Resolution of huge thrombi in bilateral ventricles caused by severe lupus cardiomyopathy

Introduction

Ventricular thrombus is an uncommon, severe condition with high morbidity and mortality. Left ventricular (LV) thrombus is complicated with LV dysfunction mainly resulting from acute myocardial infarction and heart failure, which could cause severe systemic embolism. ¹ Right ventricular (RV) thrombus often originates from deep venous thrombosis (DVT) and is accompanied by pulmonary emboli. Also, RV thrombi can be caused by heart failure, atrial fibrillation, and devices. ² Simultaneous bilateral ventricular thrombi have been seldom reported.

Systemic lupus erythematosus (SLE) is a multiorgan disease characterized by the formation of autoantibodies and immune complexes. This disease often involves the cardiovascular system and may affect all parts of the heart, including the pericardium, conduction system, myocardium, valves, and coronary arteries. The prevalence of cardiovascular involvement in patients of SLE has been estimated to be >50%. ³ The most common intracardiac manifestation is Libman–Sacks endocarditis, with most cases involving the mitral valve. Intracardiac thrombi are reported rarely. Herein a case is described of a woman with simultaneous LV and RV thrombi caused by lupus myocardiopathy, which resolved following immunosuppressive and anticoagulation treatment.

Case presentation

A 42-year-old woman was admitted to the hospital because of a 4-month history of edema in the bilateral lower extremities, malar rash, and facial erythema. Cough, dyspnea and orthopnea developed 1 month before presentation while the other symptoms worsened. No hemoptysis, chill, oral ulcer, arthralgia, morning stiffness, gross hematuria and photosensitivity are present. In the local hospital, methylprednisolone, losartan, and metoprolol were initiated. The patient was then transferred to the authors’ hospital.

On admission, blood pressure was 126/96 mmHg, pulse rate was 120 beats/min, respiratory rate was 28 breaths/min, and body temperature was 38.1°C. Butterfly erythema and pale-looking skin were observed. Jugular venous distention was noted on physical examination. On cardiac auscultation, rhythm was tachycardic but regular. Weak summation gallops were heard at the cardiac apex, and no pericardial friction rubs were appreciated. Moist rales on both lung fields were audible. Shifting dullness was positive. The patient described a heavy feeling in the lower extremities, and pitting edema was evident.

Laboratory tests showed hemoglobin 85 g/L, white blood cells 8.47 × 10⁹/L, and platelets 236 × 10⁹/L. Urinalysis was positive for 4+ protein, red blood cells 99/high power field, white blood cells 125/high power field. Urine protein excretion was 5.03 g/24 hours. Blood biochemistry analysis revealed the following: serum albumin 25.7 g/L, globulin 48 g/L, blood nitrogen urea 20 mmol/L, serum creatinine 117 μmol/L, estimated glomerular filtration rate 49.63 mL/min/1.73 m², uric acid 487 μmol/L. Antinuclear antibody was positive (1:320), anti-dsDNA was negative, and anti-Sm and anti-RNP antibodies were positive. Serum complement 3 (C3) was 0.403 g/L (normal, 0.785–1.52 g/L), and serum C4 was 0.0436 g/L (normal, 0.145–0.360 g/L). Rheumatoid factor was 30.70 IU/mL. Serologic testing for anti-neutrophil cytoplasmic antibodies and anti-glomerular antibodies were negative. C-reactive protein was 59.2 mg/L, erythrocyte sedimentation rate was 97.0 mm/hour.

Cardiac enzymes were elevated as follows: troponin T 230 ng/L (normal, 0–14), pro-brain natriuretic peptide >35000 pg/mL (normal, 0–153), creatine kinase-MB 1.95 ng/mL (normal, <2.88). Coagulation test showed prothrombin time 14.6 seconds (international normalized ratio 1.24), fibrinogen 4.82 g/L (normal, <4), fibrinogen degradation products 26.1 mg/L (normal, <5), d-dimer 9.48 mg/L (normal, <0.55). Antiphospholipid antibody was normal at 2.59 RU/mL (normal, <12).

Chest computed tomography scan revealed an enlarged cardiac silhouette, pericardial effusion, and pulmonary edema. A transthoracic echocardiography demonstrated thrombi in both ventricles (Figure 1(a) and (b)), severe mitral regurgitation, and moderate tricuspid regurgitation. The LV ejection fraction (LVEF) was decreased to 35.4%.

