Thromboangiitis Obliterans  

Thromboangiitis Obliterans  

• Thromboangiitis obliterans (TAO), also known as Buerger disease, is an uncommon, segmental nonatherosclerotic, inflammatory vascular disease that most commonly affects small- and medium-sized arteries, veins, and nerves of the extremities. ¹²³ 
• It is strongly associated with tobacco use and is characterized by the segmental presence of highly cellular and inflammatory thrombotic occlusions with relative sparing of the vascular wall. ² In comparison to intima and media involvement in atherosclerosis, TAO involves infiltration in all three layers of the arterial wall histologically. ⁴ 
• The disease is named after Leo Buerger (i.e., Buerger disease), who first published a detailed description of the disease process found in amputated limbs of patients in 1908. ⁴

Synonyms

• Buerger disease
• TAO
• Presenile gangrene

Epidemiology & demographics

Prevalence

Although TAO has been observed worldwide, it is most prevalent in the Mediterranean, Asia, the Middle East, and Eastern Europe, where the rate of tobacco use is higher. ⁵ Overall prevalence is declining in North America and Western Europe. ⁵

• •In the U.S., the prevalence is 12.6 in 100,000.
• •Among patients with peripheral artery disease, the prevalence of TAO has been reported to range as low as 0.5% to 5.6% in Western Europe to as high as 45% to 63% in India and 16% to 66% in Korea and Japan, although there are reports of changing demography including an increase in the number of non-Asians affected. ^3 , 5
• •It is reported to be as high as 80% among Ashkenazi Jews. ⁵

Predominant Gender & Age

TAO affects predominantly males (70% to 91%), typically between the ages of 25 and 45. However, recent studies suggest an increasing incidence among women (11% to 23%), likely reflecting increasing use of cigarettes among women. ⁶

Risk Factors

• •Smoking (tobacco, cigar, and marijuana) ⁶
• •Chewing tobacco
• •Male sex
• •Asian ethnicity
• •Chronic periodontal infections have been linked; however, a causative association has not been firmly established ⁷

Genetics

• •Those with increased levels of HLA-A9, HLA-B5, and HLA-54 may be more susceptible to TAO. ⁶

Physical Findings & Clinical Presentation

• •Typical presentation: Young male less than 45 yr old with a strong history of tobacco use.
• •Signs of digital ischemia on physical exam ² :
  • 1.Prolonged capillary refill with dependent rubor
  • 2.Absent or diminished distal pulses
  • 3.Digital skin discoloration/cyanosis, Raynaud phenomenon
  • 4.Digital ulcerations
  • 5.Gangrene
  • 6.Superficial thrombophlebitis in a migratory pattern of tender nodules, especially in young people, may be highly suggestive of TAO.
• •Other common symptoms:
  • 1.Paresthesias.
  • 2.Claudication with involvement of arch of foot is an early and specific sign of TAO.
  • 3.As disease progresses, typical claudication symptoms develop and eventually resting pain and digit ulceration.
  • 4.The predominance of distal limb involvement helps distinguish TAO from peripheral artery disease. Among 825 TAO patients, 5% involved upper extremities, 75% involved lower extremities, and 20% both. ²
  • 5.On rare occasions with advancement of disease, the proximal arteries can become involved, and more dramatic presentations can develop involving the visceral, cerebral, renal, ocular, and coronary arteries, including case reports of coronary artery dissection, acute kidney injury, and papillo-phlebitis. ²

What causes Thromboangiitis Obliterans?

• •The etiology of TAO remains unclear; however, a multifactorial mechanism has been proposed involving a combination of genetic susceptibility, tobacco exposure, prothrombotic factors, and autoimmune response.
• •Impaired endothelium-dependent vasorelaxation in the peripheral vasculature of patients has been noted.

There is a growing body of evidence to suggest that alterations in the autoimmune response play a role in disease progression. Cell-mediated sensitivity to types I and III collagen are detected with increased frequency in patients with thromboangiitis obliterans. ⁸ The immunology of TAO is complex, with multiple pathways implicated. It is a matter of current study.

Differential Diagnosis

• •Atherosclerosis
• •Acquired or inherited hypercoagulability
• •Thromboembolic disease
• •Vasculitides including polyarteritis nodosa
• •Autoimmune and connective tissue diseases, i.e., systemic lupus erythematosus (SLE), CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), and scleroderma
• •Diabetic angiopathy
• •Acrocyanosis
• •Traumatic arterial thrombosis
• •Occupational (chronic vibration syndrome, hypothenar hammer syndrome)
• •Ergotamine, lead, or drug poisoning
• •Disseminated intravascular coagulation
• •Marijuana-associated peripheral arteriopathy (subject of a case report)

How is this condition diagnosed?

