
infection, maintaining a moist environment, and management selective removal of circulating immunoglobulins and antibodies
of wound margin are the hallmarks for the treatment of ischemic from patient’s plasma using immunoadsorption techniques.341,342
ulcers associated any vasculitis.325 Given the absence of a proven In one study, agonistic autoantibodies directed against G-protein
benefit and its high cost, hyperbaric oxygen therapy should be coupled receptors were identified in 9 out of 11 patients. The
Figure 138.8 Limb salvage after autologous bone marrow–derived mononuclear cell therapy. Preoperatively (left),
this patient had a nonhealing ischemic wound of the great toe and required high doses of narcotic analgesics. After
surgical débridement (right), complete healing was achieved at 3 weeks and maintained at 24 months.
authors concluded that elimination of agonistic autoantibodies mononuclear cells,351-354 autologous peripheral blood stem
by immunoabsorption may relieve immune-mediated vasospasm cells,355,356 mesenchymal stem cells derived from human umbilical
and improve microcirculation.343 cord blood,357 autologous adipose tissue-derived stem cells,358
and autologous whole bone marrow stem cells359 into ischemic
Growth Factors limbs can restore limb function by increasing new collateral
Basic fibroblast growth factor and vascular endothelial growth vessel formation.360 We and our colleagues have also demonstrated
factor (VEGF) may play a role in patients with CLI due to that the implantation of autologous bone marrow mononuclear
BD. Isner and colleagues treated seven limbs in six patients cells in the ischemic limbs of patients with TAO is associated
with TAO (three men, three women; mean age, 33 years) in with improved rest pain scores (P < .0001), peak walking time
an open-label, dose-escalating, phase 1 clinical trial to document (P < .0001), quality of life (P < .0083), and augmentation of
the efficacy and safety of gene transfer of naked plasmid DNA collateral formation at 24 weeks in 78% of patients.352,361,362
encoding VEGF (phVEGF165) via intramuscular injection in Healing of ischemic ulcers was achieved in 83% of the study
the treatment of CLI.344 Ulcers, which had not healed for more group (Fig. 138.8). Subsequent studies and meta-analysis sup-
than 1 month before therapy, healed completely in 3 of 5 limbs ported intramuscular bone marrow cell administration as a
after intramuscular phVEGF165 gene therapy. Nocturnal pain relatively safe, feasible, and potentially effective therapy in
at rest was relieved in the remaining two patients, although patients with CLI and TAO.360,363 Bone marrow-derived
both continued to have claudication. Two patients with advanced mononuclear cell therapy induced long-term improvement
distal forefoot gangrene ultimately required below-knee amputa- leading to an amputation-free rate of 91% (95% CI: 82%-100%)
tion despite evidence of improved perfusion. This report suggests at 3 years in the Therapeutic Angiogenesis by Cell Transplantation
that angiogenesis induced by phVEGF165 gene transfer may (TACT) Trial.364 A combined approach of intraarterial and
provide an effective therapy for patients with advanced TAO intramuscular injections may maximize the chances of local
that is unresponsive to standard interventions.344 Another study deposition of stem cells in the ischemic limb.365
demonstrated higher VEGF plasma levels in patients with TAO Another method of stimulating angiogenesis by inserting
compared with controls (P = .008), showing the existence of intramedullary K-wires has been suggested by Inan and associ-
a natural defense mechanism for ischemia and new collateral ates.366 Fenestration of the tibia at six sites with EPC mobilization
formation.345 A recent Phase I/IIa open-label four dose-escalation from bone marrow using recombinant human granulocyte
clinical study assessing the safety, tolerability, and efficacy of a colony-stimulating factor was also reported recently by Kim
single intramuscular administration of DVC1-0101 in patients and associates in 27 patients (34 lower limbs) with BD.367 Over
with PAD also involved two patients with TAO.346 DVC1-0101 a mean follow-up period of 19 months, 13 of 17 limbs with
is a new gene transfer vector based on a nontransmissible nonhealing ulcers healed. This technique resulted in a similar
recombinant Sendai virus (rSeV) expressing the human fibroblast degree of new vascular collateral network development367
growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2). The investiga- compared with autologous bone marrow mononuclear cells
tors concluded that DVC1-0101 was safe, effective, and resulted aspirated from the iliac crest and implanted into the intermeta-
