Ventricular mural thrombi – An occult occurrence?

ABSTRACT

Background:

Ventricular mural thrombi are rare occurrences and form one of the common mechanical complications of myocardial infarctions. They also occur in patients with nonischemic myocardial disorders and even in those devoid of cardiac diseases. Clinical detection often depends on the size of the thrombi.

Aim:

This study was aimed at ascertaining the etiopathogenesis of mural thrombi with a clinicopathologic correlation.

Materials and Methods:

This was a 12-year retrospective observational study reviewing the autopsy records of all cases showing ventricular mural thrombi. The location, size, morphology, and histologic appearances of the thrombi were noted. The cases, depending on the etiology, were categorized into myocardial ischemic (Group 1), myocardial nonischemic (Group 2), and non-myocardial (Group 3) causes. These features were correlated with the clinical settings.

Results:

There were 93 cases of mural thrombi with an almost equal sex distribution and a mean age of 45.9 years. The cause was ischemic heart disease in most of the patients (Group 1, 46.2%), while 21.5% and 32.3% of patients belonged to Group 2 and Group 3, respectively. Unlike the large and dominantly left ventricular thrombi seen in Group 1, the other two groups frequently had biventricular involvement, location in the intertrabecular spaces, and a high microscopic detection. Clinical diagnosis had been made in only 3.2% of patients. Thromboembolism was noted in other organs in 34.4% of the total cases.

Conclusion:

Ventricular thrombi should be ruled out in patients with evidence of systemic and/or pulmonary thromboembolism, even in those without any cardiac disorders.

Introduction

Hemostasis is a physiological mechanism resulting in cessation of bleeding at the site of vascular injury due to clotting of blood. In contrast to this phenomenon, thrombosis is formation of solid plugs from the constituents of blood within the intact vasculature during life; these produce local injury by impeding blood flow or distant injury by embolization. The three primary abnormalities (“Virchow’s triad”)[1] leading to vascular thrombosis are endothelial injury with activation/alteration of gene expression in these cells, stasis or disruption of laminar blood flow that promotes platelet adherence/activation, and hypercoagulability of blood. These mechanisms also serve as prerequisites for thrombi occurring in the chambers of the heart (mural thrombi). In general, they are uncommon since the shear forces within the heart prevent platelet adherence/activation. But when they occur, they are often located in the atrial appendages or are attached to the valves (vegetations). Ventricular mural thrombi (VMTs) are rarer occurrences, explained on the basis of high pressure and continuous flow of blood.[2] The aim of this study was to elucidate the etiopathogenesis of VMT and analyze the clinicopathologic features.

Materials and Methods

The autopsy records from the cardiovascular pathology section of a large tertiary care center were reviewed for a period of 12 years (2010–2021), and cases indexed as VMT were retrieved for analysis. Data on patient demographics, clinical presentation and diagnosis, investigations, and treatment were obtained from the medical records in the department. The heart specimens had been fixed using 10% buffered formalin, dissected as per the flow of blood and described in detail. The location, size, morphology, and histologic appearances of the thrombi were noted. The thrombi were then classified based on their location (right ventricular, left ventricular, or biventricular), size (macroscopic or microscopic), morphology (flat or protruding), and histology (fresh and/or organized). Based on the etiology, the cases with thrombi were categorized into myocardial ischemic (Group 1), myocardial nonischemic (Group 2), and non-myocardial (Group 3) causes. These features were correlated with the clinical settings. Other organs were also studied for the presence of thromboembolism. The Institutional Ethics Committee Clearance was taken in March 2019.

Results

Demographics: In a span of 12 years, there were 93 cases of VMT at autopsy, seen in 45 men and 48 women, 13 of whom had been pregnant. The age range was from 3 to 87 years, with the mean age being 45.9 years. The associations included diabetes mellitus (19 patients), hypertension (19 patients), tobacco use (seven patients), alcoholism (six patients), collagen vascular disorders (three patients), pulmonary hypertension (two patients), and rheumatic heart disease, oral cancer, and chronic myeloid leukemia in one patient each.

Clinical presentation: The symptomatology and the clinical diagnoses have been outlined in Table 1. Dyspnea was the most common symptom in all the three groups, but was invariably accompanied by several other nonthoracic complaints, particularly lower limb gangrene/cellulitis (21 patients, 22.6%). Thrombosis in the visceral or iliac arterial system had been noted in seven patients on imaging studies, three of which had been associated with left ventricular thrombus.