Diagnostic evaluation for thromboangiitis obliterans is summarized in the below table . There are no universally accepted diagnostic criteria, but several have been proposed over the years. Biopsy would provide a definitive diagnosis but is rarely needed, and a clinical diagnosis can be established in patients who meet the following criteria ⁶ :

• •History of smoking or tobacco use
• •Onset before the age of 50 yr
• •Evidence of distal extremity ischemia
• •Typical angiographic findings of TAO (sensitive but not specific)
• •Absence of atherosclerotic risk factors other than smoking

Diagnostic Evaluation for Thromboangiitis Obliterans

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Clinical	Laboratory	Imaging and Physiologic Testing
Digit ulcers	Complete blood cell count	Echocardiography
Gangrene	Liver function tests	Arteriography
Venous nodules or cords	Serum creatinine	Segmental pressures
Sensory deficits	Fasting blood glucose	Arterial waveform analysis
Allen test	Sedimentation rate
Ankle-brachial index	Antinuclear antibody
	Rheumatoid factor
	Complement
	CREST serology
	Scleroderma serology
	Hypercoagulability
	Toxicology screen

CREST, Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.

Laboratory Tests

• •There are no specific tests to diagnose TAO. The primary goal of laboratory testing is to exclude alternative diagnoses. The following labs are usually normal or negative in patients with TAO but should be obtained:
  • 1.Inflammatory markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
  • 2.Autoimmune panel: Antinuclear antibodies (ANA), rheumatoid factor (RF), anticentromere and anti-SCL70
  • 3.Hypercoagulability workup: Lupus anticoagulant, anticardiolipin antibody, proteins C and S, antithrombin III, prothrombin gene mutation, and factor V Leiden
  • 4.Toxicology screen: Cocaine, amphetamine, cannabis
  • 5.CBC and metabolic panel
• •If there is clinical suspicion for the disease but the patient denies use of tobacco, a urine cotinine level can be ordered to confirm suspicion of recent smoking. ⁹
• •Recent data has suggested the utility of a neutrophil/lymphocyte ratio in routine evaluation. ¹⁰ Another recent study also associated TAO with elevated homocysteine levels. ¹¹

Noninvasive vascular evaluation

• •Ankle-brachial index if lower-extremity signs or symptoms, wrist-brachial index for upper-extremity signs or symptoms with digit pressures should be performed.
• •Digital plethysmography may demonstrate attenuated, flattened arterial waveforms.
• •Allen test.
• •Some investigative modalities are laser Doppler volumetry and laser speckle imaging, which have been suggested as adjuvant imaging modalities to assist with diagnosis.
• •These nonspecific tests assess perfusion to distal extremities and do not distinguish TAO from other forms of peripheral vascular disease.

Imaging Studies

• •Noninvasive evaluation with computed tomographic angiography (CTA), magnetic resonance angiography (MRA), or duplex ultrasonography can assist.

• •Echocardiography may be required to rule out thromboembolic causes.
• •Angiography remains the gold standard and may be performed to define the extent of disease, to confirm the diagnosis, and potentially to deliver therapeutic interventions. ¹²
• •Typical angiography findings in TAO are described below.

Angiographic Findings in Thromboangiitis Obliterans (Buerger Disease)

From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.

• •Involvement of small- and medium-sized vessels; palmar, plantar, tibial, peroneal, radial, and ulnar arteries; and digital arteries of fingers and toes
• •Normal extremity arteries proximal to the popliteal and distal brachial levels
• •Absence of proximal atherosclerosis and vascular calcification
• •No source of thrombus
• •Abrupt transition from a normal, smooth proximal artery to an area of occlusion
• •Symmetric and segmental arterial involvement
• •Tortuous “corkscrew” collaterals are suggestive, but not pathognomonic, of Buerger disease

Pathology

Although not necessary, biopsy helps confirm diagnosis and is useful in atypical presentations.

• •Histology differs based on three phases:
  • 1.Acute phase: Neutrophil infiltration and granulomatous formation and vascular occlusion from inflammatory thrombus, which occludes the vessel lumen but often spares the vessel wall.
  • 2.Subacute phase: Thrombus organizes further with platelet adherence.
  • 3.Chronic phase: No inflammatory mediators, organized thrombus and vascular fibrosis occlude vessels. May resemble atherosclerotic disease.

