Non-bacterial thrombotic endocarditis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

The association between thromboembotic events and malignancy was made by Armand Trousseau in the year 1865. In 1926, Dr. Benjamin Sacks and Dr. Emmanuel Libman published cases of “valvular masses” that were examined clinically and during autopsies and found to be free of all microorganisms. These masses were initially named “indeterminate endocarditis“.

According to Allen and Sirota,  Non-bacterial thrombotic endocarditis may be classified according to morphology into 5 subtypes.

Although the exact pathogenesis of non-bacterial thrombotic endocarditis is not completely understood, endothelial injury correlated with a hypercoagulable state has been implicated. Pathogenesis can be sub-sectioned into four factors thought to be involved in instigating NBTE. These include; Immune complexes, Hypoxia , Hypercoagulability, andCarcinomatosis. Conditions associated with nonbacterial thrombotic endocarditis include; Malignancies, Systemic autoimmune diseases (SLE is the most common,Hypercoagulable states, Chronic inflammatory states, Heart failure with valvulopathy, e.t.c.

Non-bacterial thrombotic endocarditis must be differentiated from other diseases that cause a new or changed heart murmur, multiple systemic emboli, +/-fever, such as infective endocarditis, degenerative valvular disease, and pulmonary infarction.

Non-bacterial thrombotic endocarditis is a rare autopsy finding. Although the exact incidence of NBTE is unknown, it is thought to be approximately 900-600 per 100,000 individuals worldwide. The prevalence of NBTE is approximately 9,300 per 100,000 individuals worldwide. Patients of all age groups may develop NBTE, usually in the 4th to 8th decade. There is no racial predilection to NBTE, and NBTE affects men and women equally.

The most potent risk factor in the development of non-bacterial thrombotic endocarditis is advanced malignancy. Other risk factors include systemic lupus erythematosus, antiphospholipid syndrome, and chronic inflammatory states.

There is insufficient evidence to recommend routine screening for non-bacterial thrombotic endocarditis.

Non-bacterial thrombotic endocarditis is an asymptomatic condition that can present acutely with recurrent thromboembolism. Prognosis is generally poor, as the disease is associated with advanced cancers, autoimmune diseases and recurrent thromboembolism.

There is no single diagnostic study of choice for the diagnosis of non-bacterial thrombotic endocarditis.

The majority of patients with non-bacterial thrombotic endocarditis are asymptomatic. Systemic embolism of the brain, liver, or spleen is a common initial clinical manifestation of NBTE, and occur in more than half of patients. Patients with NBTE may have a positive history of malignancy, disseminated intravascular coagulation, antiphospholipid syndrome, autoimmune disease such as systemic lupus erythematosus, e.t.c

There are no specific physical exam findings for non-bacterial thrombotic endocarditis. Patients with NBTE may show signs of systemic thromboembolism, cardiac dysfunction, and underlying diseases.

There are no specific diagnostic laboratory findings associated with non-bacterial thrombotic endocarditis. Tests are usually conducted to detect the underlying cause of NBTE and differentiate it from infective endocarditis.

There are no x-ray findings associated with non-bacterial thrombotic endocarditis. However, a chest x-ray may be helpful in the diagnosis of complications of NBTE, which include, cardiomegaly pulmonary congestion, pleural effusion, and calcifications due to the lesions.

Echocardiography may be helpful in the diagnosis of non-bacterial thrombotic endocarditis. It is especially important in visualizing valvular vegetations suggestive of NBTE. The vegetations in NBTE are typically <1cm, broad-based, and irregularly shaped. 75% of vegetations affect the mitral valves and less commonly have been found to involve all the cardiac valves.

Whole-body CT or MRI may be helpful in the diagnosis of non-bacterial thrombotic endocarditis. It may show evidence of systemic embolism in patients with undetermined NBTE.

There are no other diagnostic studies associated with non-bacterial thrombotic endocarditis.

There is no treatment for non-bacterial thrombotic endocarditis; the mainstay of therapy is the identification and treatment of the underlying condition, with an aim to reduce the risk of systemic embolism. Unless there is a specific contraindication, anti-coagulation with IV unfractionated heparin or subcutaneous low molecular weight heparin is recommended in all patients with a clinical diagnosis of NBTE.