Table 1.

Clinical manifestations, clinical diagnosis, and autopsy findings

Group 1 (n=43)			Group 2 (n=20)		Group 3 (n=30)
Symptoms
Dyspnea	22		Dyspnea	12		Dyspnea			11
Chest pain	06		Chest pain	01		Chest pain			01
Cough	02		Cough	04		Cough			01
Fever	03		Fever	08		Hemoptysis			01
Trauma	01		Abdominal pain	06		Fever			08
Altered sensorium	04		Loose motions	01		Altered sensorium			03
Abdominal pain	09		Jaundice	01		Hemiparesis			02
Loose motions	02		Reduced urine output	01		Localizing cerebellar symptoms			01
Reduced urine output	01		Lower limb weakness	01		Abdominal pain			09
Lower limb gangrene/cellulitis	17		Pedal edema	01		Loose motions			01
Gluteal abscess	01					Reduced urine output			03
Generalized anasarca	01					Pregnancy-related complications			03
						Postoperative wound infection			01
						Lower limb gangrene/cellulitis			04
Clinical diagnosis
Not specified	02	Acute confusional state		01		Dead on arrival			01
Warfarin toxicity and intracranial hemorrhage	01	Pleural effusion		01		Left hemiparesis			01
Acute myocardial infarction	02	Acute myocarditis		01		Intracranial hemorrhage due to			01
Ischemic heart disease	07	Dilated cardiomyopathy		01		blast crisis
Takayasu’s arteritis	01	Peripartum cardiomyopathy		03		Acoustic neuroma			01
Pulmonary tuberculosis	01	Pulmonary tuberculosis		01		Acute myocardial infarction			01
Chronic obstructive lung disease	01	Tuberculous enteritis and		02		Congestive heart failure			01
Pulmonary thromboembolism	01	perforative peritonitis				Bronchopneumonia			02
Acute gastroenteritis	01	Ischemic bowel disease		03		Pulmonary tuberculosis			01
Ischemic bowel disease	04	Pre-eclampsia with		01		Swine flu			01
Necrotizing enterocolitis	01	Disseminated intravascular		01		Pulmonary thromboembolism			01
Acute pancreatitis	01	coagulation (DIC)		02		Rectus sheath abscess			01
Chronic pancreatitis	01	Hemolysis, Elevated liver		02		Duodenal ulcer perforation			01
Iron-deficiency anemia	01	enzymes and low platelets				Ileal perforation			01
Traumatic fracture	01	syndrome with DIC		01		Tuberculous enteritis			01
Gluteal abscess	01	Acute leptospirosis				Alcoholic liver disease			02
Peripheral arterial disease	16	Undifferentiated fever under evaluation				Liver abscess			01
		Dorsal myelopathy				Acute pancreatitis with pseudocyst			01
						Obstructive uropathy			02
						Chronic kidney disease			01
						Pregnancy-related complications			04
						Peripheral arterial disease			04
Other noncardiac autopsy findings
Intracerebral hemorrhage	01	Disseminated tuberculosis		04		Intracerebral hemorrhage	01
Bronchopneumonia/abscess	06	Bronchopneumonia		03		Left cerebellopontine angle	01
Fibrocaseous tuberculosis	01	Pulmonary tuberculosis		01		schwannoma	04
Disseminated tuberculosis	01	Diffuse alveolar damage		02		Disseminated tuberculosis	05
Diffuse alveolar damage	02	Lupus pneumonitis		01		Bronchopneumonia/abscess	05
Centrilobular emphysema	05	Acute fibrinous- organizing		01		Pulmonary tuberculosis	06
Mixed dust pneumoconiosis	01	pneumonia				Diffuse alveolar damage	01
Usual interstitial pneumonitis	01	Acute pyelonephritis		01		Primary pulmonary hypertension	01
Lupus pneumonitis	01	Chronic pyelonephritis		01		Liver abscesses	01
Lung squamous cell carcinoma	01	Benign nephrosclerosis		01		Liver cirrhosis	01
Ileal neuroendocrine carcinoma	01	Lupus nephritis		01		Liver nodular regenerative hyperplasia	01
Liver cholangiocarcinoma	01					Acute pyelonephritis
Acute tubular necrosis	01	Pulmonary thromboembolism		04		Renal cortical necroses		01
Chronic tubulointerstitial nephritis	01	Ischemic bowel disease		03		Benign nephrosclerosis		01
Benign nephrosclerosis	05					Diabetic nephropathy		01
Diabetic nephropathy	01					Candidal cystitis		01
Lupus nephritis	02					Chronic myeloid leukemia		01
Pulmonary thromboembolism	06					Gastric adenocarcinoma		01
Kidney/spleen infarctions	04					Renal cell carcinoma		01
Ischemic bowel disease	01					Endometrioid carcinoma		01
Acute pancreatitis	05					Cerebral infarction		01
						Acute pancreatitis		02
						Pulmonary thromboembolism		10