TREATMENT

MEDICAL THERAPY

• The below is the summary of the treatment options for thromboangiitis obliterans. Smoking cessation is the only definitive treatment for TAO. Complete abstinence may halt progression of disease and prevent flares. Use of nicotine replacement should be avoided due to risk of keeping disease active, but use of other smoking-cessation pharmacotherapy (e.g., bupropion or varenicline) is reasonable. The hazards of continued smoking in patients with TAO seem to be independent of factors such as number of cigarettes smoked per day. ^2 , 3
• •To date, there is no proven standard-of-care pharmacotherapy, and thus therapeutic options have been limited to prostaglandin analogs and vasodilators for palliative treatment.
  • 1.Lloprost, a prostaglandin analog, has been associated with reduced rest pain and greater healing of ischemic ulcers; however, it is not associated with a reduction in the amputation rate. The oral formulation has been shown to be no more effective than placebo. One randomized controlled trial showed that iloprost outperformed aspirin for ulcer healing and reducing pain, though amputation rates were unchanged between the two therapies. ¹³
  • 2.Vasodilators (calcium channel blockers, alpha-blockers, cilostazol, sildenafil) may be helpful in symptom relief but have not been studied in prospective clinical trials. ¹³
  • 3.Bosentan, an endothelin receptor antagonist most commonly used in pulmonary arterial hypertension, has been used as a non-FDA approved therapy. ¹³
• •Aspirin is routinely administered. There is limited evidence supporting the routine use of antiplatelet, anticoagulant, or thrombolytic agents. Among 18 patients with TAO treated with anticoagulation, 92% showed complete ulcer healing and 94% relief of pain after 14 days of treatment. Further studies are underway. ¹³
• •Daily foot and hand hygiene will prevent ischemic ulcers, as well as avoidance of trauma, vibration, and cold.

Treatment Options for Thromboangiitis Obliterans

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Tobacco cessation (only known, proven, established, and effective therapy)

Medical therapy

• Prostacyclin and its analogues
• Aspirin
• Selective low-dose intraarterial streptokinase
• Bosentan, a dual endothelin-1 receptor antagonist
• Cyclophosphamide
• Guanethidine sympathetic blocks
• Serotonin blockers
• Sarpogrelate
• Intramuscular injections of vascular endothelial growth factor
• Phosphodiesterase type 5 (PDE5) inhibitors
• Omalizumab

Endovascular Therapies

• •Extended angioplasty of each tibial and foot artery obstruction

Surgical Treatment

• •Sympathectomy
• •Arterial reconstruction
• •Omental transfer
• •Kirschner wire in medullary canal of tibia

Experimental Therapies

• •Intramuscular injection of vascular endothelial growth factor
• •Autologous whole bone marrow stem cell transplantation by fenestration
• •Immunoadsorption
• •Beperminogene perplasmid use

Interventional therapy

• •Pneumatic compression has been used to augment perfusion to the lower extremities in patients with severe claudication or critical limb ischemia who are not revascularization candidates.
• •Endovascular treatment with extended angioplasty at the tibial and foot arteries remains an option for patients with TAO and critical limb ischemia. This modality has prevented major amputations, with studies reporting a technical success rate of 66.7%-91%, a limb salvage rate of 92%-100%, sustained clinical improvement in 84.2% of patients, and complete wound healing in ischemic ulcers.
• •Surgical revascularization usually is not feasible due to the distal and diffuse nature of the disease. However, bypass may be considered in patients with more proximal disease or suitable distal target vessels.
• •Use of a spinal cord stimulator has been shown to improve regional perfusion and symptoms. It relieves pain through several mechanisms, including preventing transmission of painful stimuli through the corresponding dermatomes, stimulating the production of inhibitory neurotransmitters, and inhibiting sympathetic vasoconstriction, which improves peripheral microcirculation.
• •Sympathectomy may be considered for patients with refractory pain and digital ischemia

Treatment Options in Thromboangiitis Obliterans (Buerger Disease)

From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.