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Figure 1.

Transthoracic echocardiography with simultaneous right and left ventricular thrombi. Panel (a) and (b) show an echo dense thrombus in the left and right ventricular cavities. The thrombi in the left ventricular cavity are predominant. Panel (c) shows no intracardiac thrombi after treatment (apical 4-chamber view).

The patient was diagnosed with lupus cardiomyopathy with thrombi in both ventricles, heart failure with reduced LVEF, lupus nephritis, and secondary nephrotic syndrome. Prednisone 50 mg/day, mycophenolate mofetil 500 mg twice daily, and hydroxychloroquine 200 mg twice daily were initiated for the control of lupus activity. Aspirin and low molecular weight heparin were administered to prevent embolism. The patient refused to take warfarin since she was unwilling to be monitored by frequent blood draws. An angiotensin-converting enzyme inhibitor, furosemide, and spironolactone were used to attenuate heart failure. After drug administration, the patient experienced transient numbness in her right limbs and hemoptysis; she then recovered quickly.

During the next few weeks, her dyspnea and edema improved significantly. Anticoagulative treatment was suspended for 3 days to perform renal biopsy. Renal pathology showed 1 cellular crescent among 16 glomeruli. Glomerular hypercellularity and mesangial proliferation were also observed (Figure 2(a)). The glomerular basement membrane was thickened. Fuchsinophilic deposits were seen beneath the endothelium (Figure 2(b)). Arteriole thrombosis and lumen stenosis were not observed. Immunofluorescence study revealed immunoglobulin G (IgG), IgA, C3, and C1q deposits in the mesangial area and capillary wall. Electron microscopy revealed electron-dense deposits in mesangial, subepithelial space (Figure 2(c)). The results of renal biopsy were consistent with lupus nephritis class III + V.

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Figure 2.

Renal pathologic profiles. Panel (a) shows glomerular hypercellularity and a cellular crescent (periodic acid–Schiff stain × 200). Panel (b) shows subendothelial fuchsinophilic deposit (periodic acid–Schiff mucin stain × 200). Panel (c) shows electron-dense deposits in subepithelial space (electron micrography × 2500).

At 2 months after the initiation of anticoagulative and immunosuppressive treatment, the patient significantly improved. Transthoracic echocardiography showed a recovery of LV systolic function (LVEF 46%) and disappearance of the thrombi (Figure 1(c)). Mitral and tricuspid regurgitation had also disappeared. Cardiac enzymes declined remarkably (pro-brain natriuretic peptide 259 pg/mL, troponin T 10.3 ng/mL, creatine kinase-MB 1.09 ng/mL). Serum complement C3 increased to 0.573 g/L, and serum C4 was normal. Serum albumin was 38.9 g/L, serum creatinine was 71 μmol/L, and serum hemoglobin was 130 g/L. Urine protein/creatinine ratio was 0.9 g/g. Aspirin and low molecular weight heparin were withdrawn. The steroids were tapered. At 1-year follow-up, complete remission of lupus nephritis was reached and the LVEF had increased to 56%.

Discussion

Left ventricular thrombus is a life-threatening complication of LV dysfunction associated with high rate of systemic embolism and morbidity and mortality. The most common precipitating factor is heart failure, followed by acute myocardial infarction. Reduced LVEF is associated with higher rate of LV thrombi. ¹ The in-hospital mortality rate for patients with LV thrombi is 7.8%. Following anticoagulative treatment, LV thrombus may resolve. Right ventricular thrombi are usually found with concurrent pulmonary emboli and associated with significant mortality. Without treatment, the mortality of RV thrombi may reach almost 100%. Often RV thrombi originate from deep vein thrombi, but they may also be caused by heart failure, devices, and atrial fibrillation. The treatment options for RV thrombus include anticoagulation, thrombolysis, and surgical thrombectomy. Optimal management remains unclear. It is noticeable that cardiac magnetic resonance(CMR) can determine the presence of LV thrombus based on avascular tissue characteristics and is considered the gold standard imaging technique in assessing thrombi. ⁴ Echocardiograms can be the primary screening tool and stratification tool to select those patients who require CMR assessment. The addition of echo-contrast medium improves the diagnostic accuracy of ventricular thrombosis. ⁵