Etiology: Sixty-three patients (67.7%) had underlying myocardial pathology, while the remaining 30 patients (Group 3, 32.3%) had no underlying myocardial disease. Among those with myocardial disease, the thrombi were related to ischemic heart disease (IHD) in 43 patients (Group 1, 46.2%, mean age 55 years), affecting 27 males and 16 females. Multifocal scarring (ischemic cardiomyopathy) [Figure 1] was present in four patients, while multifocal fresh/healing microinfarctions were seen in three other patients. In the remaining 36 patients, the infarction was regional and related to coronary atherosclerosis; the right coronary artery was involved in only four patients. The infarcts were acute in 11 patients [Figure 2a, subendocardial in two], acute-on-chronic in three, and chronic in 22 [Figure 2b, subendocardial in one]. Associated conditions included hypertension-induced left ventricular hypertrophy (LVH) in nine patients and calcific aortic stenosis, left ventricular aneurysm, Leriche’s syndrome, and Takayasu arteritis in one case each. Nonischemic myocardial pathology was identified in 20 patients (Group 2, 21.5%), consisting of seven men and 13 women (mean age of 35.5 years). The diseases noted were lymphocytic myocarditis (nine cases), peripartum cardiomyopathy (PPCM; six cases, with associated systemic lupus erythematosus in one patient), dilated cardiomyopathy (DCM, two cases), and one case each of myocardial miliary tuberculosis [Figure 3], giant cell myocarditis [Figure 4], and thrombotic phase of endomyocardial fibrosis (EMF). Patent foramen ovale, lipomatous hypertrophy of interatrial septum, hypertension-induced LVH, and nonbacterial thrombotic endocarditis of the mitral valve were the additional cardiac findings observed in one patient each. Of the 30 patients (12 men and 18 women, mean age of 42.6 years, 32.3%) devoid of myocardial disorder (Group 3), the thrombus formation was associated with pregnancy (six patients, of which two patients also had septicemia and one patient each had swine flu and disseminated intravascular coagulation), septicemia (six patients) [Figure 5a], tuberculosis (five patients, one with ankylosing spondylitis), and malignancy (four patients, chronic myeloid leukemia, gastric adenocarcinoma [Figure 5b], renal cell carcinoma, and endometrioid carcinoma). Additional findings were rheumatic heart disease, hypertension-induced LVH, obesity, and chronic thromboembolic pulmonary hypertension. Six others did not have an obvious cause or association.

Figure 1.

Case of ischemic cardiomyopathy: (a) enlarged globular heart with a rounded apex; (b) serial transverse slices showing dilatation of LVC, mild thinning of the myocardium, and several whitish areas identified circumferentially; (c) close-up of the posterior wall P with adherent small fresh thrombi in the intertrabecular spaces (arrows) and ischemic scars. A = anterior wall, AA = ascending aorta, IVS = interventricular septum, L = lateral wall, LAA = left atrial appendage, LV = left ventricle, LVC = left ventricular cavity, PT = pulmonary trunk, RA = right atrium, RV = right ventricle, RVC = right ventricular cavity

Figure 2.

(a) fresh transmural infarct (yellow with broad zone of hyperemia) involving the anterior wall A and adjoining parts of the lateral wall L and IVS. Note red-brown friable layer of mural thrombus; (b) case of systemic lupus erythematosus with healed infarction with myocardial thinning and endocardial thickening in the territory of the left anterior descending artery with associated apical occlusive fresh thrombus. IVS = interventricular septum, LVC = left ventricular cavity, P = posterior wall, RVC = right ventricular cavity

Figure 3.

Case of tuberculosis: (a) biventricular gray-white fresh thrombi in the intertrabecular spaces; (b) necrotizing granulomatous inflammation around an intramural coronary artery; (c) large nodule of cavitating caseous necrosis in the left lower lobe. A = anterior wall, IVS = interventricular septum, L = lateral wall, LVC = left ventricular cavity, P = posterior wall, RVC = right ventricular cavity

Figure 4.

