Left ventricle pedunculated thrombi risks and outcomes: a case report and literature review

Abstract A 42-year-old male with ischemic cardiomyopathy presented with acute bilateral femoral artery embolization. After management with embolectomy and fasciotomy in both femoral arteries, transthoracic echocardiography revealed two pedunculated highly mobile left ventricle (LV) thrombi. Given the procedural risk, anticoagulation therapy was recommended over surgery. However, the bleeding risk impeded the continuation of anticoagulation, which increased the thrombus size. Multiorgan failure and disseminated intravascular coagulopathy followed and the patient died. We also systematically reviewed the PubMed and Scopus databases for pedunculated LV thrombi cases and retrieved 74 and 63 reports respectively. Of these, 37 relevant reports (45 cases) plus 11 reports from the manual search were included for data extraction, a total of 56 cases besides our case. Based on the etiologies and risks, LV thrombi are predictable and preventable, especially after ischemic events. A clear diagnostic algorithm and vigilant follow-up are needed as well as multidisciplinary management once a diagnosis is confirmed.


INtRoDUCtIoN
A left ventricle (LV) thrombus is defined as an echo-dense mass near an akinetic or hypokinetic ventricular wall that is visible in at least two different views. 1 LV thrombi formation following acute myocardial infarction (MI) or dilated cardiomyopathy (DCM) is predisposed by Virchow's triad (MIinduced endothelial injury and the subsequent elevation of catecholamine levels, 2 inflammationtriggered hypercoagulability, and blood stasis due to segmental wall motion). 3About 6.3% of STsegment elevation MI (STEMI) cases and 19.2% of anterior STEMI cases with LV ejection fraction (EF) <50% are complicated with LV thrombus formation within two weeks to three months of the onset of myocardial injury.Other risk factors of LV thrombus formation are dilated heart failure, hypercoagulable states, nonischemic cardiomyopathy, and Takotsubo cardiomyopathy. 4LV thrombi develop in 1.3% 5 to 2.2% 4 of patients with acute Takotsubo cardiomyopathy and are significantly associated with the presence of both apical ballooning and high troponin level >10 ng/mL.Pedunculated LV thrombi have a higher embolic potential than mural thrombi, depending on the extent of protrusion into the left ventricle, mobility, and the pedunculated shape.There is no theory explaining the exact mechanism or combination of factors that favor the formation of pedunculated thrombi.7][8] Herein, we depict a case of pedunculated LV thrombus that presented with bilateral acute lower limb ischemia and review the literature for similar case presentations highlighting the main risks and outcomes.

MetHoDoLoGY
We searched PubMed and Scopus databases using the keyword search terms "left ventricle OR left ventricular" AND pedunculated AND "thrombus OR thrombi".All published reports presenting cases of pedunculated left ventricular thrombus were included with no restriction on age or year of publication.

