Thromboangiitis Obliterans (Buerger Disease)

Thromboangiitis obliterans (TAO) describes a segmental, nonatherosclerotic inflammatory disorder that primarily involves the small and medium arteries, veins, and nerves of the extremities. Although TAO was initially thought to be a disease confined exclusively to men, epidemiologic studies demonstrate a growing population of women with the disorder. Also known as Buerger disease, TAO has an extremely strong pathophysiological relationship with tobacco use, usually in the form of heavy cigarette smoking.

In 1879, von Winiwarter provided the first description of a patient with TAO. He presented the case of a 57-year-old man who had reported pain in his feet for 12 years. Histopathological examination of an amputation specimen from this patient demonstrated intimal proliferation, luminal thrombosis, and fibrosis. von Winiwarter hypothesized that the observed endarteritis and endophlebitis were distinct from atherosclerosis. In his landmark paper 29 years later, Leo Buerger published a detailed report of the pathological findings of 11 amputated limbs from patients with the disease. Buerger coined the term “thromboangiitis obliterans” to describe the characteristic observations of endarteritis and endophlebitis typical of the disease. Like von Winiwarter, Buerger made a point to distinguish the clinical and pathological findings of TAO from those of atherosclerosis.

In 1928, Allen and Brown described the clinical and pathological characteristics of 200 cases of TAO seen at the Mayo Clinic from 1922 to 1926. All patients were heavy smokers, and the pathological findings were virtually identical to those described in Buerger’s original paper.

Epidemiology

Although it is observed worldwide, TAO is more prevalent in the Middle East and Far East than in North America and Western Europe. Prior to the late 1960s, overdiagnosis of TAO was frequent. Of 205 cases originally diagnosed as TAO at Mount Sinai Hospital from 1933 to 1963, only 33 were later believed to be compatible with the diagnosis, 28 were considered questionable, and 144 were determined to be incorrect.

The reported number of new patients diagnosed with TAO in the United States and Europe has declined largely due to the adoption of stricter diagnostic criteria and a reduction in tobacco use. The overall incidence of TAO is higher in regions of the world where the consumption of tobacco is greater. At the Mayo Clinic, over a 40-year period, the prevalence rate of patients with the diagnosis of TAO has decreased from 104 per 100,000 patient registrations in 1947 to 13 per 100,000 patient registrations in 1986. The prevalence rate of TAO in patients with peripheral artery disease varies across Europe and Asia: 1% to 3% in Switzerland, 0.5% to 5% in West Germany, 1.2% to 5.6% in France, 4% in Belgium, 0.5% in Italy, 0.25% in the United Kingdom, 3.3% in Poland, 6.7% in East Germany, 11.5% in Czechoslovakia, 39% in Yugoslavia, 80% in Israel (among Ashkenazy Jews), 45% to 53% in India, and 16% to 66% in Japan and Korea. In Asia, a greater proportion of patients with limb ischemia has been attributed to TAO than in the United States and Europe.

The overall incidence of TAO also appears to be declining in South Asia and Japan. In particular, the ratio of new patients with TAO to new patients with atherosclerotic peripheral artery disease has declined precipitously. In particular areas of Southeast Asia, including India, TAO has been associated with lower socioeconomic class and smoking unrefined homemade tobacco cigarettes called bidi.

Although it has been considered a disease of young men, TAO also occurs in women. The mean age at onset of TAO is estimated to be 38 years. The reported incidence was less than 2% in the majority of published case series before 1970. Subsequent studies have demonstrated a much higher prevalence of TAO among women, ranging from 11% to 23%. The increasing prevalence of TAO among women has been attributed to rising consumption of tobacco products.

Etiology and pathogenesis

TAO is a vasculitis characterized by a highly cellular inflammatory thrombus with relative sparing of the vessel wall. The precise etiology of TAO remains unknown. TAO is distinct from other vasculitides because levels of acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein and commonly measured autoantibodies are typically normal. However, it has been suggested that abnormalities in immunoreactivity and other factors may contribute to the inflammatory process.

Tobacco

Exposure to tobacco is critical to the initiation, maintenance, and progression of TAO. Although smoking tobacco is by far the most frequent precipitating factor, TAO may also develop as a result of chewing tobacco, snuff, or marijuana use. The association between heavy tobacco use and TAO is so strong that it is typically considered to be a sine qua non for the diagnosis. The mean Brinkman index score (number of cigarettes smoked per day multiplied by the number of years of smoking) is 780. It has been hypothesized that some patients develop an immunological reaction to a constituent of tobacco that triggers small vessel occlusive disease. Because only a small proportion of smokers worldwide eventually develop TAO, other factors are believed to contribute to disease pathogenesis.