Case of giant cell myocarditis: (a) the heart has been bisected to show moderate dilatation of LVC, granular thrombus at the apex (arrow), and focally congested myocardium; (b) lymphocytic infiltrate with multinucleated giant cells and fibrosis (H and E, ×100). AA = ascending aorta, AV = aortic valve, H and E = hematoxylin and eosin, IVS = interventricular septum, L = lateral wall, LVC = left ventricular cavity, MV = mitral valve, RAA = right atrial appendage, RVC = right ventricular cavity, TV = tricuspid valve

Figure 5.

Transverse slices of the ventricles in cases of: (a) septicemia with occlusive fresh thrombus occupying the entire apical one-third of LVC (note the presence of concentric hypertrophy); and, (b) disseminated gastric adenocarcinoma with mural fresh thrombi in the intertrabecular spaces. A = anterior wall, IVS = interventricular septum, L = lateral wall, LVC = left ventricular cavity, P = posterior wall, RVC = right ventricular cavity

Ventricular involvement and thrombus location and type: Among 93 cases of VMT, 50 patients (53.7%) had left ventricular thrombi, 22 (23.7%) had right ventricular thrombi, and 21 (22.6%) had biventricular thrombi. The thrombi had been fresh in most cases (47 hearts). VMT was identified by transthoracic echocardiography and computed tomography in three of our patients (two in Group 1 and one patient with EMF). Of the 43 cases in Group 1, the thrombi were seen in the left ventricle in 40 patients (93%), with concomitant right ventricular thrombus in two of 40 cases. Only three cases (7%) had isolated involvement of the right ventricle. Thrombotic obliteration of the apices was seen in 21 cases (48.8%, left ventricular apex 20 cases [Figure 6], right ventricular apex one case). In the remaining cases, the thrombi were seen in the intertrabecular spaces, two of which were identified on histology. Organizing or organized thrombi were seen in only eight cases (18.6%). In sharp contrast to the ischemic group, right ventricular involvement (five of 20 – 25% and 14 of 30 – 46.7%) and biventricular involvement (nine of 20 – 45% and 10 of 30 – 33.3%) were frequently observed in Group 2 and Group 3 patients, respectively. Isolated involvement of the left ventricle was seen in six patients each in both these groups (30% and 20%, respectively). Thrombotic obliteration of the apices/apex was present in 11 of the 50 hearts of groups 2 and 3 (22%). Rest of the 39 hearts (78%) had thrombi within the intertrabecular spaces [Figure 7a and b], of which 22 were identified on microscopy [Figure 7c and d].

Figure 6.

Cases of healed myocardial infarction: (a) transverse slices of the ventricles showing fresh occlusive apical thrombus; and, (b) bisected heart with organized apical thrombus. A = anterior wall, AA = ascending aorta, AV = aortic valve, IVS = interventricular septum, L = lateral wall, LVC = left ventricular cavity, MV = mitral valve, P = posterior wall, RVC = right ventricular cavity

Figure 7.

Fresh polypoidal thrombi in: (a) right ventricle in a case of uterine endometrioid carcinoma; and, (b) left ventricle in a case of dilated cardiomyopathy; (c) histologically identified fresh thrombus in the right ventricle (H and E, ×100); and, (d) organized thrombus in the left ventricle (H and E, ×250). H and E = hematoxylin and eosin, LAC = left atrial cavity, LVC = left ventricular cavity, MV = mitral valve, RVC = right ventricular cavity

Pulmonary or systemic thromboembolism was present in 30 patients (34.4%). Other findings at autopsy are given in Table 1. It is also to be noted that other predisposing factors that had been the causes of VMTs in group 3 were also seen in the other two groups as well [highlighted in italics in Table 1].

