Epidemiology and Etiology

Epidemiology

• Thromboangiitis obliterans (TAO) is most prevalent in regions and countries with heavy tobacco use:
  • Mediterranean 
  • Middle East 
  • Asia
• Decreasing rates in North America and Western Europe are due to the decline in cigarette smoking:
  • Current rate of 12.6‒20 cases per 100,000 
  • Unclear how vaping will affect TAO cases
• Men > women (3:1)
• The majority of patients present before the age of 45.

Etiology

• Tobacco use is seen in all patients with TAO: 
  • Heavy cigarette smokers (most common)
  • Cigar smokers
  • Marijuana users (cannabis arteritis) 
  • Smokeless tobacco users (chewing tobacco and snuff)
• Potential genetic predisposition: 
  • HLA-A9 
  • HLA-B5
  • HLA-A54

Pathophysiology

• General pathophysiology is not well known:
  • An inflammatory and immunologic pathogenesis is postulated.
  • Tobacco use could be a toxic trigger, or cause a delayed hypersensitivity reaction.
• 3 pathologic phases:
  • Acute phase: 
    • Occlusive, inflammatory thrombi develop in arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries and veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins of distal extremities.
    • Microabscesses and inflammatory cells are present.
    • Internal elastic lamina is intact.
    • External elastic lamina may be disrupted.
  • Intermediate (subacute) phase: 
    • Progressive organization of the inflammatory thrombus 
    • Vascular fibrosis is seen.
  • Chronic phase: 
    • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is no longer present.
    • Organized thrombus and vascular fibrosis remain.
    • Indistinguishable from other types of occlusive arterial disease in the chronic phase
• Other possible contributors: 
  • Endothelial dysfunction
  • ↑ Cytokine production
  • Prothrombotic factors

Clinical Presentation

Clinical presentation

• Young smoker (< 45 years of age)
• ≥ 2 extremities are usually involved (many times all 4 are involved)
• Symptoms:
  • Intermittent claudication of the feet, legs, hands, or arms
  • Progresses to pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain of the digits at rest
  • Ulcerations on the fingers, toes, or feet
  • Paresthesias
  • Color changes of digits
  • Episodic arthralgias or arthritis (usually wrists and knees)

Physical exam

• Superficial thrombophlebitis (approximately 50% of cases):
  • An early manifestation
  • Often migratory
  • Tender nodules and cords
  • Follows a venous distribution
• Raynaud’s phenomenon (vasospasm of the digits in response to cold or emotional stress):
  • Another early manifestation
  • Reversible pallor, cyanosis, or erythema of the digits
  • May be asymmetric
• Digital ischemia (most common presentation):
  • Rubor or cyanosis of the digit (“Buerger’s color”)
  • Sensory abnormalities
  • Cool extremities
  • Diminished distal pulses
  • Ischemic ulcerations
  • Gangrene

Diagnosis

Clinical criteria

The diagnosis can be established without biopsy if the following criteria are met:

• Age less than 45 years
• Current or recent tobacco use
• Distal extremity ischemia on objective vascular testing:
  • Allen test: With simultaneous compression of the radial and ulnar arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries, the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand remains pale after alternately releasing.
  • Ankle-brachial index (ABI) 
  • Wrist-brachial index (WBI)
  • Typical arteriographic findings of TAO 
• Exclusion of other potential causes

Workup

• Biopsy: 
  • Rarely needed, but is the only modality that will give definitive diagnosis
  • May biopsy subcutaneous nodules or superficial thrombophlebitis
  • Findings: 
    • Inflammatory intraluminal thrombus, which is highly cellular 
    • Sparing of the vessel wall
  • Biopsy non-healing ulcers or lesions to rule out cancer.
• Laboratory tests: 
  • Used to rule out other causes of vascular disease
  • The following should all be normal:
    • Complete blood count (CBC) with differential
    • Complete metabolic panel
    • Urinalysis
    • Antinuclear antibody, rheumatoid factor, complement, anti-centromere antibody, anti- scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma 70 antibody → rule out vasculitis
    • Antiphospholipid antibody, partial thromboplastin time (PTT), prothrombin time (PT), factor V Leiden, antithrombin III, protein C and S, prothrombin gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations → rule out hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States disorders 
    • Toxicology panel → evaluate for cannabis arteritis
• Imaging:
  • Angiography:
    • Evaluates the extent of the disease
    • Non-atherosclerotic, segmental, occlusive lesions in small- to medium-sized vessels
    • Formation of small collateral vessels around the occlusion (“corkscrew collaterals”)
    • Similar findings can be seen in other autoimmune disorders
  • Computed tomography with angiography (CTA) and magnetic resonance with angiography (MRA): can be used, but may not provide adequate detail
  • Echocardiogram: used to rule out a cardioembolic source

