Nonbacterial thrombotic endocarditis in a patient with primary antiphospholipid syndrome.

Nonbacterial thrombotic endocarditis (NBTE) is described in patients with mucin-producing cancers and connective tissue disorders (usually SLE). We report NBTE in the setting of primary antiphospholipid antibody syndrome (APS). A 65-year-old female with APS was incidentally found to have thickened mitral leaflets on transthoracic echocardiogram with no signs of infection. Transesophageal echocardiogram (TEE) showed a mobile mitral mass (1.4 × 0.7 cm) and moderate mitral regurgitation. Differential diagnoses included bacterial endocarditis, NBTE, thrombus or tumor. Given the history of primary APS, the absence of fever and negative blood cultures, NBTE was considered. Low-molecular-weight heparin, hydroxychloroquine and corticosteroid were initiated. Repeat TEE in a week revealed shrinkage of the mass (0.6 × 0.7 cm), indicating an inflammatory nature. Lifelong anticoagulation is indicated regardless of embolism occurrence. Hydroxychloroquine and corticosteroids may have roles in the treatment. Determining and treating the underlying etiology is important.

INTRODUCTION

Nonbacterial thrombotic endocarditis (NBTE) is a rare non-infectious cause of endocarditis in which there is deposition of sterile platelet thrombi on heart valves, particularly the mitral and aortic valves. This condition is described mostly in patients with advanced malignancy and connective tissue diseases. We report a case of NBTE in a patient with primary antiphospholipid antibody syndrome (APS) who had dramatic improvement after medical management.

CASE REPORT

A 65-year-old African American female presented to the hospital for a follow-up of a mitral valve mass seen on transthoracic echocardiogram (TTE) while being admitted to an outside hospital for diverticular lower gastrointestinal bleeding. Computed tomography (CT) of abdomen and pelvis showed colonic diverticulosis without evidence of cancer. Her past medical history was significant for APS (diagnosed by persistently positive antiphospholipid [aPL] antibody and recurrent lower extremity deep vein thrombosis) for which she was on long-term rivaroxaban, non-obstructive coronary artery disease and hypertension. Rivaroxaban was held. She was hemodynamically stable. Hemoglobin level remained stable at around 10 g/dl (normal 11.5–16). The diverticular bleeding resolved spontaneously. TTE for elevated cardiac biomarkers (troponin-I 0.31 ng/ml [normal 0–0.04]) during the hospitalization incidentally showed mildly thickened anterior and posterior mitral leaflets. No murmur was appreciated on physical examination. Blood cultures were negative. She was discharged on therapeutic dose of enoxaparin instead.

She subsequently received transesophageal echocardiogram (TEE) at our institution which showed a large (1.4 × 0.7 cm) mobile, shaggy, echogenic mass located at the coaptation line on both leaflets of the mitral valve (Fig. 1). There was moderate mitral regurgitation. She was afebrile and did not have any signs of systemic embolization including petechiae, splinter hemorrhage, flank pain, or focal neurological deficits. Three sets of blood cultures were consistently negative. Blood tests revealed positive speckled-pattern antinuclear antibody (ANA) with a titer of 1:160. Magnetic resonance imaging (MRI) of the brain showed small subacute lacunar infarcts without evidence of embolic infarct (Fig. 2).

Figure 1:

TEE revealing a broad based, irregular, mobile mitral mass (1.4 × 0.7 cm) on the atrial surface of the mitral leaflet, involving the co-optation points.

Figure 2:

Diffusion weighted imaging of MRI showing no evidence of acute embolic stroke.

The possibility of NBTE or mitral valve thrombus was considered given the presence of vegetation in the absence of fever, negative blood cultures and history of APS. The patient was commenced on enoxaparin, prednisone 100 mg daily and hydroxychloroquine 200 mg twice a day. TEE performed 1 week later showed a significant reduction in the size of the mitral valve vegetation (0.6 × 0.7 cm) (Fig. 3). The patient was discharged with an 8-week course of steroid taper, hydroxychloroquine, and indefinite warfarin (INR goal 2.0–3.0). At a follow-up visit 6 months later, TEE showed resolution of the mitral valve vegetation with very small residual nodular focal calcific densities on the mitral valve leaflets with mild to moderate mitral regurgitation. She had age-appropriate cancer screening after discharge including a normal mammogram and a colonoscopy showing diverticulosis and tubular adenoma.

Figure 3:

Repeat TEE revealed regression of the mitral valve vegetation (0.6 × 0.7 cm).

DISCUSSION

NBTE is a rare non-infectious cause of endocarditis in which there is a deposition of sterile platelet thrombi consisting of platelets, fibrin, immune complexes and mononuclear cells on heart valves, particularly the mitral and aortic valves [1]. The prevalence ranged between 0.3% and 9.3% [2]. Although NBTE is commonly related to malignancies, which account for 80% of the cases [1], it can occasionally be a clinical manifestation of autoimmune diseases [3]. Endothelial injury, immune complexes, hypoxia, hypercoagulability and carcinomatosis have been hypothesized to play a role in the pathogenesis [4]. Patients are often asymptomatic but could present with thromboembolism. Vegetations in NBTE are easily dislodged since there is little inflammatory reaction at the site of attachment [5, 6]. Diagnosis of NBTE requires the presence of vegetations on echocardiogram and exclusion of infective endocarditis. Multiple blood cultures should be taken to rule out any infectious causes. TEE has 90% sensitivity for the detection of NBTE [4].

