Nonbacterial thrombotic endocarditis

INTRODUCTION — Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that refers to a spectrum of noninfectious lesions of the heart valves that is most commonly seen in advanced malignancy. NBTE is often an autopsy finding. However, some patients are diagnosed antemortem presenting with the signs and/or symptoms of systemic embolization and require therapy.

The epidemiology, pathogenesis, clinical presentation, evaluation, diagnosis, and treatment of NBTE are presented in this topic. The clinical manifestations and treatment of infective endocarditis are discussed separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

EPIDEMIOLOGY — Nonbacterial thrombotic endocarditis (NBTE) is a rare condition most often found postmortem with rates in autopsy series ranging from 0.9 to 1.6 percent [1-6]. It has been reported in every age group, most commonly affecting patients between the fourth and eighth decades of life with no sex predilection [1,7-9]. Patients with advanced malignancy and those with systemic lupus erythematosus are the most common populations affected by NBTE.

One autopsy series reported that, compared to the general population, patients with underlying malignancy have a higher rate of NBTE (1.25 versus 0.2 percent) [2,3]. When compared to other malignancies, higher rates were reported in those with adenocarcinoma (eg, lung, colon, ovary, biliary and prostate) (2.7 versus 0.47 percent) with the highest rates observed in patients with mucin-secreting and pancreatic adenocarcinoma (10 percent) [3,7,10].

In patients with systemic lupus erythematosus, observational studies using transthoracic echocardiography have reported prevalence rates of 6 to 11 percent, with higher rates (43 percent) observed when the more sensitive transesophageal echocardiography was performed [11,12]. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Valvular disease'.)

PATHOGENESIS — The term "nonbacterial thrombotic endocarditis" (NBTE, marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis) is a form of noninfectious endocarditis, that is characterized by the deposition of sterile platelet thrombi on heart valves (mostly aortic and mitral). NBTE commonly affects undamaged valves although some reports suggest NBTE can occur in patients with valvular pathology [6,8,13]. It is a separate entity to culture-negative endocarditis which is due to infectious etiologies that are not readily identified.

NBTE is associated with a number of conditions, of which advanced malignancy is the most common (80 percent of cases) [1,3,7,8,14-18] followed by systemic lupus erythematosus. Less common etiologies include inflammatory conditions such as antiphospholipid syndrome, rheumatoid arthritis, sepsis, and burns.

The initiating factor in the pathogenesis of NBTE is unknown, but endothelial injury in the setting of a hypercoagulable state is thought to be critical for the development of NBTE. Endothelial damage caused by circulating cytokines, such as tumor necrosis factor or interleukin-1, may trigger platelet and fibrin deposition, particularly in the presence of an activated coagulation system (eg, disseminated intravascular coagulation, malignancy, antiphospholipid syndrome). (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults".)

The vegetations in NBTE consist of thrombi interwoven with strands of fibrin, immune complexes and mononuclear cells ("white thrombus") [6]. Vegetations vary in size from microscopic to large and exuberant. When thrombi are large, the term verrucous endocarditis is used (also known as Libman-Sacks endocarditis) (picture 1).

Compared to vegetations in infective endocarditis, vegetations in NBTE are easily dislodged since there is little inflammatory reaction at the site of attachment. Thus, in NBTE there is a greater tendency for vegetations to embolize and cause extensive infarction. This was best illustrated in a six-year study of 76 patients with systemic lupus erythematosus (SLE) where the presence of vegetations was an independent risk factor for the development of neuropsychiatric SLE (odds ratio 13.4) [19]. There were three times more cerebral microemboli events per hour and a higher brain lesion load in patients with vegetations than those without vegetations [19].

CLINICAL PRESENTATION AND EVALUATION — Patients with nonbacterial thrombotic endocarditis (NBTE) are typically asymptomatic until embolization occurs. The investigation should focus on evaluating the patient for the signs and symptoms of embolization, obtaining an echocardiogram, and defining the underlying cause.

Signs and symptoms — Patients with NBTE are often asymptomatic and cardiac murmurs are infrequently noted, occurring in less than half of patients. Fever is uncommon, but when present, may be an underlying manifestation of malignancy. The major clinical manifestations of NBTE result from systemic emboli rather than valvular dysfunction (eg, heart failure) with up to 50 percent of patients with NBTE presenting with embolic phenomena [7,8].