We searched MEDLINE database using keywords “biventricular thrombosis” and “biventricular thrombi”. About fifty cases of thrombi in bilateral chambers have been reported. The majority were caused by cardiomyopathy, myocarditis, and acute myocardial infarction. It has sporadically been described in the setting of hypereosinophilic syndrome, patent foramen ovale and other rare diseases. In almost all cases, the patients experienced heart failure with reduced ejection fraction, suggesting that reduced ejection fraction remains the risk of biventricular thrombi. Of note, only 4 cases originated from autoimmune disorders (Table 1), including lupus (the present case), antiphospholipid syndrome (APS),^6,7 and Behçet disease. ⁸ Simultaneous LV and RV thrombi caused by lupus has not been reported before this present case.

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Table 1.

Summary of cases with biventricular thrombi caused by autoimmune diseases.

Case No.	Gender	Age (years)	Essential diseases	EF (%)	Treatment	Outcome	Reference
1	M	52	APS	30	Anticoagulants, steroids, and plasmapheresis	Thrombi resolved, EF:50%	6
2	F	45	APS	30	warfarin	Thrombi resolved	7
3	M	18	Behçet's disease	/	Heparin/steroid/cyclophosphamide	Thrombi resolved	8
4	F	42	Lupus	35.4	LMWH, steroid, MMF	Thrombi resolved. EF:56%	/

APS: antiphospholipid syndrome; EF: ejection fraction; LMLH: low molecular weight heparin.

Systemic lupus erythematosus is a common chronic noninfectious autoimmune disorder involving multiple organs, including the heart, kidney, and other organs. Cardiac manifestations develop in most patients with SLE at some time during the course of disease. Cardiac complications of SLE become a major cause of death in this population and include pericarditis, myocarditis, endocarditis, coronary artery disease. Intracardiac thrombi are rarely reported, although they are a severe complication with high morbidity and mortality.

The most important risk factors at disease onset for developing a thromboembolic event in SLE patients are nephritis, cryoglobulins, and a positive lupus anticoagulant. ⁹ Antiphospholipid syndrome can occur secondary to lupus and be associated with thrombosis. Deep venous thrombosis and pulmonary embolism are the most common manifestations of primary APS. Ventricular thrombi in APS were reported. Hypercoagulable state and myocardial injury of APS contribute to ventricular thrombi. In addition to secondary APS, ventricular thrombi—especially LV thrombi—in lupus are mainly associated with myocardiopathy such as myocarditis, and Takotsubo cardiomyopathy.

Myocarditis has been identified in about 9% of patients with lupus. Postmortem studies found an average prevalence of myocarditis was 57%. Pathologically, lupus myocarditis is characterized by edema and focal aggregates of inflammatory cells in the myocardial interstitium; diffuse immunocomplex deposition in perivascular areas; intimal hyperplasia; and intramural arterial thickening with luminal narrowing. Lupus myocarditis is primarily an immune complex–mediated vasculitis, followed by complement activation, inflammation, and myocardial injury. Ventricular wall motion abnormalities caused by severe myocardial injuries contribute to the formation of ventricular thrombi. Immunosuppressive and anticoagulative treatment could improve autoimmune myocardial injuries and resolve LV and RV thrombi. Systemic embolism should be cautioned because these thrombi may be massive and unstable.

Intracardiac thrombi caused by ventricular dysfunction should be differentiated from Libman–Sacks endocarditis, which is the most prevalent form of cardiac involvement in patients with lupus. These lesions are sterile, fibrinous vegetation most commonly found in the left chamber, particularly the ventricular surface of the mitral valve. On echocardiography, these vegetation appear as small masses with irregular borders and echo density, firmly attached to the valve surface without independent mobility. The organization of these fibrin-platelet thrombi on the altered valve leads to fibrosis and subsequent valve dysfunction. Transthoracic echocardiography and magnetic resonance imaging can differentiate them.

Conclusion

This report is the first of simultaneous LV and RV thrombi caused by lupus myocardiopathy. Immunosuppressive and anticoagulative treatment improved heart function and resolved the thrombi. Cardiac complications of lupus should be evaluated routinely.