Thromboangiitis Obliterans

Definition

Thromboangiitis obliterans (TAO), also known as Buerger disease (BD) or von Winiwarter–Buerger syndrome, is a rare inflammatory, nonatherosclerotic, occlusive, peripheral vascular disease primarily involving infrapopliteal and infrabrachial medium and small-sized arteries and veins. It is predominantly a disease of young men, with onset typically before the age of 45 to 50 years. The prevalence in women, however, has been increasing related to increased tobacco use. ^{, , ,} The disease is more common among people of the Middle East, Asia, Mediterranean region, and Eastern Europe but is rare in Africa, Western Europe, and North America. TAO is typically manifested by distal extremity ischemia involving the feet, legs, or hands leading to critical limb ischemia (CLI), ischemic ulcerations, digital gangrene, and limb infection. ^{, ,}

TAO develops as a response to environmental factors primarily with smoking, resulting in major and minor amputations with a high degree of morbidity and disability resulting in unemployment, psychological, behavioral, social, and financial costs. ^, Pathologically, TAO is characterized by a highly inflammatory thrombus and preservation of all layers of the arterial wall, including internal elastic lamina. ^, The disease frequently involves adjacent or superficial veins and nerves. TAO has been classified under non-necrotizing, non-granulomatous, medium, and small-vessel vasculitis. However, TAO has not been included in the revised 2012 Chapel Hill consensus conference nomenclature of vasculitiis. ^, Absence of markers of inflammation and autoantibodies is unique for TAO compared to other types of vasculitis. ^, Patients experience periods of acute exacerbation 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, and multi-organ involvements have also been described. Reduction in the extremity amputation rate can be achieved by smoking cessation. For optimal outcomes, an interdisciplinary care team approach is required for the management of TAO patients.

Brief Historical Review

Reports resembling TAO have appeared in medical writings since the mid-1800s, but the cases were labeled arteriosclerosis obliterans (ASO) or frostbite because of the lack of pathologic confirmation. In 1879, Felix von Winiwarter described a 57-year-old man with a lengthy history of foot pain that eventually progressed to gangrene and limb loss, which is now recognized as the first published case of a patient with CLI. ^{, ,} In 1898, Haga reported similar clinical features resulting in spontaneous gangrene. In 1908, Leo Buerger described a new and unusual form of progressive vaso-occlusion in Polish and Russian immigrants who underwent amputation for “Spontan-gangrän” . Based on his findings, Buerger called the disease “ thromboangiitis obliterans ” to distinguish it from ASO. Subsequently, Buerger emphasized the association of migrating thrombophlebitis with thrombo-angoiitis. Buerger’s 32-chapter, 628-page monograph entitled “ The Circulatory Disturbances of the Extremities ” was published in 1924. Allen and Brown reviewed 200 patients diagnosed with TAO who were evaluated at the Mayo Clinic from 1922 to 1926. However, between the 1930s and 1960s, numerous investigators expressed skepticism concerning the identity of TAO. In the early 1960s, several authorities considered TAO a distinct diagnosis that should be separated from ASO. Today, TAO is accepted as a definite medium and small-vessel vasculitis with a typical clinical picture, natural history, and histopathology. ^{, , , , ,}

Population Affected

According to the World Health Organization (WHO), there are currently an estimated 1.3 billion smokers globally, and over 80% live in low- and middle-income countries. TAO is found worldwide and affects both sexes and all races; however, the incidence varies by geographic location, ^{, , , , ,} and uneven gender distribution. ^, Buerger’s view of the disease as being restricted mainly to the Jewish race is no longer valid. ^, TAO is more common in the Middle East, Asia, the Mediterranean, and Eastern Europe but is rare in Africa, central Europe, and North America. The prevalence of TAO among all patients with peripheral arterial disease varies throughout the world; 0.75% in North America, 0.5 to 5.6% in Western Europe, 3%–39% in Eastern Europe, 6.6% in Turkey, 80% Israel among Jews of Ashkenazi ancestry, 16% in Japan, 66% in Korea, and 45%–63% in India. ^{, ,}

TAO has a striking predominance in men, especially in series reported before 1960. The reported incidence of TAO in women was less than 1% in most published series in that era. Indeed, only two of Buerger’s 500 reported cases were women. However, TAO is no longer exclusively seen in the male population. ^, Rising use of tobacco products by young women lead to the decrease in gender differences in the current series, in which 9.8% to 30% of patients were women. ^{, , , ,} Currently, TAO affects men at a 4-fold to a 10-fold higher rate than women. ^{, , , , ,} A limited number of pregnancies among patients with active TAO has also been reported.