The mitral valve lesion in our patient is most likely NBTE given her underlying disease of APS and no evidence of infection demonstrated by repeatedly negative blood cultures. There was no evidence of cancer on CT abdomen and pelvis, colonoscopy or mammogram. APS is an immune-mediated acquired thrombophilia defined by vascular thrombosis with persistent antiphospholipid antibodies on two or more occasions at least 12 weeks apart [7]. Heart valve disease (HVD) is the most frequent cardiac manifestation of APS, occurring in 14.3% of the patients [8]. HVD is defined by the presence of valve lesions and/or moderate to severe valve dysfunction in the absence of a history of rheumatic fever or IE [7]. The pathogenesis behind HVD and APS involves inflammation and thrombotic mechanisms [9-11].

Patients with NBTE should be anticoagulated given the high rates of systemic embolization [4]. Anticoagulants of choice for NBTE in APS are heparin (unfractionated or low-molecular-weight) followed by warfarin (target INR 2.0–3.0) indefinitely [12]. There has been no trial showing direct comparison between long-term heparin and warfarin in NBTE. Older studies showed that heparin was effective in preventing thromboembolism in NBTE [5, 13]. However, in malignancy-associated NBTE, little benefit has been observed with warfarin in preventing thromboembolism [13]. It is worth mentioning that most of the patients in these previous trials had malignancy-associated NBTE. There has been no trial comparing heparin versus warfarin in NBTE related to autoimmune/inflammatory conditions. Warfarin has been shown to be beneficial in preventing recurrent thrombotic events among patients with APS [14]. Anticoagulation should be continued indefinitely, since recurrent thromboembolism is frequent following its discontinuation [15].

Hydroxychloroquine can be considered in APS especially in patients with coexisting SLE to prevent thrombosis [16]. There is no strong evidence supporting the use of HCQ in APS without SLE. Longer use of HCQ has been shown to reduce thrombosis in SLE patients with positive aPL antibody [17]. HCQ was associated with lower risk of thrombosis in asymptomatic aPL-positive individuals [16]. The addition of HCQ to standard therapy was shown to significantly improve obstetrical outcomes in APS with pregnancy [18]. Rituximab has been used to treat complications of APS such as thrombocytopenia, skin and heart valve involvement as well as to treat catastrophic APS [19, 20]. There has been no trial showing the role of rituximab in NBTE. However, rituximab has recently been shown to prevent recurrent thrombotic complications in warfarin-resistant SLE-associated APS [21]. There was a disagreement whether corticosteroid therapy could be helpful for acute valve inflammation. Poor data regarding the efficacy of corticosteroids do not enable firm recommendations to be made [22, 23]. The indications for surgery are similar to IE and include heart failure, acute valve rupture, though reports suggested that prevention of recurrent embolization was the most common reason for surgery [4, 24].

Our patient developed NBTE while being on Rivaroxaban. Warfarin is the standard anticoagulation of choice for long-term secondary prevention of venous thromboembolism in APS. Based on a systematic review [25], 16% of APS patients treated with direct oral anticoagulants developed recurrent thrombosis. This rate is relatively higher than that of APS patients treated with moderate intensity warfarin (goal INR 2–3) in previous trials (3.4–5.5%) [26, 27]. A prospective trial comparing rivaroxaban and warfarin in APS patients also demonstrated higher endogenous thrombin potential in the rivaroxaban group, suggesting a higher thrombotic risk [28]. It was unclear why the patient was on Rivaroxaban rather than aspirin or warfarin as she had been treated at an outside institution. This could point towards suboptimal anticoagulation as a possible reason for this patient developing NBTE.

There was a concern that treating this patient with anticoagulant alone might not be sufficient because she developed NBTE while being on rivaroxaban (though not the anticoagulation of choice in APS as discussed above). Although HCQ has little evidence for its use in APS without SLE, it has been shown to be beneficial in aPL-positive individuals [16, 17]. In addition, HCQ is a relatively safe drug with very low rates of serious adverse reactions [29]. The fact that she had dramatic improvement of the mitral valve vegetation after receiving prednisone and hydroxychloroquine in addition to enoxaparin suggested that inflammatory process might play a role in the pathogenesis. Moreover, heparin also has anti-inflammatory effects in addition to antithrombotic property and has been shown to affect various inflammatory mediators [30]. Enoxaparin, which is a derivative of heparin, has been shown to decrease cytokine release in asthmatic patients [31]. The anti-inflammatory property of heparin may well be another reason for its role in the treatment of NBTE. The size of the vegetation decreased by half at 1 week and completely resolved at 6 months. Previous reports showed that the time to complete resolution ranged from 1 month to 1 year [32-34]. Further studies are needed to confirm the efficacy of hydroxychloroquine and corticosteroids in these patients.

In summary, we present a case of asymptomatic NBTE in the setting of APS while on anticoagulation. The patient had dramatic improvement of NBTE after initiation of hydroxychloroquine and corticosteroid in addition to low-molecular weight heparin. This suggested inflammatory nature of the lesion. Though controversial, the use of corticosteroids and immunosuppressive therapy can be considered in NBTE secondary to APS. Further studies are needed to determine their efficacy. Surgery is indicated for severe valvular dysfunction and recurrent embolism despite anticoagulation. Multidisciplinary approach to management is of paramount importance.