Thromboangiitis Obliterans (Buerger Disease)

Background

Thromboangiitis obliterans (TAO), an inflammatory vasculopathy also known as Buerger disease, is characterized by an inflammatory endarteritis that causes a prothrombotic state and subsequent vaso-occlusive phenomena. The inflammatory process is initiated within the tunica intima. It characteristically affects small and medium-sized arteries as well as veins of the upper and lower extremities. The condition is strongly associated with heavy tobacco use, and disease progression is closely linked to continued use. (See Pathophysiology and Etiology.)

Patients often present with moderate-to-severe claudication that can quickly progress to critical limb ischemia featuring rest pain or tissue loss. Features of acute limb ischemia (eg, pain, paresthesia, palor, mottling, poikilothermia, paresis, and pulselessness) are common signs and symptoms encountered in the emergency setting.^{[1, 2, 3, 4]} (See Presentation.)

Pharmacologic therapy is generally ineffective; abstinence from tobacco is the only measure known to prevent disease progression. (See Treatment.) Given the arteritis of the small and medium-sized vessels, surgical or endovascular revascularization may not be possible, because of the absence of a distal target for revascularization. As the disease evolves, amputation may be the only viable option.

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Pathophysiology and Etiology

As noted, the development of TAO is strongly associated with heavy use of tobacco, and the progression of the disease is closely linked to continued use.

A few observations suggest the existence of an immunologic phenomenon leading to vasodysfunction and inflammatory thrombi. Patients with TAO exhibit hypersensitivity to intradermally injected tobacco extracts, increased cellular sensitivity to collagen types I and III, elevated serum anti–endothelial cell antibody titers, and impaired peripheral endothelium-dependent vasorelaxation. They also show a higher prevalence of human leukocyte antigen (HLA)–A9, HLA-A54, and HLA-B5, suggesting a genetic component to the disease.

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Epidemiology

United States statistics

The prevalence of TAO has decreased over the past decade, partly because the prevalence of smoking has decreased but also because the diagnostic criteria have become more stringent. In 1947, the prevalence of the disease in the United States was 104 cases per 100,000 population. Since then, the prevalence has fallen to an estimated 12.6-20 cases per 100,000 population.

Age-, sex-, and race-related demographics

Most patients with TAO are aged 20-45 years; the disease does not occur in pediatric or elderly patients. TAO is more common in males (male-to-female ratio, 3:1); however, the incidence in women is believed to be increasing, probably as a consequence of the growing frequency of smoking among women. The disease is relatively less common in people of northern European descent; natives of India, Korea, and Japan, along with Israeli Jews of Ashkenazi descent, have the highest incidence of TAO.^[5]

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Prognosis

Death from TAO is rare. Between 1999 and 2007, according to data from the US Centers for Disease Control and prevention (CDC), TAO (code I73.1 in the International Classification of Diseases, Tenth Revision [ICD-10]) was the underlying cause of 117 deaths in the United States.^[6]

A striking dichotomy is observed in the prognosis of patients with TAO, which is dependent on whether absolute avoidance of tobacco is achieved. Among patients who stop using tobacco, 94% avoid amputation; among patients who stop using tobacco before progression to critical limb ischemia, the amputation rate is near 0%. In stark contrast, among patients who continue using tobacco, there is an 8-year amputation rate of 43%.

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Patient Education

Patients with TAO must be repeatedly advised to cease all use of or exposure to tobacco products (including chewing tobacco, nicotine patches and gums, and second-hand smoke) and reassured that if they are able to discontinue tobacco use, the disease will remit and amputation will be avoided.

Physicians should counsel patients that the level of tobacco avoidance required to achieve resolution of their disease often necessitates that they rigorously limit their exposure even to secondhand smoke. This can be extremely difficult for patients who live with another smoker, and it is therefore not unreasonable to consider referring such patients (and their loved ones) to multidisciplinary smoking cessation programs.

For patient education resources, see the Healthy Living Center and the Lung and Airway Center, as well as Cigarette Smoking.