There are no recommended therapeutic interventions for the management of non-bacterial thrombotic endocarditis

Surgery is not the first-line treatment option for patients with non-bacterial thrombotic endocarditis and is usually reserved for patients with either heart failure, acute valve rupture, or recurrence of thromboembolism despite adequate anticoagulation. It is important to weigh the risks associated with the patient’s underlying condition with the benefits of surgery.

There are no established measures for the primary prevention of non-bacterial thrombotic endocarditis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

The association between thromboembotic events and malignancy was made by Armand Trousseau in the year 1865. In 1926, Dr. Benjamin Sacks and Dr. Emmanuel Libman published cases of “valvular masses” that were examined clinically and during autopsies and found to be free of all microorganisms. These masses were initially named “indeterminate endocarditis“.

• The association between thromboembotic events and malignancy was made by Armand Trousseau in the year 1865.^[1]
• Non-bacterial thrombotic endocarditis (NBTE) was first discovered by Zeigler,^[2] in 1888 following his identification of vegetation in cardiac valves associated with inflammatory states.
• In 1926, Dr. Benjamin Sacks and Dr. Emmanuel Libman^[3] published cases of “valvular masses” that were examined clinically and during autopsies and found to be free of all microorganisms. These masses were initially named “indeterminate endocarditis”.
• In 1936, The name non-bacterial thrombotic endocarditis was coined by Gross and Friedberg. ^[4]. They postulated that the attachment of fibrin to cardiac valves is the cause of non-bacterial thrombotic endocarditis.
• In recent years it has been suggested that NBTE is a hypercoagulable state caused by a malignancy that leads to a surge in tumor necrosis factor and interleukin-1, resulting in the formation of thrombi.^[5]
  
• More recently, in addition to malignancies, NBTEs have been associated with infectious and autoimmune diseases and more recently, sepsis and burns.^[6][7][8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

According to Allen and Sirota, non-bacterial thrombotic endocarditis may be classified according to morphology into 5 subtypes

According to Allen and Sirota,^{[1] [2]} Non-bacterial thrombotic endocarditis may be classified according to morphology into 5 subtypes:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

Although the exact pathogenesis of non-bacterial thrombotic endocarditis is not completely understood, endothelial injury correlated with a hypercoagulable state has been implicated. Pathogenesis can be sub-sectioned into four factors thought to be involved in instigating NBTE. These include; Immune complexes, Hypoxia , Hypercoagulability, andCarcinomatosis. Conditions associated with nonbacterial thrombotic endocarditis include; Malignancies, Systemic autoimmune diseases (SLE is the most common,Hypercoagulable states, Chronic inflammatory states, Heart failure with valvulopathy, e.t.c.

• Although the exact pathogenesis of non-bacterial thrombotic endocarditis is not completely understood^[1], endothelial injury correlated with a hypercoagulable state has been implicated.
• The main culprit that has been identified is damage to the endothelium and consequent exposure of subendothelial connective tissue to circulating platelets, platelet deposition and the formation of initial thrombi by the migration of inflammatory mononuclear cells^[2].
• Deposited vegetation may be microscopic or large, and may have a wart-like appearance (verrucae)^[3].
• Depositions are more common in left-sided heart valves^[4] and do not require prior damage to the valve ( although they NBTE can also arise in preexisting valvular disease)^[5].
• Pathogenesis can be sub-sectioned into four factors thought to be involved in instigating NBTE. These include^[6];

1. Immune complexes^[7]
2. Hypoxia ^[8][9],
3. Hypercoagulability^[10], and
4. Carcinomatosis^[11]

• Circulating immune complexes was first identified in the formation of NBTE by Williams in 1980^[12].
• Since that time, immunohistochemical techniques have been used to identify immunoglobulin and complement deposits within vessel walls in the zone of neovascularization of verrucose valvular lesions.^[13]
• These findings are especially found in patients with systemic lupus erythematosus (SLE)^[14].

• Several studies have associated hypoxia with NBTE^[15][16][17].
• These studies were conducted in both human^[16][15] and animal^[17] models and they found that, increased or persistent exposure to hypoxic insult can lead to an increase in circulating tissue factor.
• Tissue factor has been found to lead to a hypercoagulable state, which may have predisposed the studied patient populations to NBTE^[15].

• The association between thrombosis and malignancy was first described by Trousseau in 1866^[18].
• In 1956 Robbins and MacDonald^[19] hypothesized that valvular degeneration and hypercoagulable state played significant roles in the origin/formation of NBTE.