Common sites of embolization include the spleen, kidney, skin, and extremities that may present as flank pain, hematuria, rash, and digital ischemia. However, emboli to the central nervous system and coronary arteries are more likely to reveal the diagnosis due to the presence of more worrisome symptoms (eg, stroke, delirium, chest pain) [18,20,21]. In one case series, stroke was the presenting complaint in 60 percent of cases [18]. Few patients present with the symptoms of valvular dysfunction with rare case reports of patients presenting with heart failure from aortic or tricuspid insufficiency [22-26]. In a six-year cross sectional study that compared patients with SLE who presented with neuropsychiatric symptoms (NPSLE) to patients with SLE without neuropsychiatric symptoms and healthy controls, NBTE and cerebral infarcts were more common in NPSLE (87 versus 28 versus 8 percent; 47 percent versus 0 and 0 percent). (See "Overview of the evaluation of stroke".)

Laboratory — There are no laboratory tests that confirm the diagnosis of NBTE with testing usually directed at distinguishing NBTE from infective endocarditis and detecting the underlying cause. We typically perform the following:

●Full assessment with complete blood count, chemistries, and liver function tests.

●At least three sets of blood cultures should be taken prior to any potential empiric antibiotic therapy. The absence of the typical organisms that cause culture-positive endocarditis and atypical organisms that cause culture-negative endocarditis help support the diagnosis of NBTE. Additional consideration can be given to testing with polymerase chain reaction and serology for the organisms that cause culture negative endocarditis (eg, Coxiella burnetii, legionella spp, and Brucella spp). The appropriate number of negative cultures and culture medium required to ensure that culture-negative endocarditis is adequately excluded is discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

●A workup for antiphospholipid syndrome (ie, testing for the presence of a lupus anticoagulant in the absence of anticoagulation and obtaining levels of antiphospholipid antibodies) and disseminated intravascular coagulation should be performed in every case of suspected NBTE. In addition, a search for malignancy and systemic lupus erythematosus with a thorough history, clinical examination, age-appropriate cancer screening, and lupus serologies is prudent. The presence of any of these diagnoses is strongly supportive of NBTE. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Diagnostic evaluation'.)

Imaging — Computed tomography of the brain or magnetic resonance imaging may be performed in those with suspected cerebral embolization due to NBTE. Although NBTE has been reported to present with widely distributed, multiple, small and large strokes, this is not a specific feature of NBTE on brain imaging [10,27]. Strokes are classically ischemic but hemorrhagic transformation can occur de novo or due to anticoagulation.

One case of NBTE has been reported using cardiac MRI [28].

Echocardiography — Patients with suspected NBTE should be evaluated with two-dimensional transthoracic echocardiography (TTE) for the presence of valvular vegetations [11,12,18]. Vegetations are frequently left-sided with two-thirds of cases involving the mitral valve, up to a quarter involving the aortic, and less commonly both valves [2,3,7,10,18]. Cases with all four valves affected by NBTE have also been reported [29,30]. Should TTE be unrevealing, proceeding to transesophageal echocardiography (TEE) should be considered in those who are suitable candidates. The purpose of echocardiography is the visualization of vegetations. However, echocardiography cannot distinguish vegetations due to thrombus or infection from those seen in NBTE.

TEE is more sensitive than TTE for the detection of vegetations, particularly for small lesions (<5 mm) [31]. This was best illustrated in a series of 51 consecutive cancer patients with cerebrovascular events who were referred for TEE [32]. Among those with nonbacterial vegetations (nine patients) who had also had a TTE and TEE, TTE missed vegetations in four cases.

TEE is an invasive procedure. Thus, the selection of patients suitable for TEE should be individualized according to performance status and life expectancy if the patient is known to have an underlying malignancy.

DIAGNOSIS — A high index of clinical suspicion is critical for the diagnosis of nonbacterial thrombotic endocarditis (NBTE). The definitive diagnosis can be made pathologically by the demonstration of thrombi on autopsy or surgical specimens. However, the routine acquisition of valvular tissue is not practical such that clinicians are reliant upon a constellation of clinical, echocardiographic, and absence of microbiologic findings for the diagnosis of NBTE. Typically, the demonstration of valvular vegetations on echocardiography in the absence of systemic infection in patients who are at high risk of NBTE provide strong evidence to support the diagnosis.