In South Asia, a large proportion of patients diagnosed with TAO belong to the lowest socioeconomic class and smoke bidi, a hand-rolled herbal cigarette made from dried betel leaves and tobacco. Bidi smoking is believed to account for the higher incidence of TAO in the Indian population.

In addition to its role in disease initiation, tobacco use is a critical factor in disease progression and continued symptoms associated with TAO. While second-hand or passive smoking has not been associated with the onset of TAO, it may play an important role in continuation of the disease process.

Genetic Predisposition

Several studies have suggested that there may be a genetic predisposition to develop TAO. Although there appears to be an association between certain human lymphocyte antigen (HLA) haplotypes and the development of TAO, no consistent pattern has been identified across patient populations. Lack of consistency in HLA haplotype predominance among various populations with TAO is likely due to genetic diversity and methodological differences in each of the studies.

In a study comparing 21 TAO patients with healthy age-, gender-, and race-matched controls, the frequency of mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) was evaluated. 5A/6A stromelysin-1 homozygosity was present in 7 of 21 (33%) TAO cases compared with 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5 to 3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) TAO cases compared with 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3 to 26.6). In another study, endothelial nitric oxide synthase (eNOS) 894 G → T and endothelin-1 (ET-1) 8000 T → C polymorphisms were assessed to determine whether either played a role in the development of TAO. Investigators found that the T allele of the eNOS 894 G → T polymorphism was protective against TAO.

Hypercoagulable States

The role of hypercoagulable states in the pathogenesis of TAO remains unclear because studies have failed to demonstrate a consistent pattern of association. Increased levels of anticardiolipin antibodies have been reported in patients with TAO.

Immunologic Mechanisms

Abnormalities in immunoreactivity are believed to play a critical role in the inflammatory process that characterizes TAO. Cellular and humoral immune responses to native human collagen Type I and Type III are increased in patients with TAO compared with those with atherosclerosis or in healthy male controls. Circulating immune complexes found in peripheral arteries of patients with TAO provide further evidence for an immunologic basis for this disease.

While the architecture of blood vessel walls is well preserved regardless of the stage of disease, cell infiltration is observed involving the thrombus and intima. Among infiltrating cells, CD3(+) T cells greatly outnumber CD20(+) B cells, and CD68(+) macrophages or S-100(+) dendritic cells are detected in higher number in the intima during acute and subacute phases. Deposits of immunoglobulins G, A, and M (IgG, IgA, IgM) and complement factors 3d and 4c are noted along the internal elastic lamina. These observations indicate that TAO represents an endarteritis that is characterized by both T-cell (cellular) and B-cell (humoral) mediated immunity in association with activation of antigen-presenting cells in the intima.

In patients with a definite diagnosis of TAO as determined by clinical criteria, linear arrangement of macrophages, B-lymphocytes, and T-lymphocytes along vascular elastic fibers has been found to be a predictable and specific inflammatory response to the internal elastic lamina of affected vessels. This finding indicates that elastic fibers are an important immunogen in the pathogenesis of the disease.

A study of 11 TAO patients detected autoantibodies directed against G-protein coupled receptors in 82%. The majority of these autoantibodies were directed against loop1 of the α1-adrenergic receptor, the endothelin-A receptor, the angiotensin-1 epitope 1 or 2, and the protease-activated receptor (PAR) loop1/2.

Endothelial Dysfunction

Abnormalities of endothelial function also appear to contribute to the pathogenesis of TAO. Although various autoantibodies commonly observed in vasculitides are typically absent, elevations in antiendothelial cell antibody titers have been documented in patients with active TAO. In the future, measurement of antiendothelial cell antibody titers among other biomarkers may serve as a useful tool in following disease activity.

Patients with TAO also demonstrate impairment of endothelium- dependent vasodilation in the peripheral vasculature. The increase in forearm blood flow response to intraarterial acetylcholine infusion is diminished in patients with TAO. In contrast, there is no significant difference in the increase in forearm blood flow response to sodium nitroprusside infusion and reactive hyperemia between the TAO patients and healthy controls.

In a study of 13 young male TAO patients and age-matched healthy smokers ( n = 11) and nonsmokers ( n = 12), TAO patients had lower numbers of endothelial progenitor cells (EPCs) and EPC colonies than both nonsmokers and smokers. These results suggest that TAO patients may have an intrinsic decrease in EPCs resulting in endothelial dysfunction that is not completely due to smoking.

Infection

Nearly two-thirds of patients with TAO have severe periodontal disease. Moderate periodontitis, severe periodontitis, and edentulism has been observed in 31%, 56%, and 13% of TAO patients, respectively. Polymerase chain reaction analysis demonstrated DNA fragments from anaerobic bacteria, in particular Treponema denticola , in both arterial lesions and oral cavities of patients with TAO but not in arterial samples from health control subjects.