There was an 8-fold decrease in the annual incidence of TAO at the Mayo Clinic (from 104 in 1947 to 12.6 in 1986, per 100,000 patient registrations). ^, The number of new patients with TAO in Japan has also been decreasing ; the ratio of TAO to ASO patients has declined from 1:3 in the 1990s to 1:10 after 2000 in Japan. Currently, TAO affects approximately 10 in 100,000 people in the European Union (estimated from the applications to the Committee for Orphan Medicinal Products). The number of patients affected by TAO is estimated at 51,000 in the European Union, and 4000 in Japan. The pooled characteristics of patients with TAO are listed in Table 139.1 .

Risk Factors

The only risk factor consistently reported is smoking. The strong correlation between tobacco use and the pathogenesis, initiation, and progression of the disease is well established. ^{, , , , ,} There is also a higher incidence of TAO among individuals with cigar and pipe smoking; habitual home-made cigarette smoking such as “bidi” smoking in India, Bangladesh, and Ceylon ; “ kawung ” smoking in Indonesia ^, ; and chewed “ miang ” (steamed tea leaves) or “ khiyo ” (the home-made raw tobacco in hand-rolled banana leaves) smoking in Thailand, or mixing cannabis with tobacco in hand-rolled cigarettes in France as well as in users of smokeless tobacco and marijuana. ^, Lower socioeconomic status, poor oral hygiene, nutritional deficits, a history of viral or fungal infection, cold injury, abuse of sympathomimetic drugs, and arsenic intoxication are reported as other possible risk factors. ^{, ,} An emerging body of evidence demonstrates that ischemia induced by cocaine, amphetamines, and cannabis addiction can closely mimic TAO symptoms or may accelerate TAO onset and presentation. Furthermore, a close relation between long-term arsenic exposure from artesian well water and endemic Blackfoot disease has been reported in Taiwan. ^, In fact, arsenic adulteration of tobacco as a causative agent for TAO has been suggested in populations smoking bidis or kawung. ^,

Etiology

The etiology of TAO is unknown; however, the close association between disease activity and tobacco use in any form is beyond any debate. ^{, , , , , ,} Genetic predisposition, immune-mediated mechanisms, hypercoagulable states, endothelial dysfunction, and an oral infection–inflammatory pathway have been implicated as potential etiologic factors. ^,

Pathology

The specific pathologic mechanisms in TAO are still unknown. Buerger disease is characterized by segmental inflammatory cell infiltration of the vessel wall and arterial or venous thrombotic occlusions. ^{, ,} Hypercellular, inflammatory thrombus formation and preserved architecture of vessel walls are well established in TAO. Earlier studies suggested TAO as a thrombotic disorder complicated by vasculitis, namely transmural neutrophilic infiltration. ^, Today, there are compelling reasons to believe that the first event is the activation of antigen-presenting cells following endothelial cell damage induced by an unidentified antigen, possibly tobacco glycoproteins. ^{, , ,} Cellular and humoral inflammation, which leads to thrombotic occlusion of the blood vessels, is restricted to the intima of the artery, which defines TAO as an endarteritis. ^, Intimal inflammation followed by T-cell infiltrations might result in early arterial occlusion, which is the pathognomonic finding in TAO. Inflammatory cell infiltration is found in the intimal layer and the thrombus. ^,

