Libman-Sacks Endocarditis

Etiology

Nonbacterial thrombotic endocarditis is frequently associated with a hypercoagulable state. The most common association of LS endocarditis is with[1]:

• Malignancies: The prevalence is 1.25% in this patient group versus 0.25% in the general population. It is mainly associated with solid tumors such as adenocarcinoma of the pancreas, colon, ovary, lung, biliary, and prostate. The rate was 2.7% in solid tumors versus 0.47% other types of malignancy.
• Systemic Lupus erythematous: Studies show that NBTE is present in 6 to 11% of lupus patients. An autopsy study reported the presence of NBTE in 50% of lupus cases. A significant correlation exists between LS endocarditis and SLE duration and severity.
• Antiphospholipid Syndrome: Whether primary (idiopathic) or secondary (SLE), studies suggested a prevalence of 33% in these patients versus 4 % in the control group of NTBE. Also, it shows that patients how to have SLE with positive antiphospholipid have a higher prevalence of this disease that patients who carry one of these diseases. 
• Others:  There are reports of cases in patients who have disseminated intravascular coagulation, rheumatoid arthritis, and sepsis.

Epidemiology

Libman-Sacks endocarditis is a rare disease that mostly found postmortem with a prevalence of about 0.9 % to 1.6%. LB endocarditis most commonly affects patients between 40 to 80 years of age, although it can occur in every age group. Studies do not show any sex predilection. However, SLE  and antiphospholipid show a predominance in women of child-bearing age of 5 to 9 times more than men, and it is more prevalent in Black and Hispanic women.[2][3] 

Pathophysiology

The initial pathology behind NBTE is unclear and needs further study. However, it appears to be due to an endothelial injury from circulating cytokines such as TNF (tumor necrosis factor) or interleukins in a hypercoagulable state patient, which results in the deposition in platelets thrombi and inflammatory molecules in the affected valves. The vegetations consist mainly of immune complexes, mononuclear cells, fibrin, and platelet thrombi. These vegetations are most often small-to-moderate in size (<10mm), but may sometimes be large and exuberant (>10mm).[1]

Histopathology of Libman-Sacks endocarditis has been described in different stages as follows :

1. Active verrucae - Consist of clumps of fibrin, which is focally necrotic, with plasma cells and lymphocytes.
2. Combined active and healed lesions: which is intermediate, has characteristics of active (necrotic) and healed (fibrous) tissues.
3. Healed lesions - Consist of vascularized, dense fibrous, and scar tissue.

History and Physical

Patients are typically asymptomatic, and the condition is often an incidental finding while evaluating for other cardiac illnesses or at postmortem. The vegetations could affect both the ventricular and atrial sides of the valves. The most affected valves are left side chamber valves (mitral followed by aortic), but other valves can also have involvement. The most common clinical manifestations are secondary to embolism. A cerebrovascular embolism can present with signs and symptoms of a stroke or a transient ischemic attack. Systemic thromboembolism can manifest as peripheral arterial embolism, presenting as cold limbs or mesenteric ischemia presenting as severe abdominal pain.

SLE patients show manifestations of the underlying disease such as constitutional symptoms (fever), malar rash, discoid rash, arthritis, oral ulcers, serositis (pleuritis, pericarditis), renal disorder (diffuse glomerulonephritis, focal segmental glomerulonephritis), neuropsychiatric, hematological issues (pancytopenia), or abnormal lab. values (ANA, Anti-dsDNA, Anti-SM). To establish a diagnosis, the clinician can use echocardiography, SLICC criteria (histological findings plus immunological tests), or EULAR/ACR criteria (10 points and above with one clinical feature). 

Antiphospholipid syndrome presents with recurrent miscarriages, abortions, and venous/arterial thrombosis.with the presence of lupus anticoagulant and IgG or IgM for anti-cardiolipin.[4][3]

Libman–Sacks lesions only rarely lead to significant valve dysfunction, and the lesions seldom embolize. However, data suggests a correlation between Libman–Sacks endocarditis and an increased risk for embolic cerebrovascular disease in SLE patients.

A 6-year, fully integrated, controlled, cross-sectional and longitudinal study revealed five significant findings: 1) NPSLE patients have more Libman-Sacks vegetations compared to SLE patients, the presence of cerebromicroembolism, neurocognitive dysfunction, and focal brain lesions; 2) patients with vegetations have three times more cerebromicroembolism per hour, lower cerebral perfusion, more strokes/TIAs, and overall NPSLE events, increased neurocognitive dysfunction, and more significant brain injury; 3) valve vegetations are a strong independent risk factor for stroke/TIA and NPSLE, neurocognitive dysfunction, brain lesions, and all three outcomes combined; 4) vegetations, cerebromicroembolism, NPSLE, neurocognitive dysfunction, and brain perfusion and lesion load improve with anti-inflammatory and/or antithrombotic therapy; and 5) patients with vegetations have poor outcomes with reduced event-free time to cerebrovascular events including stroke/TIA, cognitive impairment, or mortality. These findings support the idea that Libman-Sacks vegetations may generate platelet or fibrin macro-or-microemboli that occlude cerebral vessels, resulting in reduced cerebral perfusion, ischemic brain injury, stroke/TIA, non-focal NPSLE syndromes, neurocognitive issues, and contribute to death. Therefore, Libman-Sacks endocarditis may be a common but under-recognized pathogenetic factor for embolic CVD in SLE.