Discussion

This autopsy study records the presence of mural thrombi in the ventricular chambers in 93 patients. Thrombus formation appeared to be almost equally distributed among men and women. However, differences were discernible when the cases were analyzed according to the etiological categories. As noted in literature, the vast majority of VMTs in this study too were seen among the cases of IHD (43 of 93 cases, 46.2%), especially among men, and exhibited a laminated morphology with a firm consistency.[2] Though the use of prompt coronary interventions and/or antithrombotic agents has decreased the incidence of this life-threatening mechanical complication, data still suggests an incidence ranging from 15% to 25%,[3,4] since the “stunned” myocardium continues to be dysfunctional despite revascularization.[5] The ventricular thrombi usually occur in the early phase of acute infarction (24 h to nearly 2 weeks of the acute episode) over the region of poorly contracting myocardium. Apart from stasis, the extent and location (particularly the anterior wall and the apex) of the acute infarctions and the local inflammatory and hypercoagulable milieu triggered by endocardial injury also play an important role[6,7,8] in some cases in response to incomplete myocardial rupture.[9] Paradoxically, there are more chances of thrombus formation with subendocardial infarcts.[5] In some cases, biventricular involvement is also known to occur, which increases when patients with IHD develop heart failure.[8,10] Regional wall motion abnormalities and postinfarction left ventricular aneurysms with blood stasis play an important role in VMTs with healed infarcts.[8] In majority of our patients, the thrombi occurred with healed infarcts, and in nearly half of our cases, there was involvement of the apex and/or anterior wall with variable degrees of protrusions into the ventricular cavity. In the remaining half, the thrombi were found plastered over the ventricular walls or obliterating the intertrabecular spaces. Comorbid conditions such as diabetes, hypertension, infective foci, or immobilization (noted in a significant number of our cases) could heighten these responses.[7]

The nonischemic group (Group 2) and the cases devoid of significant structural abnormalities (Group 3) had three interesting features. The thrombi were more frequently located in both ventricles and the right ventricle. The thrombi were mainly present in the intertrabecular spaces and appeared polypoidal as opposed to the laminated morphology of thrombus in Group 1 patients. Thirdly, they were also picked up more often on histopathologic examination. The basic mechanism in Group 2 was invariably related to reduced ventricular contractility and accompanying wall motion abnormalities with ensuing blood stasis, as seen in cases of myocarditis, DCM (including PPCM), and patients with heart failure;[11] the incidence of thrombi ranged from 2% to 36%. But more importantly, an element of increased thrombogenicity is also conferred by platelet activation and high levels of proinflammatory cytokines and procoagulants, not only in cases of myocarditis, but also in heart failure.[12] VMT in Group 2 in the current study was represented mainly by DCM/PPCM and myocarditis. Thrombosis is also part of the natural history of EMF[13] (seen in one of our cases in Group 2). Apart from a setting of ventricular dysfunction, intracardiac thrombi, including VMTs, also form due to hypercoagulability. These include pregnancy (even without other associated risk factors for hypercoagulability),[14] septicemic states,[15] underlying malignancy,[16] inflammatory bowel disease (IBD),[17] and even disseminated tuberculosis.[18] IBD was not in the current series; other conditions were present in 70% of our patients without any myocardial diseases. The pathogenetic mechanisms that operate in these diseased states include alterations in the activity of platelets, procoagulants, and anticoagulants; subtle cardiac dysfunction may also be noted as in cases of sepsis. Six of the 30 patients in group 3 (20%) did not have any cardiac disease or other pre-requisites for thrombogenesis. In such cases, it is important to bear in mind the occurrence of primary antiphospholipid syndrome[19] and inherited thrombophilic states.[20] These six patients had not been investigated to rule out such inherited thrombophilia.

Transthoracic echocardiography is the commonly employed modality in the diagnosis of intracardiac thrombi (sensitivity of 90%–95% and specificity of 85%–90%) because of its access, safety, and convenience.[11,21] However, small immobile apical mural thrombi or those plastered to the endocardium are often less echo-dense, leading to a difficulty to distinguish them from the underlying myocardium, and hence, cardiac magnetic resonance imaging, though expensive and time-consuming, is nowadays considered the gold standard of diagnosis of ventricular thrombi.[11,21] In three of our patients, VMT was detected on transthoracic echocardiography and computed tomography. Accurate diagnosis is crucial since these patients would receive anticoagulant therapy to reduce embolic complications from VMTs, along with other medications or procedures related to the cause of VMTs. Such therapy may also be considered in those with ventricular wall abnormalities without any evidence of thrombus.[11,21] A sizable proportion of our patients had embolism to the lungs, visceral organs, and the lower limbs. This study emphasizes the need to rule out VMTs in all cases where the phenomenon of thromboembolism is suspected clinically, particularly in cases of cerebrovascular accidents, pulmonary embolism, mesenteric ischemia, acute renal failure, and peripheral arterial disease.

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Conflicts of interest

There are no conflicts of interest.