Pathology

Pathologically, TAO is distinguished by inflammatory thrombus that affects small- and medium-sized arteries and veins. The histopathology of the involved blood vessels varies according to the stage at which the tissue sample is obtained. TAO involves three phases: acute, subacute, and chronic ( Fig. 42.1 ). The histopathology is most likely to be diagnostic of TAO in samples obtained during the acute phase of the disease. As the disease progresses from the subacute to chronic phases, the histopathology of TAO becomes virtually indistinguishable from other obstructive vascular diseases that result in fibrosis of the blood vessels in their end-stage. Because the histological appearance can vary from patient to patient and depends upon the stage of the disease, a pathological diagnosis of TAO may be challenging in some cases. Furthermore, the pathological diagnosis may be inconclusive if only amputated specimens or occluded arteries and veins are examined. Subacute and chronic phase lesions have far fewer characteristic features and therefore are rarely diagnostic for TAO.

Fig. 42.1, Histopathological stages of thromboangiitis obliterans.

Acute Phase

The acute phase of TAO comprises an occlusive, highly cellular, inflammatory thrombus. Polymorphonuclear neutrophils, microabscesses, and multinucleated giant cells are often present around the periphery of the thrombus ( Fig. 42.2 ). The presence of multinucleated giant cells is characteristic of, but not specific for, TAO.

Fig. 42.2, Typical acute histological lesion in a vein obtained from a patient with thromboangiitis obliterans (A). Close-up of the boxed area in A, demonstrating a microabscess in the thrombus and two multinucleated giant cells (hematoxylin and eosin, × 64 [A], × 400 [B]).

Inflammatory thrombus is observed with greatest frequency in biopsies of areas demonstrating acute superficial thrombophlebitis taken from patients with TAO. While it is unclear whether the vascular lesions of TAO are primarily thrombotic or inflammatory, the pattern of intense inflammatory cell infiltration and cellular proliferation observed in the acute phase of the disease is particularly distinctive. Acute phlebitis without thrombosis, acute phlebitis with thrombosis, and acute phlebitis with thrombus containing microabscesses and giant cells may coexist in different segments of the same affected vein if it is biopsied at an early stage.

Subacute (Intermediate) Phase

During the subacute or intermediate phase, progressive organization of the inflammatory thrombus takes place in affected arteries and veins. While some degree of inflammatory infiltrate remains within the thrombus, the vessel wall is generally spared. Partial recanalization of the vessel and disappearance of microabscesses may also be observed in the subacute phase.

Chronic (End-Stage) Phase

The chronic phase is characterized by organized thrombus with areas of extensive recanalization, prominent vascularization of the media, and adventitial and perivascular fibrosis. Because they represent the end products of vascular injury and occlusive thrombosis, chronic phase arterial lesions are the least distinctive of the three morphological stages of TAO. However, focal residual inflammation within the organized thrombus may suggest TAO in an end-stage lesion. Chronic phase lesions in TAO frequently mimic atherosclerotic vascular disease. In some patients, especially those over 40 years of age, both TAO and atherosclerotic vascular disease may coexist and thereby create further diagnostic uncertainty.

Additional Histologic Features

In all three phases of TAO, the normal architecture of the vessel wall adjacent to the occlusive thrombus, including the internal elastic lamina, remains intact. This observation distinguishes TAO from atherosclerotic vascular disease and from other systemic vasculitides in which there is typically disruption of the internal elastic lamina and the media. “Skip” areas in which normal vessel segments are observed between diseased ones are common in TAO. In addition, the intensity of the periadventitial inflammatory reaction can be quite variable in different segments of the same vessel.

Corkscrew collateral vessels, typically seen in areas of arterial occlusion in patients with TAO, may originate from the vasa nervorum rather than the vasa vasorum.

Immunohistochemical Features

Studies focusing on immunohistochemistry have provided a limited understanding of the role of the cytoskeleton and other cellular elements in TAO. Soon after the inflammatory thrombus has occluded the vessel lumen, spindle cells migrate from the media through fenestrations in the internal elastic lamina into the intima to populate the periphery of the thrombus. These spindle cells express vimentin and alpha-1-actin and originate from smooth muscle cells of the media. Capillaries appear along the margins of the thrombus. Endothelial cells express factor VIII-related antigen and Ulex europaeus agglutinin.

As the thrombus organizes during later stages of the disease, the spindle cells differentiate into fibroblasts and lose their positive staining for alpha-1-actin. Demonstration of the internal elastic lamina by collagen type IV markers confirms that the lamina remains intact in TAO and that smooth muscle cells migrate from the media to the intima via fenestrations. Newly formed capillaries within the thrombus are noted.

Immunohistochemically, the process of thrombus organization in TAO is virtually identical to that of ordinary thrombus with the exception of the characteristic inflammatory component. However, infiltration of smooth muscle cells from the media results in a more hypercellular thrombus and rapid organization.

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