Libman-Sacks endocarditis

A 38-years old male with a history of deep vein thrombosis (DVT) and pulmonary embolism (PE) was admitted for progression of dyspnea (NYHA IIIb/IV), intense retrosternal chest pain during exertion and a newly diagnosed systolic and diastolic murmur. 

Upon admission, no signs of infection, systemic peripheral embolizations such as Petechiae, Osler's nodes or Janeway lesions were present. 

Laboratory results: 

CRP: 73,1 (normal range: 0-5 mg/l), 

PCT: 0,23 (normal range: 0-05 µg/l)

Urea: 15,8 mmol/l (normal range: 3.2 - 7.4 mmol/l)

Creatinine: 205 umol/l  (normal range: 64.0 - 104.0 µmol/l)

WBC: ​​ 7,1 x 10^9/l (normal range: 4.0 - 10.0 10^9/l )

PLT: 59 x 10^9/l (normal range: 150 - 400 10^9/l )

RBC: 4,32 x 10^9/l (normal range: 4.00 - 5.80 10^12/l )

Hgb: 105 g/l (normal range: 135 - 175 g/l)

aPTT ratio: 4,71 (normal range: 0,8 - 1,2)

INR: 1.29 (normal range: 0,8 - 1,2)

Image 1 ECG on admission: Sinus tachycardia. No signs of ACS or PE.(Image 1)

Echocardiography on admission documented a dilated left ventricle (EF 45-50%), aortic regurgitation ¾, moderate aortic stenosis (gradient 43/29 mmHg), masses on aortic valve (Image 2-3, Video 1-3).

Image 2: Echo on admission, dilated left ventricle

Image 3: Moderate aortic stenosis with a maxPG: 43 mmHg

‍Video 1: Aortic regurgitation 3/4 

Video 2: Presence of vegetations on aortic valve leaflets

Video 3: Vegetations on aortic valve leaflets

The patient was admitted to the hospital with suspected infective endocarditis (IE). Initially, empirical antibiotic treatment was started according to current ESC guidelines for the management of infective endocarditis (https://doi.org/10.1093/eurheartj/ehad193). Therefore, the patient was treated with Gentamicin, Oxacillin and Ampicillin.

Nevertheless, repeated blood and urine cultures were negative.

As part of further investigation, CT angiography of the coronary arteries was performed, but did not show any pathology. Labeled white blood cell SPECT-CT revealed embolization to the spleen, but showed no signs of active cardiac infection was documented..

Laboratory tests showed thrombocytopenia and raised suspicion for antiphospholipid syndrome. To confirm the diagnosis, specific tests were performed, including autoantibodies and antiphospholipid syndrome laboratory screening. Immunology screening came back with positive anti-dsDNA autoantibodies and a positive panel for antiphospholipid antibodies as shown below:. 

‍S-anti-dsDNA (CIA - Chemiluminescent immunoassays): 66,6 kIU/l (normal range: 0-26,9 kIU/l)

S-anti-dsDNA (IF - Immunofluorescence): +++

S-anti-Cardiolipin IgG: 570,4 kIU/l (normal range: 0-20 kIU/l)

S-anti-beta2-glycoprotein I IgG: 3111,2 kIU/l (normal range: 0-20 kIU/l)

S-anti-phosphatidylserine IgG: 46,9 kIU/l (normal range: 0-9,9 kIU/l)

S-anti-phosphatidylinositol IgG: 47,5 kIU/l (normal range: 0-9,9 kIU/l)

The positive anti-dsDNA result suggested a possible component related to systemic lupus erythematosus (SLE), while the positive antiphospholipid syndrome panel confirms the diagnosis of antiphospholipid syndrome.

Based on these results, treatment for antiphospholipid syndrome was initiated with high doses of corticosteroids and hydroxychloroquine. Due to persistent findings on aortic valve, patient underwent surgical AVR (aortic valve replacement). Vegetations were found not only on AV but also on the aortic wall. Panbacterial PCR of the valve material was performed with a negative result. NBTE diagnosis was given.

After ruling out infection by PCR testing, antibiotic treatment was discontinued.

To meet the diagnostic criteria of EULAR, after 12 weeks, we repeated the immunology screening which came out with persistent positive results, thus confirming the diagnosis of APS.

The patient was indicated for lifelong anticoagulation therapy due to antiphospholipid syndrome.

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Libman Sacks endocarditis:

Is a type of NBTE (non-bacterial thrombotic endocarditis), also known as verrucous or marantic endocarditis.

Pathophysiology:

• Characterized by sterile vegetations on heart valves
• Mostly affects the left-sided mitral and aortic valves
• Caused by the deposition of immune complexes, fibrin, and platelet thrombi

Is associated with:

• SLE (systemic lupus erythematosus)
• Antiphospholipid syndrome
• Malignancies (most often solid tumors)
  

Diagnosis:

• Echocardiography is the primary diagnostic tool
• Vegetations appear as valve masses, typically on the ventricular surface of the mitral valve or the aortic side of aortic valve
• Differential diagnosis includes infective endocarditis, which must be ruled out

Treatment:

• Management of underlying SLE or APS
• Immunosuppressive therapy (corticosteroids, hydroxychloroquine, etc.)
• Anticoagulation in patients with APS or history of thromboembolism
• Valve surgery in cases of severe valvular dysfunction or recurrent embolic events

Prognosis:

• Generally good with appropriate management of underlying condition
• Risk of valvular deterioration and embolic events
• Regular echocardiographic follow-up recommended

Complications:

• Valvular dysfunction (regurgitation more common than stenosis)
• Thromboembolic events
• Increased risk of infective endocarditis

Prevention:

• Optimal control of SLE and APS
• Regular cardiac evaluations in SLE/APS patients
• Appropriate anticoagulation when indicated

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Antiphospholipid syndrome:

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a predisposition to thrombosis and recurrent pregnancy morbidity. It arises from the production of circulating antiphospholipid antibodies (aPL) that target phospholipid-protein complexes on cell surfaces.