 In a study of 76 patients with SLE, the presence of LS endocarditis correlated with a higher risk for embolic cerebral vascular disease.[5]

Evaluation

A high index of clinical suspicion is crucial for the diagnosis of nonbacterial thrombotic endocarditis (NBTE). A firm diagnosis can be made pathologically by the demonstration of platelet thrombi on autopsy or surgical specimens. No laboratory tests exist to confirm the diagnosis of LS endocarditis. In patients suspected of LS endocarditis, a full assessment should be done with complete blood count, complete metabolic panel, and blood cultures to differentiate from other etiologies such as infective endocarditis. A hypercoagulable workup is also necessary in each case suspected of LS endocarditis, including lupus anticoagulant and antiphospholipid antibodies. However, the primary evaluation for LSE is by echocardiography.least three sets of blood cultures should be taken before any potential empiric antibiotic therapy. The absence of the typical causative organisms for culture-positive endocarditis and atypical organisms that are etiological for culture-negative endocarditis can provide support for the diagnosis of NBTE.

Trans-esophageal echocardiography has greater sensitivity and specificity than trans-thoracic echocardiography. Irregular borders, heterogeneous echo density, and an absence of independent motion characterize the masses (i.e., verrucous vegetations) found on the cardiac valves and endocardium. These are usually small, sessile masses, but they can be as large as 10 mm. The basal and mid-portion of the mitral and aortic valves are involved most commonly. Diffuse or focal leaflet thickening of the mitral and aortic valves are observable. The involved valves may exhibit regurgitation. Coexisting cardiac complications of systemic lupus erythematosus may include effusion or thickening of the pericardium.[6]

A workup for a hypercoagulable state (in particular testing for the presence of a lupus anticoagulant and elevated levels of antiphospholipid antibodies) and disseminated intravascular coagulation (DIC) are a requirement in every case of suspected NBTE. Also, a search for malignancy and systemic lupus erythematosus with a thorough history, clinical examination, age-appropriate cancer screening, and lupus serology is prudent. The presence of any of these diagnoses is strongly supportive of NBTE.

Echocardiography — Patients with suspected NBTE should have an evaluation with two-dimensional transthoracic echocardiography (TTE) for the presence of valvular vegetations.[7] 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.[8] There are also cases with all four valves affected by NBTE.[9] If TTE is unrevealing, proceeding to transesophageal echocardiography (TEE) merits consideration 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 due to aggregations of platelets and fibrin, as seen in NBTE.

Treatment / Management

The optimal treatment approach continues to be poorly defined, primarily because many recommendations regarding management originate from expert opinion and small observational case studies rather than randomized trials.

Medical treatment for patients with LS endocarditis is not well established, partially due to the scarcity of information on the natural progression of the disease in untreated patients. The underlying disease (SLE or APS) also requires treatment. Anticoagulation merits consideration as secondary prevention for thromboembolic phenomena in patients who have had a thromboembolic event. Warfarin with an INR goal of 2 to 3 has been considered the gold standard in patients with newly diagnosed APS presenting with their first thrombosis. In cases of significant valvular dysfunction, surgical decisions should be according to established guidelines for valvular heart disease. Patients with LS should be closely followed up during treatment, as they can still develop thromboembolic phenomena while on anticoagulation.[5][10][5] Scheduled echocardiography (every 3 to 6 months) should also be a consideration to follow the progression/resolution of the disease.[11][11](B2)

Surgery: The indications for surgery (vegetation excision or valve replacement) are the same as for infective endocarditis (e.g., 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 essential, preservation of the valve may be possible in some cases of NBTE. Most case studies also report postoperative anticoagulation when feasible, especially in those with a systemic reason for embolization (e.g., antiphospholipid syndrome).[12]

Treatment for underlying disease — Clinicians should treat the underlying condition (e.g., malignancy, systemic lupus erythematosus) when appropriate. However, due to the metastatic nature of some malignancies, this strategy is often ineffective in the absence of effective systemic therapy.

Differential Diagnosis

Different diseases or pathologies that are known to causes vegetations with the heart valves should be ruled out before diagnosing LSE; these include:

• Infective endocarditis: either positive or negative culture
• Rheumatic valvular disease
• Atrial myxoma
• Degenerative valvular disease
• Infective endocarditis 
• Vasculitis
• Cholesterol emboli syndrome occurs when atherosclerotic plaque becomes disrupted, and cholesterol crystals embolize distally. Clinical manifestations depend on the location of the embolic source, the extent of embolization, and the degree of preexisting disease in the affected vascular bed; they may include systemic or cerebral embolism
• Fibroelastoma
• Lamb's excrescences: originate at valve closure sites (most commonly on the aortic valve). They appear to be normal variants, but some reports propose embolic potential. Laboratory studies should include a complete blood count, complete metabolic panel, and blood cultures to exclude infective endocarditis. A workup for SLE and APS is necessary if the patient does not already have these as established diagnoses.

Prognosis

The prognosis of LS endocarditis requires further study, and there continues to be a need for additional research to better define prognosis. From clinical observations, the prognosis of LS is considered poor.  Patients may develop recurrent thromboembolic events, cognitive disability, and death.[5]

Prognosis — The prognosis of NBTE has not undergone formal evaluation. 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. 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). The long-term outcome for most patients with malignancy-associated NBTE is poor because it is typically associated with disseminated and incurable malignancies

Prognosis is probably dependent on the underlying disease activity of systemic lupus erythematosus and associated renal and myocardial dysfunction.