Nonbacterial Thrombotic Endocarditis

Nonbacterial thrombotic endocarditis (NBTE, marantic endocarditis) is the formation of sterile fibrin and platelet vegetations on normal or minimally abnormal heart valves. The mitral and aortic valves are involved most often.

It is found in about 1% of autopsies, and more often in advanced cancer. It is usually silent until an embolic event.

Causes are hypercoagulable states, mainly adenocarcinoma (lung, pancreas, ovary, stomach, colon), haematological malignancy and antiphospholipid syndrome.

Other settings are systemic lupus erythematosus, sepsis, burns, HIV infection, kidney disease and indwelling catheters.

The vegetations are small (usually under 10 mm), sit along the line of valve closure, and rarely destroy the valve.

Pathophysiology. Tissue factor, mucin producing tumour products, cytokines and a prothrombotic state deposit platelets and fibrin on injured endothelium. The vegetations are friable, so fragments embolise to the brain, kidneys, spleen, limbs and coronary arteries.

• Embolic events are the usual presentation: stroke with several infarcts in different territories, transient ischaemic attack, peripheral arterial emboli, splenic or renal infarction, and myocardial infarction.
• A murmur is found in only a minority and fever is uncommon.
• Features of the cause: weight loss and cachexia in cancer, livedo and recurrent thrombosis in antiphospholipid syndrome, joint, skin and renal features in lupus, and bleeding or bruising in disseminated intravascular coagulation.

Red flags.

• Multiple embolic infarcts in different territories in a patient with cancer or antiphospholipid antibodies
• Fever with a vegetation (infection must be excluded)
• Heart failure from severe regurgitation
• Disseminated intravascular coagulation (falling platelets and fibrinogen, raised D-dimer)
• Haemorrhagic transformation of a stroke

• Blood cultures. Three sets from separate sites before any antibiotic, held for 5 days. Persistently negative cultures separate NBTE from infective endocarditis.
• Transthoracic then transoesophageal echocardiography. Small, sessile or broad based, irregular vegetations on the atrial surface of the mitral valve or the ventricular surface of the aortic valve, without valve destruction or abscess.
• Brain MRI. Multiple small cortical and subcortical infarcts in several vascular territories.
• Coagulation. Platelets, fibrinogen, D-dimer, PT and aPTT. Lupus anticoagulant, anticardiolipin and anti-beta-2 glycoprotein I antibodies (repeated at 12 weeks to confirm). Antinuclear and anti-double-stranded DNA antibodies. HIV test.
• Cancer search. CT of the chest, abdomen and pelvis, with tumour markers and further imaging or biopsy directed by findings.
• Other embolic sites. Imaging of the kidneys, spleen, limbs and coronary arteries as indicated.

Differential diagnosis.

• Infective endocarditis
• Libman-Sacks endocarditis
• Lambl excrescences and papillary fibroelastoma
• Atrial myxoma and valvular thrombus
• Rheumatic and degenerative valve disease with calcification
• Cardioembolism from atrial fibrillation
• Cancer related arterial thrombosis and vasculitis

Treat the cause and anticoagulate.

• While infection cannot be excluded, start empirical antibiotics after three sets of blood cultures: vancomycin 25 to 30 mg/kg intravenously as a loading dose (maximum 3 g), then 15 to 20 mg/kg every 8 to 12 hours (usual maximum 2 g for each dose), adjusted to a trough of 15 to 20 mg/L or an AUC of 400 to 600 mg·h/L, lengthening the interval and using levels in renal impairment, with ceftriaxone 2 g intravenously every 24 hours. Stop when cultures stay negative at 5 days and the picture favours NBTE.
• Unfractionated heparin 80 units/kg intravenous bolus, then 18 units/kg/h, adjusted to anti-Xa 0.3 to 0.7 IU/mL or an aPTT ratio of 1.5 to 2.5, no fixed maximum. Check platelets on days 5 to 14 for heparin induced thrombocytopenia. Reduce or withhold with bleeding, thrombocytopenia under 50 x 109/L, or haemorrhagic stroke. It is preferred with severe renal impairment or when procedures are planned.
• Enoxaparin 1 mg/kg subcutaneously every 12 hours for long term use in cancer, and 1 mg/kg once daily at creatinine clearance under 30 mL/min, with anti-Xa monitoring in renal impairment, extremes of weight and pregnancy. Continue while the hypercoagulable state persists.
• Warfarin is ineffective in cancer associated NBTE and recurrent emboli occur on it. In antiphospholipid syndrome, use warfarin 5 mg orally once daily at the start (2 to 3 mg in older adults, liver impairment or interacting drugs), adjusted to an INR of 2.0 to 3.0, no fixed maximum, with INR every 2 to 3 days at the start, weekly until stable, then every 4 to 12 weeks. Avoid direct oral anticoagulants in antiphospholipid syndrome.
• Direct oral anticoagulants have too little data in NBTE to be advised. Aspirin and other antiplatelet drugs alone do not prevent emboli.
• Treat the underlying cancer, infection, lupus or antiphospholipid syndrome with the specialist team. Remove unnecessary catheters.

Stroke. Intravenous thrombolysis is withheld until infective endocarditis is excluded, because of haemorrhage risk. Mechanical thrombectomy for large vessel occlusion. Start anticoagulation after imaging excludes haemorrhagic transformation (timing is contested and depends on infarct size).

Valve surgery. Reserved for severe regurgitation with heart failure, or recurrent embolism despite therapeutic anticoagulation, in a patient with an expected survival of over 6 months and controlled underlying disease. Repair is preferred to replacement.

Special groups. Pregnancy: warfarin is teratogenic in weeks 6 to 12. Use enoxaparin 1 mg/kg subcutaneously every 12 hours with a peak anti-Xa of 0.8 to 1.2 IU/mL 4 to 6 hours after the dose (1 mg/kg once daily at creatinine clearance under 30 mL/min). Cancer: balance the bleeding risk from thrombocytopenia and mucosal tumours with the embolic risk.

Monitoring. Repeat echocardiography at 6 to 12 weeks and with any new embolic event. Platelets, creatinine, haemoglobin and anti-Xa or INR as indicated. Neurological review.

Referral and escalation. Refer to cardiology, with oncology or rheumatology for the cause. Urgent for stroke, haemodynamic compromise, heart failure or bleeding on anticoagulation.