Two cases of acute myocarditis with multiple intracardiac thrombi: the role of hypercoagulable States.

In acute myocarditis, thrombus formation is an important prognostic factor. Early diagnosis and treatment of intracardiac thrombus is critical, especially when there are multiple thrombi. When a patient presents with multiple cardiac thrombi not only cardiac disorders, but other diseases such as malignancies, rheumatologic disorders and thrombophilia must be considered in the differential diagnosis. Although the presence of hypercoagulable states does not generally affect the treatment choice, it may have an impact on continuation and duration of the anticoagulant therapy. In this paper, we present two cases of acute myocarditis with multiple intracardiac thrombi. Additionally, these cases had hypercoagulable states which might have contributed to the thrombus formation.

INTRODUCTION

Intracardiac thrombus may develop as a consequence of multiple underlying cardiac disorder affecting valves and myocardium. The presence of a hypercoagulable state may contribute to the formation of multiple cardiac thrombi and may have an impact on the duration of anticoagulant therapy. We present two cases of acute myocarditis with concomitant hypercoagulable states and multiple intracardiac thrombi.

CASE REPORT

Case 1

A previously healthy 43-year-old male patient was admitted to our outpatient clinic with complaints of progressive shortness of breath and leg swelling, from which he had been suffering since the flu-like disease he had three weeks earlier. Physical examination revealed bilateral rales at lower lobes, and pretibial edema. ECG showed sinus tachycardia (112/bpm), with no ischemic changes. Complete blood count and routine biochemistry were unremarkable. Two-dimensional echocardiogram revealed a dilated left ventricle (LVED: 63 mm, LVES: 55 mm) with severe diffuse hypokinesis, depressed left ventricle ejection fraction (30%, biplane Simpson method), mild mitral and tricuspid regurgitation, and multiple thrombi: Apical thrombi in both ventricles with the left ventricular apical thrombus and mobile, a mural left ventricular thrombus, and a right atrial thrombus [Figure 1a-c]. Cardiac thrombus and/or dissection image in the right anterolateral wall of the thoracoabdominal aorta was also observed.

Figure 1

(a) Transthoracic echocardiography, Apical 4-chamber view, Multiple intracardiac thrombus in the right atrium, right ventricle and left ventricle, (b) Transoesophageal echocardiography, mid-oesophageal view. A thrombus or intramural hematoma with mobile particles in the posterior wall of the descending aorta, (c) Transoesophageal echocardiography, upper-oesophageal view. A large thrombus in right atrium, (d) Transthoracic echocardiography, Apical 4-chamber view. No evidence of residual thrombus

Transesophageal echocardiogram (TOE) was performed which revealed a thrombus or intramural hematoma with mobile particles in the posterior wall of the descending aorta and dense spontaneous echo contrast in the descending aorta [Figure 1b]. After the blood samples had been obtained for the thrombosis workup, anticoagulation with unfractionated heparin (UFH) was started. Heart failure treatment, including carvedilol, perindopril, spironolactone, hydrochlorothiazide, and indapamide were also initiated. Thrombosis workup revealed a serum homocysteine level of 57.5 μmol/L (normal range 6-17 μmol/L) and mildly elevated IgM anticardiolipin antibodies at 12.7 (URL 12). Twelve hours later the plasma homocysteine level was still elevated at 50 μmol/L.

During the differential diagnosis, Behcet's disease and other rheumatologic disorders were ruled out. Screening for occult malignancy was negative. Seeking for a genetic predisposition of hypercoagulability, the patient was screened for relevant mutations and found heterozygous (C677T) for Methylene Tetrahydrofolate Reductase (MTHFR) gene mutation. Thus, the patient was discharged with warfarin therapy at a compensated status. A follow-up transthoracic and transesophageal echocardiogram at one month, showed no evidence of residual thrombus [Figure 1d]. Left ventricle was within normal dimensions and ejection fraction (54%) was close to the normal.

Case 2

A 59-year-old male patient with a history of atrial fibrillation and cerebrovascular accident presented to the emergency room with pulmonary edema. Myocardial infarction was ruled out by cardiac enzymes screening and ECG recordings. Transthoracic 2-dimensional echocardiogram showed global hypokinesis of the left ventricle, depressed ejection fraction (35%), biatrial dilatation, moderate mitral regurgitation and multiple intracardiac thrombi. Transesophageal echocardiography confirmed multiple thrombi: A 1.6 × 1.5 cm mural thrombus in the right atrium near the superior vena cava and a 1.5 × 0.8 cm thrombus in the right atrium near the inferior vena cava [Figure 2a-c].