ResULts presentation of case
A man in his 40s with a history of diabetes mellitus, systemic arterial hypertension (SAH), and ischemic heart disease with resultant ischemic heart failure presented with bilateral lower limb pain and loss of motor and sensory activity.The patient was evaluated in the emergency department and the evaluation revealed acute bilateral lower limb ischemia that prompted an immediate surgical intervention.
Five years before the current presentation, the patient reportedly had extensive anterior STEMI (Figure 1) that was treated with streptokinase and rescue percutaneous intervention (PCI).Coronary angiography showed 80% stenosis of the proximal left anterior descending (LAD) artery, for which a drug-eluting stent was deployed.The patient's transthoracic echocardiography (TTE) showed an EF of 45% with an akinetic apical and mid septum, apical and mid anterior, and apical inferior segments; normal LV dimensions; and dilated left atrium.Over four years, the patient had deteriorating heart failure with EF 30%, akinetic anteroseptal and mid to apical septal segments, a restrictive pattern of diastolic function, dilated LV and left atrium, and mild mitral regurgitation.On examination, the vital parameters recorded systolic blood pressure of 90 mmHg, heart rate of 89/min, respiratory rate of 18/min, and temperature of 36.Laboratory investigations were notable for leukocytosis (15,300 cells/microliter), elevated cardiac enzymes (CK-MB 130 U/L; troponin I 71, 6-fold the upper normal limit), and an international normalized ratio (INR) of 1.Other laboratory test results were normal (hemoglobin, platelets, serum creatinine, serum urea, arterial blood gas).Arterial duplex revealed bilaterally damped monophasic flow across the external iliac artery down to the superficial femoral artery.Furthermore, there was no detectable flow distally down to the infra-popliteal arteries.The patient's acute limb ischemia was managed surgically by bilateral mechanical thrombectomy and fasciotomy.
A TTE was obtained after the operation and elucidated decreased EF (20%, measured by M-mode) with global hypokinesia and a large pedunculated irregular hypermobile LV thrombus at the LV apex measuring 4.32*2.82cm (Figure 2).An electrocardiogram revealed left bundle branch block and prolonged QT interval.
Cardiothoracic surgery consultation refused the surgery for the procedural risks and, because of this, anticoagulation treatment (with warfarin 5 mg once daily and enoxaparin sodium 100 mg twice daily) was decided on after counseling with the patient.Soon after the operation, the patient's condition deteriorated and required endotracheal intubation.The deterioration entailed circulatory collapse and multiorgan failure (acute kidney injury, ischemic/ shocked liver, and disturbed consciousness level).Furthermore, the patient exhibited a bleeding tendency (hematemesis, melena, and nasal bleeding), which necessitated discontinuation of the anticoagulation.As a consequence, the thrombus increased in size to measure 4.7*3.9cm (Figure 3) by TTE.The laboratory test results were then notable for low hemoglobin (7.4 g/dl), low platelets (87* 10 3 /UL), elevated renal function test values (serum creatinine 6 mg/dl; urea 267 mg/dl); elevated liver function test values (AST 1145; ALT 1063), and elevated serum potassium (6.5 mmol/dl).The patient eventually died.This manuscript conforms to the Helsinki Declaration and local ethical guidelines.

systematic review of literature
Searches of PubMed and Scopus databases retrieved 74 and 63 articles, respectively.After removing duplicates, 90 records were eligible for title and abstract screening, which revealed 66 reports to be eligible for full-text screening.Only cases reporting pedunculated thrombus/thrombi at the first assessment for any etiology were included; records with irretrievable data were excluded; reports of mural thrombus/thrombi that transformed into pedunculated thrombi during follow-up were also excluded for carrying different risks.Only 45 cases from 37 papers met our inclusion and exclusion criteria.A manual search revealed 11 more pertinent cases.Our report was included in the analysis (Figure 4)/ flowchart), reaching a final total of 57 cases analyzed.
The vast majority of LV thrombi were located at the apex (73.6%; 42/57) followed by the interventricular septum (8.7%; 5/57).However, some cases exhibited more than one thrombus at two or more sites and three cases did not report the thrombus site (Table 2).About 16 (28%) cases developed LV thrombus despite having normal systolic function on presentation.The etiology of the LV thrombus was idiopathic in 10/16 of these cases, due to a hypercoagulable state in two cases, and due to ulcerative colitis inflammatory condition in two cases.It is worth stating that SAH was a risk factor in 4/16 (25%), and the ECG showed abnormal changes in only 3/16 (18.7%) of these cases.
Thirty-three patients (57.8%) developed distal emboli at different sites, the most common of which was the brain (N=14), followed by the arterial system of the lower limb (N=13).Other sites are listed in Table 1 (see the Appendix).The definitive treatment for most cases was surgical removal (75.4%;N=43).Furthermore, three cases responded well to oral anticoagulation with warfarin.While five cases responded well to heparin infusion, four did not show any improvement, and the management plan was changed to surgery, tirofiban, recombinant tissue plasminogen activator (RTPA), or streptokinase.