in significant improvements of limb function.346 tarsal region, the gastrocnemius muscle, and the dorsum of the
foot or forearm.352 Recently, functional impairment of endothelial
Stem Cell-Based Therapeutic Angiogenesis progenitor cells was confirmed in TAO patients compared to
Angioblasts isolated from peripheral blood or bone marrow– healthy nonsmokers and smokers.368 Ongoing work is focused
derived CPCs can be incorporated into sites of active angio- on understanding the mechanisms of therapeutic angiogenesis,
genesis, providing a key factor in re-endothelialization.347 including vascular stem cell niches, mobilization, homing, and
Culture-expanded CPC transplantation in an animal model of vascular repair.369
limb ischemia improved neovascularization and blood flow
recovery and reduced limb necrosis and autoamputation by
50% compared with controls.348 Preclinical,349 and clinical studies
ACKNOWLEDGMENTS
in patients with peripheral artery disease and CLI,350 including We sincerely thank Drs. Shigehiko Shionoya and Jeffrey W.Olin,
TAO, suggest that the implantation of autologous bone marrow the authors of this chapter in previous editions, for their
outstanding work, which has provided invaluable insights into Kobayashi M, Ito M, Nakagawa A, Nishikimi N, Nimura Y. Immu-
Buerger disease, and Drs. Isinsu Kuzu and Suat Aytac of the nohistochemical analysis of arterial wall cellular infiltration in
Buerger’s disease (endarteritis obliterans). J Vasc Surg. 1999;29:
Ankara University School of Medicine for their scientific 451–458.
assistance and the provision of pathology and radiology
This original study describes important histologic observations from 33
illustrations.
specimens of nine patients with Buerger disease. The investigators
concluded that Buerger disease was a vasculitis (endarteritis) induced
by an antigen in the intimal layer and subsequent activation of T-cell
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prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, the blood, resulting in an immunoreaction closely linked to Notch
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with previous studies, the investigators report an excessive late mortality management principles of Buerger disease. The concept “No tobacco,
in patients with TAO compared with the US population. However, no Buerger disease” is reintroduced.
the risk of amputation in previous smokers is eliminated by 8 years Ohta T, Ishioashi H, Hosaka M, Sugimoto I. Clinical and
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This is the first study investigating the use of autologous bone marrow associated with poor long-term results although it shortens the healing
mononuclear cell implantation for patients with Rutherford grade process of ischemic ulcers.
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This landmark review summarizes the clinical features, pathogenesis,
with ischemic ulcers. Relief of rest pain without the need of narcotic
diagnostic criteria, and recommendations for the treatment of throm-
analgesics improved in all patients.
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Isner JM, Baumgartner I, Rauh G, et al. Treatment of thromboangiitis
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The first report that documents the results of six patients with Buerger criteria for Buerger disease and important hallmarks of the clinical
disease who were treated with gene therapy as part of a larger phase-I picture.
clinical trial to document the safety and efficacy of intramuscular gene The European TAO Study Group. Oral iloprost in the treatment
transfer of naked plasmid DNA-encoding vascular endothelial growth of thromboangiitis obliterans (Buerger’s disease): a double-blind,
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This intriguing study documents the angiogenesis facilitated by fenestra-
A complete reference list can be found online at www.expertconsult.com
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138 CHAPTER

INTRODUCTION 1809 Pharmacologic Treatment 1821

primarily involving infrapopliteal and infrabrachial medium and

and America. TAO is typically manifested by distal extremity

induced by cocaine, amphetamines, and cannabis addiction

the acute phase include an occlusive, highly cellular arterial

rest, ischemic ulcers, or gangrene) documented by noninvasive

35mm 60° 36mm 60°

7mm 55° 6mm

radiography and magnetic resonance imaging to determine the

required amputation compared with 18% in the aspirin group.262

28. Shionoya S. What is Buerger’s disease? World J Surg. 1983;7:

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