• The relationship between carcinomatosis and NBTE has been vastly studied and established^[20].
• 50% of malignancies associated with NBTEs are adenocarcinomas of the lung and ovary^[21][22].
• It has been established that malignancies place patients in a hypercoagulable state which can then predispose them to valvular damage, clot formation, and NBTE^[23].
  

• The mitral valve is most commonly affected in NBTE, followed by the aortic valve and less frequently, the tricuspid valve^[24].
• The vegetations in NTBE are formed from the strands consisting of fibrin, immune complexes, neutrophils, lymphocytes, and histiocytes^[25].
• As there is some inflammatory reaction at the site of attachment of vegetation, they can easily dislodge, embolize and cause serious infarctions^[26].

Conditions associated with nonbacterial thrombotic endocarditis include^[1][27]:

• Malignancies
• Systemic autoimmune diseases (SLE is the most common)
• Hypercoagulable states
• Chronic inflammatory states
• Heart failure with valvulopathy

• On gross pathology, small (1-5mm) and sterile vegetations that occur on normal cardiac valves, and are composed of platelets and fibrin are characteristic findings in NBTE^[28].

• On microscopic histopathological analysis, degenerating platelets interwoven with fibrin strands, granulomatous tissue, and fibrotic foci,^[29] are characteristic findings of NBTE.
• The evolution of vegetation in NBTE has been described in three stages;
  • Stage 1 (active verrucae); Consists of fibrin clumps on and within the valvular leaflet tissue (focally necrotic), along with plasma cells and lymphocytes.
  • Stage 2 (Combined active and healed lesions); Contains fibrous, vascularized tissue adjacent to necrotic and fibrinous areas.
  • Stage 3 (Healed lesions); Consists of dense, fibrous, and vascularized tissue.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

Non-bacterial thrombotic endocarditis must be differentiated from other diseases that cause a new or changed heart murmur, multiple systemic emboli, +/-fever, such as infective endocarditis, degenerative valvular disease, and pulmonary infarction.

Non-bacterial thrombotic endocarditis must be differentiated from other diseases that cause a new or changed heart murmur, multiple systemic emboli, +/-fever, such as;^{[1][2][3][4][5][6]}.

• Infective endocarditis,
• Degenerative valvular disease, and
• Pulmonary infarction.

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

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As [disease name] manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. [Subtype name 1] must be differentiated from other diseases that cause [clinical feature 1], such as [differential dx1] and [differential dx2]. In contrast, [subtype name 2] must be differentiated from other diseases that cause [clinical feature 2], such as [differential dx3] and [differential dx4].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

Non-bacterial thrombotic endocarditis is a rare autopsy finding. Although the exact incidence of NBTE is unknown, it is thought to be approximately 900-600 per 100,000 individuals worldwide. The prevalence of NBTE is approximately 9,300 per 100,000 individuals worldwide. Patients of all age groups may develop NBTE, usually in the 4th to 8th decade. There is no racial predilection to NBTE, and NBTE affects men and women equally.

• Non-bacterial thrombotic endocarditis is a rare autopsy finding^[1].
• It is a rare disease that tends to affect patients with advanced malignancies^[2][3] and patients with autoimmune disorders^[4].
• Although the exact incidence of NBTE is unknown, it is thought to be approximately 900-600 per 100,000 individuals worldwide^[5][6].

• The prevalence of NBTE is approximately 9,300 per 100,000 individuals worldwide^[7].

• Patients of all age groups may develop NBTE^[8].
• NBTE commonly affects individuals between the ages of 40-80years of age^[7][9].

• There is no racial predilection to NBTE^[8].

• NBTE affects men and women equally^[7][8].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2]

Non-bacterial thrombotic endocarditis is an asymptomatic condition that can present acutely with recurrent thromboembolism. Prognosis is generally poor, as the disease is associated with advanced cancers, autoimmune diseases and recurrent thromboembolism.

• Non-bacterial thrombotic endocarditis is an asymptomatic condition that can present acutely with recurrent thromboembolism.

• Common complications of non-bacteral thrombotic endicarditis include:
  • systemic thromboembolism
  • cerebral ischemia
  • Heart failure
  • Death

• Prognosis is generally poor, as the disease is associated with advanced cancers, autoimmune diseases and recurrent thromboembolism.

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