Pathogenesis:

The exact mechanisms of aPL-mediated injury are not fully understood, but likely involve a combination of factors:

• Procoagulant effects: aPL antibodies can activate platelets, endothelial cells, and the complement cascade, promoting thrombin generation and clot formation.
• Anti-annexin A5 effects: aPLs may interfere with the anticoagulant properties of annexin A5, further tipping the balance towards thrombosis.
• Inflammation: aPLs might contribute to an inflammatory state that damages blood vessels and promotes clot formation - Virchow trias

Clinical Manifestations:

• Thrombosis: Venous and arterial thrombosis can occur at any site, with deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and myocardial infarction being the most common presentations. APS can also manifest as thickening of heart valves or presence of vegetations.
• Pregnancy Morbidity: Recurrent pregnancy loss (especially late miscarriages), premature birth, intrauterine growth restriction, and preeclampsia are frequent complications.
• Other: Livedo reticularis (skin rash), thrombocytopenia (low platelets), and neurological manifestations (e.g., headaches, seizures) can occur. 

Diagnosis:

The diagnosis of APS is based on clinical criteria and laboratory testing. EULAR ( European Alliance of Associations for Rheumatology) defines APS as the presence of at least one clinical manifestation:

1. Macrovascular (venous thromboembolism)

• Includes unexplained and confirmed: pulmonary embolism, deep vein thrombosis, splanchnic thrombosis, renal vein thrombosis, cerebral venous thrombosis, retinal vein thrombosis/occlusion

2. Macrovascular (arterial thrombosis)

• Includes unexplained and confirmed: myocardial infarction, peripheral/splanchnic/retinal artery thromboses, stroke, other organ infarcts without visualized thrombus

3. Microvascular

• Suspected: livedo racemosa, livedoid vasculopathy lesions, antiphospholipid antibody nephropathy, pulmonary hemorrhage, aPL nephropathy (by pathology), pulmonary hemorrhage (by BAL or pathology), myocardial disease, adrenal hemorrhage or microthrombosis

4. Obstetric

• Prefetal or fetal loss
• Preeclampsia with severe features
• Placental insufficiency with severe features

5. Cardiac valves

• Valve thickening (otherwise unexplained)
• Valve vegetation (otherwise unexplained)

6. Hematology

• Thrombocytopenia: unexplained lowest platelet count between 20 and 130 × 10^9/liter

and at least one laboratory-confirmed positive result after 12 weeks following the first test:

• Antiphospholipid antibody: Anti-cardiolipin antibody (aCL) or anti-beta2-glycoprotein I (aβ2GPI) antibody. 
• Lupus anticoagulant (LAC): A test that detects aPLs that interfere with phospholipid-dependent coagulation assays.

Classification:

• Primary APS: Occurs in the absence of another underlying autoimmune disease.
• Secondary APS: Develops in association with another autoimmune condition, most commonly systemic lupus erythematosus (SLE).

Treatment:

• Thromboprophylaxis: Main treatment is a life-long anticoagulation therapy with warfarin. For APS, the effectiveness of NOACs, LMWH, or antiplatelet therapy as monotherapy has not been sufficiently proven. 
• Pregnancy management: Low-dose aspirin with or without heparin is used during pregnancy to lower the morbidity.
• Management of underlying disease: If APS is secondary to another condition, treatment of the primary disease is crucial.

Prognosis:

Early diagnosis and proper treatment can significantly improve the prognosis and reduce the risk of complications in APS patients. However, it remains a chronic condition requiring long-term management.

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References:

1. Roldan C, Tolstrup K, Macias L et al. Libman-Sacks Endocarditis: Detection, Characterization, and Clinical Correlates by Three-Dimensional Transesophageal Echocardiography. J Am Soc Echocardiogr. 2015;28(7):770-9. doi:10.1016/j.echo.2015.02.011

2Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart Valve Involvement (Libman-Sacks Endocarditis) in the Antiphospholipid Syndrome. Circulation. 1996;93(8):1579-87. doi:10.1161/01.cir.93.8.1579 - Pubmed

3  Cervera R, Font J, Paré C et al. Cardiac Disease in Systemic Lupus Erythematosus: Prospective Study of 70 Patients. Ann Rheum Dis. 1992;51(2):156-9. doi:10.1136/ard.51.2.156 - Pubmed

4 Petri M. Antiphospholipid syndrome. Transl Res. 2020 Nov;225:70-81. doi: 10.1016/j.trsl.2020.04.006. Epub 2020 May 12. PMID: 32413497; PMCID: PMC7487027.

5 Pessach I, Kyriakou E, Kalampokas E, Kalampokas T, Bitsani A, Kotsianidis I. Antiphospholipid syndrome in cardiovascular disease and cancer. Eur J Haematol. 2023 Dec;111(6):834-843. doi: 10.1111/ejh.14096. Epub 2023 Sep 4. PMID: 37667555.

6 Gorantla A, Schaible M, Sivakumar SS, Kishore A, Andrew-Palmer W, Unal S, Ramirez M, Panduranga V, Budzikowski AS. Embolic Phenomena of Libman-Sacks Endocarditis and Antiphospholipid Syndrome. Cureus. 2023 Oct 13;15(10):e46957. doi: 10.7759/cureus.46957. PMID: 38021689; PMCID: PMC10640721.

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Authors: Peter Mišún, Michal Pazderník