NBTE should be suspected in patients with acute stroke or coronary ischemia with underlying cancer, systemic lupus erythematosus, or antiphospholipid syndrome. It should also be suspected in patients with acute stroke or multiple widely distributed emboli of unknown etiology as well as in those with presumed infective endocarditis who are unresponsive to, or progressing poorly on, antibiotic therapy [20,32].

The diagnosis of NBTE can be difficult to establish antemortem because of the paucity of symptoms and late presentation. In addition, fever due to the underlying malignancy can lower the clinical suspicion for NBTE. Additionally, following embolization, small remnants on affected valves (≤3 mm) may result in false negative findings because such small vegetations are not readily identified by echocardiography.

Differential diagnosis — There are no pathognomonic signs or symptoms or echocardiographic features that are specific to NBTE. The major alternative diagnosis is infective endocarditis (IE) and negative cultures can facilitate the distinction between these two entities. Special attention should be paid to ruling out IE with select culture media and serology for typical and atypical organisms, particularly in those with a history of antibiotic exposure. As with IE, a new or changed murmur at the left sternal border may alert the clinician to the presence of NBTE, but this is an unusual finding which is not sensitive or specific for the diagnosis. Widely distributed and recurrent emboli of varying sizes (small to large) may favor NBTE, occurring in up to 50 percent of patients [9,10,13,27]. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

TREATMENT — Treatment of nonbacterial thrombotic endocarditis (NBTE) usually consists of systemic anticoagulation and therapy directed at treating the underlying malignancy or associated condition. Surgery with valve debridement or excision is infrequently performed, but may have a role in some patients who do not have advanced malignancy. However, small retrospective studies suggest that the prognosis from NBTE is poor with morbidity due to neurocognitive dysfunction and death from recurrent embolization or the underlying malignancy despite therapy.

Anticoagulation — Unlike patients with infective endocarditis and patients with acute ischemic stroke, patients with NBTE with or without evidence of systemic emboli (including central nervous system lesions) are routinely anticoagulated provided there is no contraindication (eg, central nervous system bleeding). The rationale for this approach is based upon clinical experience and retrospective studies, as well as the known fragile nature of vegetations and the high rates of recurrent and extensive embolization in this population [7,9,18,33,34]. However, similar to ischemic stroke, the risk of anticoagulation is hemorrhagic conversion of embolic events. Computed tomography of the brain should be performed in patients with NBTE before anticoagulation to rule out intracranial hemorrhage.

Therapeutic dose subcutaneous low molecular weight (LMW) heparin or intravenous unfractionated heparin should be used, rather than warfarin or a direct thrombin or factor Xa inhibitor (eg, dabigatran, apixaban, edoxaban, rivaroxaban; these agents should be avoided if antiphospholipid antibody is suspected). Although no formal comparison between heparin and warfarin has been reported in patients with NBTE, older studies suggest that warfarin is less effective than heparin in reducing the rate of recurrent embolization [7,9,33]. Warfarin may however have a role in the management of patients with NBTE with extended survival in the setting of autoimmune or inflammatory disorders. Anticoagulation with direct thrombin or factor Xa inhibitors has not been evaluated to support their routine use as anticoagulants for this indication. This practice is in agreement with the American College of Chest Physicians guidelines on antithrombotic therapy for valvular heart disease [33].

Anticoagulation should be continued indefinitely, since recurrent thromboembolism has occurred in patients following its discontinuation [35]. Discontinuation of anticoagulation is appropriate when complications such as life threatening bleeding or heparin-induced thrombocytopenia occur.