Management, Complications, and Prognosis

Management

• Tobacco cessation:
  • Most effective way to “treat” TAO, and decreases the risk of amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation
  • Counseling on complete abstinence of tobacco and cannabis is required.
  • Medications: 
    • Only non-nicotine products are used (bupropion, varenicline).
    • Avoid nicotine patches and gum due to a concern that they may continue the disease.
  • Failure of tobacco cessation will lead to disease progression.
• Intermittent pneumatic compression: 
  • Limited data
  • Useful in small vessel occlusive disease of other etiologies
  • Can be used for painful ulcerations, but improvement is slow
• Vasodilators: 
  • Alleviate symptoms only
  • Medication options:
    • Prostacyclin analogues (iloprost)
    • Phosphodiesterase (PDE) inhibitors (cilostazol, pentoxifylline)
    • Alpha-adrenergic receptor antagonists
    • Nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates
    • Calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) (frequently used for Raynaud’s phenomenon)
• Revascularization:
  • May not be feasible due to distal disease
  • Arterial bypass surgery:
    • Reserved for severe ischemia
    • Requires a suitable target
  • Thrombolytic therapy and angioplasty are rarely used.

Complications

• Infection
• Ulcerations
• Gangrene
• Amputation
• Occlusion of coronary, renal, splenic, or mesenteric arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries causing organ ischemia

Prognosis

• 94% of patients who stop smoking will avoid amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation.
• 43% of patients who continue using tobacco will require amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation within 8 years.

Differential Diagnosis

• Peripheral artery disease Peripheral artery disease Peripheral artery disease (PAD) is obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. The disease can be a result of atherosclerosis or thrombosis. Patients may be asymptomatic or have progressive claudication, skin discoloration, ischemic ulcers, or gangrene. Peripheral Artery Disease (PAD): atherosclerotic arterial narrowing resulting in ischemia to the distal limbs. Risk factors include hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hyperlipidemia, diabetes, tobacco use, and increased age. Patients will have intermittent claudication, cyanosis, ischemic ulcers, and gangrene. The clinical picture, along with abnormal ABIs, will establish the diagnosis and differentiate PAD from TAO. Management includes risk factor modification, antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents, PDE inhibitors, and revascularization.

• Thromboembolic disease: vascular occlusion due to a dislodged thrombus from a more proximal source. The presentation depends on the source, size, and location of the embolism, but includes acute limb ischemia Acute limb ischemia Acute limb ischemia (ALI) is a major vascular emergency because of the rapid decrease in limb perfusion that causes a potential threat to limb viability. The majority of cases are caused by arterial thrombosis due to plaque progression or embolism, but ALI can also be caused by blockage of the venous drainage. Acute Limb Ischemia and blue toe syndrome. The clinical history, hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States workup, and imaging aid in the diagnosis, and a source will typically be suspected or found on workup, which differentiates thromboembolic disease from TAO. Management includes anticoagulation and revascularization. 

• Vasculitis: a vascular inflammatory disease, often resulting in ischemia, necrosis, and organ damage. Any vessel can be involved, which differentiates vasculitis from TAO. Etiologies include autoimmune disorders, drugs, and infections. Patients present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, arthralgias, arthritis, as well as potential end-organ damage. Diagnosis involves inflammatory markers, autoimmune serology, infectious workup, and biopsy. Management depends on the underlying cause.

• Popliteal artery entrapment syndrome: an uncommon condition in which an abnormally positioned, or enlarged, calf muscle compresses the popliteal artery. The compression leads to obstruction of blood flow to the lower extremity, and resembles the distal extremity ischemia, ulceration, or necrosis of TAO. The diagnosis is made with imaging, which will differentiate popliteal artery entrapment syndrome from TAO. Management includes avoiding any inciting exercise and vascular surgery Vascular surgery Vascular surgery is the specialized field of medicine that focuses on the surgical management of the pathologies of the peripheral circulation. The main goal of most vascular procedures is to restore circulatory function to the affected vessels by relieving occlusions or by redirecting blood flow (e.g., bypass). Vascular Surgery evaluation.

• Frostbite Frostbite Injuries due to cold weather are common among children and athletes who are involved in sports played in cold conditions. Frostbite is a direct freezing injury to the peripheral tissues and occurs when the skin temperature drops below 0°C (32°F). Common sites of frostbite include the nose, ears, fingers, and toes. Frostbite: injury due to freezing of the tissues that can be associated with vascular thrombosis. Frostbite Frostbite Injuries due to cold weather are common among children and athletes who are involved in sports played in cold conditions. Frostbite is a direct freezing injury to the peripheral tissues and occurs when the skin temperature drops below 0°C (32°F). Common sites of frostbite include the nose, ears, fingers, and toes. Frostbite commonly affects the fingers, toes, nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, ears, cheeks, and chin. A severe cold exposure history is present, and findings include numbness, white or cyanotic discoloration of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, bullae, eschar, or tissue necrosis. The diagnosis is clinical, and management involves rewarming and wound care. Severe injuries receive thrombolysis and prostacyclin therapy.

• Raynaud’s syndrome: arterial vasospasm that causes episodes of reduced blood flow to the fingers and toes, typically due to cold exposure or stress. The affected digits may be transiently pale, cyanotic, or hyperemic, and accompanied by numbness or pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Findings are generally symmetric. Secondary Raynaud’s syndrome can be seen with TAO, which will show asymmetric findings. Diagnosis is clinical, and management includes cold exposure avoidance and vasodilators.