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History

Because a firm diagnosis of thromboangiitis obliterans (TAO; also referred to as Buerger disease), is difficult to establish, a number of different diagnostic criteria have been proposed.^[7] In 1990, Olin et al asserted that the following criteria must be met for the diagnosis to be made with reasonable certainty^[8] :

• Age younger than 45 years
• Current (or recent) history of tobacco use
• Presence of distal extremity ischemia (indicated by claudication, pain at rest, ischemic ulcers, or gangrene) documented by noninvasive vascular testing
• Exclusion of autoimmune diseases, hypercoagulable states, and diabetes mellitus by laboratory tests
• Exclusion of a proximal source of atheroemboli by echocardiography and arteriography
• Consistent arteriographic findings in the clinically involved and noninvolved limbs

Most patients with TAO (70-80%) present with distal ischemic rest pain or ischemic ulcerations on the toes, feet, or fingers (see the image below).^{[9, 10]} Progression of the disease may lead to involvement of more proximal arteries, but involvement of large arteries is unusual.

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Feet of patient with thromboangiitis obliterans (Buerger disease). Note ischemic ulcers on distal portion of left great, second, and fifth toes. Altho....

Patients may also present with claudication of the feet, legs, hands, or arms and often describe experiencing the Raynaud phenomenon (a pathologic vasospastic process involving pain, paresthesias, and color changes of the digits of the hands and feet in response to cold or anxiety).

Patients who seek medical attention late in the course of their disease may present with foot infections and, occasionally, with florid sepsis.

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Physical Examination

Patients with TAO can develop painful ulcerations (see the image below) or frank gangrene of the digits. The hands and feet of patients with the disease are usually cool and mildly edematous.

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Tobacco smoke stains on male patient's fingers suggest diagnosis of thromboangiitis obliterans (Buerger disease). Patient presented with small, painfu....

Superficial thrombophlebitis (often migratory) occurs in almost half of patients with TAO (see the image below). Paresthesias (numbness, tingling, burning, hypoesthesia) of the feet and hands and impaired distal pulses in the presence of normal proximal pulses are usually found in patients with severe disease. More than 80% of patients present with involvement of three or four limbs.

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Superficial thrombophlebitis of great toe in patient with thromboangiitis obliterans (Buerger disease).

In 1996, Papa et al proposed a point-scoring system to support or contest the diagnosis of TAO on the basis of the following criteria^[11] :

• Distal extremity (feet, toes, hands, or fingers) involvement
• Onset before age 45 years
• Tobacco use
• Exclusion of atherosclerosis or proximal source of emboli
• Absence of a hypercoagulable state
• Absence of definable arteritis (eg, progressive systemic sclerosis or giant-cell arteritis)
• Classic arteriographic findings
• Involvement of digital arteries of finger or toes
• Segmental involvement (ie, “skip areas”)
• “Corkscrew collaterals”
• No atherosclerotic changes
• Classic histopathologic findings
• Inflammatory cellular infiltrate within thrombus
• Intact internal elastic lamina
• Involvement of surrounding venous tissues

The scoring system is applied as indicated in Table 1 and Table 2 below.

Table 1. Scoring System for Diagnosis of Thromboangiitis Obliterans^[11]

View Table

See Table

Table 2. Numerical Scores Defining Probability of Diagnosis of Thromboangiitis Obliterans

View Table

See Table

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Complications

Potential complications of TAO include the following:

• Ulcerations
• Gangrene
• Infection
• Need for amputation
• Rare occlusion of coronary, renal, splenic, or mesenteric arteries

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Approach Considerations

No specific laboratory tests confirm or exclude the diagnosis of thromboangiitis obliterans (TAO; also known as Buerger disease).

Arteriographic abnormalities consistent with TAO are sometimes seen in limbs that are not yet clinically involved; therefore, arteriography of all four limbs may be required. Echocardiography and computed tomography (CT) angiography (CTA) should always be performed in patients thought to have TAO in order to exclude a proximal source of thromboemboli or atheroemboli as the cause of distal vessel occlusion.

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Laboratory Studies

The primary goal of a laboratory workup in patients thought to have the disease is to exclude other disease processes in the differential diagnosis. Tests often used as markers for the diagnosis of systemic vasculitis, such as the acute-phase reactants, yield negative results in patients with TAO. Tests commonly ordered include the following:

• Complete blood count (CBC) with differential
• Liver function tests
• Renal function tests
• Urinalysis
• Glucose (fasting)
• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• Antinuclear antibody (ANA)
• Rheumatoid factor (RF)
• Complement
• Anticentromere antibody
• Scl-70 antibody
• Antiphospholipid antibodies

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Arteriography

The hallmark angiographic findings in patients with TAO are nonatherosclerotic, segmental occlusive lesions of the small and medium-sized vessels (eg, digital, palmar, plantar, tibial, peroneal, radial, and ulnar arteries) with formation of distinctive small collateral vessels around areas of occlusion, known as corkscrew collaterals (see the image below). These corkscrew collaterals represent dilated vasa vasorum of the occluded arteries, which are now serving to provide distal perfusion, albeit at significantly higher resistance than the native vasculature.