Surgery — Although not formally evaluated in prospective trials, surgical intervention for NBTE-associated vegetations has been reported and may be considered in select cases where the risk benefit is favorable [11,13,18,36]. The indications for surgery (vegetation excision or valve replacement) are the same as for infective endocarditis (eg, heart failure, acute valve rupture) but reports suggest that prevention of recurrent embolization is the most common reason for surgery. In contrast to infective endocarditis where complete removal of infected tissue is important, preservation of the valve may be possible in some cases of NBTE. Due to the high risk of recurrence, most case studies also report postoperative anticoagulation when feasible especially in those with a systemic reason for embolization (eg, antiphospholipid syndrome). When considering surgery, the benefits should be weighed against the risks in the context of the life expectancy from the underlying condition. (See "Surgery for left-sided native valve infective endocarditis".)

Treatment for underlying disease — Treatment of the underlying condition (eg, malignancy, systemic lupus erythematosus) should be attempted when appropriate. However, due to the metastatic nature of some malignancies this strategy is often ineffective in the absence of effective systemic therapy. For patients with systemic lupus erythematosus (SLE), the occurrence of NBTE valvular lesions may occur at any time, and their presence does not correlate with disease activity [37]. It is unknown whether NBTE improves with cancer therapy; however the same lack of relationship with outcome is thought to exist. Thus, anticoagulation should probably continue regardless of the response to therapy for the underlying disease.

Although many patients may be placed on empiric antibiotics during investigation, they do not need to be continued unless infective endocarditis is diagnosed or suspected in the absence of positive blood cultures.

Follow-up — The optimal follow-up has not been defined and should be tailored to the individual patient. However, during therapy it is prudent that patients be followed clinically for complications of NBTE (eg, infective endocarditis, embolization despite anticoagulation) as well as for complications of therapy (eg, bleeding, thrombocytopenia). In addition, echocardiography at a defined period (eg, six weeks to three months) should also be considered to follow progression or resolution of valvular vegetations which has been observed in some studies [11,19].

Prognosis — The prognosis of NBTE has not been formally evaluated. However, clinical experience and data from retrospective studies suggest that the prognosis is grim despite anticoagulation due to the strong association between NBTE and advanced malignancy [18]. Similarly, in patients with systemic lupus erythematosus (SLE), one six-year longitudinal cross sectional study reported poor outcomes due to recurrent stroke (25 percent), cognitive disability (24 percent), and death (9 percent) [19].

SUMMARY AND RECOMMENDATIONS

●Terminology and epidemiology – The term "nonbacterial thrombotic endocarditis" (NBTE, marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis) is a form of noninfectious endocarditis, that is characterized by the deposition of thrombi on heart valves (mostly aortic and mitral). (See 'Epidemiology' above.)

NBTE is a rare condition, most often found postmortem with rates in autopsy series ranging from 0.9 to 1.6 percent. It has been reported in every age group, most commonly affecting patients between the fourth and eighth decades of life with no sex predilection. (See 'Epidemiology' above.)

●Pathogenesis – NBTE is associated with a number of conditions, of which advanced malignancy and systemic lupus erythematosus are the most common. Other less common etiologies include inflammatory conditions such as antiphospholipid syndrome, rheumatic heart disease, rheumatoid arthritis, and burns. Compared to infective endocarditis, there is a greater tendency for vegetations to embolize and cause extensive infarction in NBTE. (See 'Pathogenesis' above.)

●Clinical manifestations and diagnostic evaluation – Patients with NBTE are typically asymptomatic until embolization occurs. The investigation should focus on evaluating the patient for the signs and symptoms of embolization, obtaining an echocardiogram, and defining the underlying cause. (See 'Clinical presentation and evaluation' above.)

●Diagnosis – A high index of clinical suspicion is critical for the diagnosis of NBTE. The demonstration of vegetations on echocardiography in the absence of systemic infection in patients who are at high risk of NBTE provides strong evidence for the diagnosis of NBTE. (See 'Diagnosis' above and 'Echocardiography' above.)

●Treatment – Treatment of NBTE usually consists of systemic anticoagulation and therapy directed at treating the underlying malignancy or associated condition. Surgery is performed in selected cases who do not have an advanced malignancy. In patients with NBTE, we suggest treatment with therapeutic dose low molecular weight heparin or unfractionated heparin rather than no anticoagulation or warfarin (Grade 2C). We continue anticoagulation indefinitely due to the high risk of recurrent systemic embolization. Despite therapy the prognosis from NBTE is generally poor. (See 'Treatment' above.)