Figure 2

(a and b) Transoesophageal echocardiography, mid-oesophageal view. Multiple intracardiac thrombus in the right atrium, (c) Transthoracic echocardiography, Apical 4-chamber view. A large thrombus in right atrium, (d) Transthoracic echocardiography, Apical 4-chamber view. No evidence of residual thrombus

Deep vein thrombosis was ruled out by bilateral lower extremity venous Doppler ultrasound. After the blood samples had been obtained for the thrombosis workup, anticoagulation with unfractionated heparin (UFH) was started (target aPTT: 50-70 ms). Heart failure treatment with ramipril, spironolactone, atenolol and digoxin was also administered.

He had two episodes of fever occurring two days apart. Empiric antibiotic therapy with ceftriaxone was initiated. Blood culture results and malignancy screenings were negative. Rheumatologic disorders were also ruled out. The patient was screened for acquired and/or inherited thrombophilia and found homozygous for MTHFR (A1298C) mutation. Lysis of the thrombi, with UFH therapy, was followed up by repeated transesophageal echocardiograms. UFH was withdrawn two weeks later upon disappearance of all intracardiac thrombi [Figure 2d]. The patient was discharged with enoxaparin 6000 twice a day, maintenance therapy. A follow-up transthoracic echocardiogram at six months showed a nearly normal ejection fraction (50%) of the left ventricle, with no evidence of residual thrombus.

DISCUSSION

Multiple chamber thrombus formation has been reported in myocardial infarction[1] and various cardiomyopathies,[23] but more frequently it was described in acute myocarditis,[4] and in case of systemic inflammation and/or hypercoagulable states.[5] There is increased risk of thrombus formation in acute myocarditis due to inflammation and stasis secondary to the decreased systolic function. Using video cardioscopy, thrombus incidence rate was shown to be higher in acute myocarditis compared to myocardial infarction and dilated cardiomyopathy, although the ejection fractions did not show any difference between the groups.[6] It should be noted that video cardioscopy is more sensitive than echocardiography in determination of the left ventricular thrombus.

Viral myocarditis leads to hyper activation of the coagulation system due to increased myocardial tissue factor (TF) expression and procoagulant activity. Increased TF thrombogenicity is also found in the blood, possibly contributing to the systemic thrombus formation during the acute phase of viral myocarditis.[7]

Acquired or inherited thrombophilia may contribute to the thrombus formation in acute myocarditis. It is well-known that MTFHR (C677T) gene mutation and hyperhomocysteinemia are important risk factors for arterial and venous thrombosis, possibly by causing damage to the endothelium and, affecting thrombocytes and coagulation factors.[8] Ucar et al., reported that hypercoagulable states such as FV Leiden, prothrombin 20210 and MTHFR gene mutations have no additional role in left ventricular thrombus formation in patients with myocardial infarction.[9] However, another study demonstrated that hyperhomocysteinemia is an independent predictor of the left ventricular thrombus formation in myocardial infarction patients treated with thrombolytics. In addition to these confounding data, there have been some cases of left ventricular thrombus in which left ventricular systolic function and dimensions were normal. In these cases the hypercoagulable states were the main contributors to the thrombus formation.[10]

In both our cases, multiple intracardiac thrombus formation can be explained by inflammation and hypercoagulable states. Our first case had hyperhomocysteinemia and was heterozygous for MTFHR (C677T) mutation. Presence of these hypercoagulable states may contribute to the thrombus formation in the heart chambers and descending aorta during acute myocarditis. Our second patient was homozygous for MTFHR (A1298C) mutation. This mutation does not cause hyperhomocysteinemia, moreover no relation between this mutation and thrombosis was found in large population studies. Since in our patient intracardiac thrombi was not resolved despite warfarin use and therapeutic INR values and persisted under parenteral anticoagulation, we suggest that MTFHR (A1298C) mutation should be taken into consideration as a possible predisposing factor to the thrombus formation.

In case of multiple cardiac thrombi, diseases other than cardiac disorders, such as malignancies, rheumatologic disorders and inherited thrombophilia, must be included in the differential diagnosis. Although the presence of hypercoagulable states generally does not affect the therapy choice, it can have an impact on continuation and duration of the anticoagulant treatment. Namely, these patients may require more aggressive anticoagulation.