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Lower-extremity arteriogram of peroneal and tibial arteries of patient with thromboangiitis obliterans (Buerger disease) demonstrates classic findings....

Such arteriographic findings suggest TAO but are not pathognomonic, because similar lesions can be observed in patients with scleroderma, CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) syndrome, systemic lupus erythematosus, rheumatoid vasculitis, mixed connective-tissue disease, antiphospholipid-antibody syndrome, and even diabetes mellitus.

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Histologic Findings

In its acute phase, TAO is characterized by highly cellular, segmental, occlusive, inflammatory thrombi, with minimal inflammation in the walls of affected blood vessels. Secondary spread from the affected small and medium-sized arteries to contiguous veins and nerves is often observed. Microscopically, the polymorphonuclear leukocyte (PMN)-predominant inflammatory cellular aggregate may form microabscesses and multinucleated giant cells.

In the subacute phase, intraluminal thrombosis progressively organizes, but it may defer to vascular recanalization.^[12] The end-stage phase of TAO is characterized by mature thrombus and vascular fibrosis.

In all three stages of the disease, the integrity of the normal structure of the vessel wall, including the internal elastic lamina, is maintained. This maintenance of structural integrity distinguishes TAO from arteriosclerosis and from other types of systemic vasculitis, in which disruption of the internal elastic lamina and the media can be extensive.

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Approach Considerations

Except for absolute tobacco avoidance, no forms of therapy are definitive for thromboangiitis obliterans (TAO; also known as Buerger disease).^[13] There is some support for a few pharmacologic approaches, but for the most part, such approaches are ineffective. Surgical revascularization usually is not feasible, because of the lack of a distal target for revascularization. Endovascular options for treatment of occlusive lesions are growing in popularity.^{[14, 15, 16]} Patients may require one or more amputations.

Indications for hospital admission include the following:

• Surgery
• Parenteral pharmacologic treatment of infection or pain that is refractory to oral medical therapy
• Intensive behavioral modification therapy for patients unable to achieve smoking cessation at home

No dietary restrictions are needed; diet has not been shown to affect the course of the disease. Cardiovascular exercise should be encouraged, restricted only by symptoms.

In the long term, outpatient management is generally appropriate for patients with TAO. Such management should include frequent follow-up examination by a physician or wound-care specialist.

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Cessation of Tobacco Use

Absolute discontinuance of tobacco use is the only strategy proven to prevent the progression of TAO. Smoking as few as one or two cigarettes daily, using chewing tobacco, or even using nicotine replacements may keep the disease active.^[17] In the rare event that a pregnant woman presents with TAO, the treatment would remain recommendation of absolute cessation of tobacco use.

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Pharmacologic Therapy

Intravenous (IV) iloprost (a prostaglandin analogue), an expensive agent unavailable in the United States, appears to be somewhat effective in improving symptoms, accelerating resolution of distal-extremity trophic changes, and reducing the amputation rate among patients with TAO.^[18] IV iloprost therapy is probably most useful for slowing progressive tissue loss and reducing the need for amputation in patients with critical limb ischemia during the period when they first discontinue cigarette smoking.

The use of thrombolytic agents to treat TAO has been proposed, but the data to support this proposal remain inconclusive, and the therapy is thus considered experimental. Isner et al reported that improved healing of ischemic ulcers and relief of rest pain was achieved in a small series of TAO patients by using intramuscular gene transfer of vascular endothelial growth factor (VEGF).^[19]

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics can be administered to palliate ischemic pain, and appropriate oral antibiotics can be used to treat mild distal extremity ulcers.

Aside from the experimental use of iloprost and thrombolytics, the use of antibiotics to treat infected ulcers, and the palliative treatment of ischemic pain with NSAIDs and narcotics, all other forms of pharmacologic treatment have been generally ineffective in the treatment of TAO, including steroids, calcium-channel blockers, reserpine, pentoxifylline, vasodilators, antiplatelet drugs, and anticoagulants.