The evolution of TAO is often categorized into three stages. In the acute phase, inflammation affecting the small-caliber and medium-caliber (1- to 5-mm diameter) arteries and veins is observed ( Fig. 139.1 ). The primary features of TAO during the acute phase include occlusive, highly cellular arterial thrombus, polymorphonuclear cell infiltration, giant cells, and micro-abscess formation; marked inflammation of the entire vessel wall and neurovascular bundle. ^{, ,} However, most of the infiltrating cells are detected in the intima. The intense inflammatory infiltration and cellular proliferation seen in acute lesions are distinctive, especially when veins are involved. Multinucleated giant cells can be seen, but fibrinoid necrosis and granuloma are not observed. During the intermediate or subacute phase, there is a progressive organization of the occlusive thrombus, with partial recanalization and disappearance of the microabscesses. 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 vessels, has been shown in detail ( Fig. 139.2 ). ^{, ,} In addition, CD68+ macrophages or S-100+ dendritic cells are found in the intima during both the acute and subacute stages. IgG, IgM, and IgA and complement factors 3d and 4c are deposited along the inner aspect of the internal elastic lamina. The chronic phase or end-stage lesion is characterized by thrombus organization followed by recanalization, prominent vascularization of the media, and perivascular fibrosis. ^{, ,} Regardless of the pathologic stage, the internal elastic lamina and the architecture of the vascular walls are well preserved in TAO, in contrast with atherosclerosis and other types of systemic vasculitis ( Fig. 139.3 ). ^{, , , ,}

Vascular Evaluation

A complete vascular examination is critical for the diagnosis. Physical examination reveals the involvement of medium and small-sized arteries with regular brachial and femoral pulses. The radial, ulnar, dorsalis pedis, or posterior tibial pulses may be absent. Digital arteries may be occluded. An abnormal Allen test, which suggests ulnar artery occlusion in a young smoker with lower extremity ulcerations, is highly suggestive of TAO. Abnormal Allen tests occurred in 63% of cases in the Cleveland Clinic series. Superficial phlebitis may be another clue to the diagnosis. Neurological examination may document peripheral nerve involvement, with sensory findings in up to 70% of patients. Calculation of the ankle–brachial index (ABI), toe–brachial index (TBI), and wrist–brachial index at rest and after exercise is recommended as the initial screening test. Seasonal variation, with exacerbation of TAO occurring more frequently in the winter, has been reported ^, ; this may be attributed to cold weather and the stimulation of vasospasm and Raynaud phenomenon.

Noninvasive Testing

Four-limb segmental arterial pressure measurements and pulse volume recordings are usually normal above the knee and markedly reduced distally. Abnormal digital plethysmographic patterns in both lower and upper extremities would objectively document distal occlusive disease in a patient meeting the clinical criteria for TAO. ^{, , , ,} Calcification of the involved arterial wall is almost always absent on plain radiography. Arterial duplex scanning is used not only to exclude proximal atherosclerotic lesions and to demonstrate distal arterial occlusive disease but also to visualize and functionally evaluate the corkscrew-shaped collaterals. Using continuous wave Doppler ultrasound monophasic waveform pattern within the corkscrew-shaped collaterals is also known as Martorell’s sign (“snake” or “dot” sign) ( Fig. 139.5 ). These findings indicate selective impairment of vascular endothelium, but not smooth muscle cells in native arteries in patients with TAO. Besides, superb microvascular imaging may have a role in the identification and classification of corkscrew collaterals. Furthermore, blood flow patterns within the corkscrew collateral arteries using computational fluid dynamics simulation from CT-angiography images may help a better understanding of the disease progression. Laser Doppler flowmetry, transcutaneous oxygen, and carbon dioxide pressures can be useful to evaluate the severity of ischemia and the effectiveness of treatment.

Emboli as a cause of distal ischemia should be ruled out, as the signs and symptoms of embolic occlusions can mimic those of TAO. Cardiac investigations, including electrocardiography, rhythm monitoring, and echocardiography, are recommended to rule out cardiac and thoracic aortic sources of emboli to the involved extremity. Abdominal ultrasonography may be considered to rule out a proximal source of emboli from an abdominal aortic aneurysm or atherosclerotic aorta.

Gadolinium-enhanced magnetic resonance angiography and multidetector computed tomographic angiography ( Fig. 139.6 ) may be useful diagnostic alternatives in patients with TAO. Furthermore, ischemic ulcerations with signs and symptoms of secondary infection should be evaluated using conventional radiography and magnetic resonance imaging to determine osteomyelitis. Recently, 18F-fluorodeoxyglucose positron emission tomography has been investigated in TAO case series but found to be an unsuitable investigative procedure for the diagnosis of TAO.