• •Cessation of tobacco products
• •Local wound care
• •Arterial reconstruction with vein graft
• •Prostaglandin analog iloprost or treprostinil sodium
• •Cilostazol
• •Hyperbaric oxygen therapy
• •Calcium channel blockers (e.g., amlodipine or nifedipine for vasospasm)
• •Intermittent pneumatic compression pump
• •Implantable spinal cord stimulator
• •Therapeutic angiogenesis
• •Amputation

Outcomes

• •Periods of exacerbation and remission are characteristic of TAO. The disease typically intensifies at the age of 30 to 40 and then abates. Patients aged 60 yr or older rarely have recurrence of symptoms. ³
• •The risk of major amputation was 11% at 5 yr, 21% at 10 yr, and 23% at 20 yr. Risk of amputation was eliminated by 8 yr after smoking cessation. Multiple amputations and progressive disability cause decline in quality of life. ³
• •One long-term follow-up of 224 patients demonstrated that in a mean of 5.7 yr, vascular events occurred in 58.9% of patients, amputation in 21.4%, and death in 1.4%.
• •Patients with TOA are prone to premature atherosclerosis, and thus the incidence of peripheral and coronary atherosclerosis is higher in this patient population. ^14 , 15

Referral

Smoking cessation counseling, rheumatology consultation, and vascular surgery consultation are recommended for any young smokers with claudication and ischemic ulcers. ²

Pearls & Considerations

• •The pathogenesis of the disease is poorly understood, but tobacco use plays a key role.
• •A multifactorial mechanism has been proposed that involves a combination of genetic susceptibility, tobacco exposure, prothrombotic factors, and autoimmune response.
• •The diagnosis is predominantly clinical, and there are no universally accepted diagnostic criteria. Biopsy can confirm diagnosis but is rarely needed.
• •Discontinuation of tobacco use is the only known definitive therapy for TAO.

Patient & Family Education

Patients with TAO must be warned about tobacco use and secondhand passive smoke. Information for patients can be obtained from the following organizations:

• •Mayo Foundation for Medical Education and Research ( www.mayoclinic.com )

References

1.Piazza G., Creager M.A.: Thromboangiitis obliterans . Circulation 2010; 121 (16): pp. 1858-1861.

2.Olin J.W.: Thromboangiitis obliterans (Buerger’s disease) . N Engl J Med 2000; 343 (12): pp. 864-869.

3.Olin J.W., et al.: The changing clinical spectrum of thromboangiitis obliterans (Buerger’s disease) . Circulation 1990; 82 (5 Suppl): pp. IV3-8.

4.Buerger L.: Landmark publication from the American Journal of the Medical Sciences, “Thrombo-angiitis obliterans: a study of the vascular lesions leading to presenile spontaneous gangrene.” 1908 . Am J Med Sci 2009; 337 (4): pp. 274-284.

5.Arkkila P.E.T.: Thromboangiitis obliterans (Buerger’s disease) . Orphanet J Rare Dis 2006; 1: pp. 14.

6.Mills J.L., Porter J.M.: Buerger’s disease: a review and update . Semin Vasc Surg 1993; 6 (1): pp. 14-23.

7.Iwai T., et al.: Oral bacteria in the occluded arteries of patients with Buerger disease . J Vasc Surg 2005; 42 (1): pp. 107-115.

8.Joviliano E.E., et al.: Etiopathogenesis, clinical diagnosis and treatment of thromboangiitis obliterans—current practices . Int J Angiol Off Publ Int Coll Angiol Inc 2009; 18 (3): pp. 119-125.

9.Hurt RD, Hays JT: Urinary tobacco alkaloid measurement in patients having thromboangiitis obliterans, Mayo Clin Proc 83(10):1187-1188; author reply 1188, 2008. https://doi.org/10.4065/83.10.1187-b .

10.Altun G, Hemsinli D: An evaluation of the neutrophil-to-lymphocyte ratio as a prognostic and predictive marker in thromboangiitis obliterans, J Turgut Ozal Med Cent . Published online January 1. https://doi.org/10.5455/jtomc.2017.11.140 .

11.Rong D., et al.: Associations between elevated plasma total homocysteine level and risk of thromboangiitis obliterans in a Chinese population: a matched case-control study . Ann Vasc Surg 2020; 62: pp. 335-341.

12.Lambeth J.T., Yong N.K.: Arteriographic findings in thromboangiitis obliterans with emphasis on femoropopliteal involvement . Am J Roentgenol Radium Ther Nucl Med 1970; 109 (3): pp. 553-562.

13.Cacione D.G., et al.: Pharmacological treatment for Buerger’s disease . Cochrane Database Syst Rev 2020; 5: pp. CD011033.

14.Dargon P.T., Landry G.J.: Buerger’s disease . Ann Vasc Surg 2012; 26 (6): pp. 871-880.

15.Choi B., et al.: The incidence, prevalence, and survival rate of thromboangiitis obliterans in Korea: a retrospective population-based study . Cardiovasc Diagn Ther 2020; 10 (5): pp. 1238-1244.