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Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy is now an accepted adjunctive measure that has been shown to provide significant clinical improvement in patients with diabetic wounds, refractory osteomyelitis, acute limb ischemia, or necrotizing soft-tissue infection. Its use in treating TOA patients without revascularization options remains experimental; the available data are extremely limited.^[20] Hyperbaric oxygen therapy does, however, provide a promising alternative treatment option that is worth investigating on larger scales.

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Surgical and Endovascular Intervention

Because of the diffuse segmental nature of TAO and the disease’s predilection for small and medium-sized arteries, surgical revascularization for TAO usually is not feasible. Nevertheless, every effort should be made to improve distal arterial flow in patients with TAO, and autologous vein bypass of coexistent large-vessel atherosclerotic stenoses should be considered in patients with severe ischemia who have an acceptable distal target vessel.

Other proposed surgical treatments for TAO are as follows:

• Sympathectomy
• Intra-arterial infusion of reserpine
• Spinal cord stimulator implantation

The ultimate surgical therapy for refractory TAO (in patients who continue smoking) is distal limb amputation for nonhealing ulcers, gangrene, or intractable pain. Amputation should be avoided whenever possible, but if it is necessary, it should be performed in a way that preserves as much of the limb as possible.

Autologous bone marrow–derived progenitor cell implantation into ischemic limbs for potentiation of angiogenesis has been performed as an experimental alternative option. Results have been satisfactory, with minimal complication rates. Larger-scale studies and longer follow-up are needed before any firm recommendations can be made about this particular therapeutic option.^[9]

Endovascular options for treatment of occlusive lesions in TAO are becoming increasingly popular, with moderate- and long-term success seen in selected patients.^{[14, 15, 16]}  

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Prevention

The following strategies are important for preventing complications from TAO:

• Use of well-fitting protective footwear to prevent foot trauma and thermal or chemical injury
• Early and aggressive treatment of extremity injuries to protect against infections
• Avoidance of cold environments
• Avoidance of drugs that lead to vasoconstriction

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Consultations

Consultations that may be considered include the following:

• Rheumatologist
• Hematologist
• Vascular surgeon
• Smoking cessation counselor

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Medication Summary

The goals of pharmacotherapy are to treat pain and reduce morbidity. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics can be administered to palliate ischemic pain.

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Naproxen (Naprosyn, Aleve, Naprelan, Anaprox)

• Dosing, Interactions, etc.

Clinical Context:  Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing COX activity, which results in decreased prostaglandin synthesis.

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Ibuprofen (Motrin, Advil, Addaprin, Caldolor)

• Dosing, Interactions, etc.

Clinical Context:  Ibuprofen is the drug of choice (DOC) for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

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Indomethacin (Indocin)

• Dosing, Interactions, etc.

Clinical Context:  Indomethacin is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

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Diclofenac (Voltaren XR, Cataflam, Zipsor, Cambia, Zipsor, Zorvolex)

• Dosing, Interactions, etc.

Clinical Context:  Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

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Ketoprofen

• Dosing, Interactions, etc.

Clinical Context:  Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.

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Class Summary

NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase (COX) activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

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Acetaminophen (Tylenol, FeverAll, Aspirin Free Anacin)

• Dosing, Interactions, etc.

Clinical Context:  Acetaminophen is the DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, who have upper GI disease, or who are taking oral anticoagulants.

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Acetaminophen and codeine (Tylenol #2, Tylenol #3, Tylenol #4)

• Dosing, Interactions, etc.

Clinical Context:  This combination is indicated for the treatment of mild to moderate pain. The available dosage strengths are as follows:

•Tylenol #2: 300 mg Tylenol/15 mg codeine

•Tylenol #3: 300 mg Tylenol/30 mg codeine

•Tylenol #4: 300 mg Tylenol/60 mg codeine

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Hydrocodone and acetaminophen (Vicodin, Lorcet, Lortab, Norco)

• Dosing, Interactions, etc.

Clinical Context:  This drug combination indicated for moderate to severe pain.

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Class Summary

Pain control is essential to quality patient care. It ensures patient comfort, promotes pulmonary toilet, and aids physical therapy regimens. Many analgesics have sedating properties that benefit patients who have sustained trauma.

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