DIsCUssIoN
Despite the absence of histopathological confirmation, our patient was diagnosed with LV thrombus because of his associated factors (history of anterior STEMI with reduced EF) and current presentation.Surgical removal is the definitive management for mobile pedunculated masses because of their high embolization risk. 61Alternatively, for cases that refused surgery or were deemed to be unfit for surgery, direct oral anticoagulants were non-inferior to vitamin K antagonist (warfarin) for treating LV thrombus. 61Based on our review, surgical removal was almost always successful, whereas oral and intravenous anticoagulation was relatively less successful (5/12; 41.6% failure rate).Furthermore, the three cases that died, including our case, were managed using anticoagulation and did not proceed to surgery.There are no clinical trials assessing the efficacy of thrombolysis via streptokinase, RTPA, or urokinase.Nonetheless, thrombolysis carries a high embolic and hemorrhagic risk despite the potential for successfully dissolving the LV thrombus. 624][65][66][67][68][69][70] This finding has been confirmed earlier where the LAD/anterior wall infarctions were significantly associated with contractile dysfunction at the apex and with decrements in the peak systolic function. 71our-dimensional magnetic resonance imaging (4D MRI) for intracardiac hemodynamic assessment was tested in anterior MI cases, which is the most reported risk for LV thrombi.It revealed reduced peak systolic flow in the mid ventricle and apex and reduced peak diastolic flow in the apex in anterior acute MI. 72 This explains the occurrence of apical thrombi in anterior/LAD MI.However, there is no reported prophylactic anticoagulation strategy to date.Accordingly, any use of prophylactic anticoagulation should be tailored on a patient-by-patient basis.Notably, prophylactic anticoagulation in LV thrombus was a class IIb recommendation according to the 2013 ACC/AHA STEMI guidelines. 73Low-dose anticoagulation with rivaroxaban 2.5 mg BID for 30 days, besides dual antiplatelet therapy (DAPT), has been tested recently. 74The low-dose rivaroxaban plus DAPT cohort had a lower incidence of LV thrombus formation than the DAPT alone cohort (0.7% and 8.6%, respectively; hazard ratio 0.08).On the other hand, anticoagulation has no role in preventing LV thrombus formation in DCM with sinus rhythm. 75The Heart Failure Long-Term Antithrombotic Study (HELAS) trial has also compared the incidence of thromboembolism with warfarin, aspirin®, or placebo in chronic heart failure. 76There was no significant difference in the incidence between the three groups.
TTE was the major diagnostic tool used in the literature cases and also in our case.Noting the difficulty of diagnosing mural thrombi and their potential of transformation into pedicled thrombi, routine assessment of patients following MI (particularly anterior MI with reduced LVEF) or cardiomyopathy diagnosis is advised for early diagnosis and management.Delayed enhancement cardiac magnetic resonance imaging (DE-CMRI) was revealed to be the most sensitive imaging modality for detecting LV thrombi and distinguishing them from the normal myocardium. 77It had a significantly higher performance than both the standard TTE and cine-CMRI for detecting LV thrombi. 78DE-CMRI has a 100% negative predictive value and 100% sensitivity. 79The absence of vascularity in the thrombi prevents late gadolinium enhancement on CMRI from increasing the sensitivity and specificity of the modality.Nonetheless, DE-CMRI cannot be afforded for all acute MI patients.So, an algorithm entailing routine non-contrast echocardiography for stratifying patients based on apical wall motion score was proposed; the presence of apical wall motion then warrants performing DE-CMRI.
Strengths and limitations: the strengths of this article lie in the complicated presentation and review of all the previously reported cases of pedunculated LV thrombi.The evidence level of each of the records from which data were extracted is given in the Appendix, Table 1, according to the Oxford Center for Evidence-based Medicine. 80In our case, the main limitation was the delayed access to TTE, which was only performed after the operation.The delayed diagnosis of the LV thrombus prevented early multidisciplinary management and early discussion between the vascular and cardiothoracic teams to decide on the optimum management plan.

CoNCLUsIoN
This report highlights a pedunculated LV thrombus in a case of ischemic cardiomyopathy with a previous history of acute anterior MI.Multidisciplinary management is a cornerstone in managing similar complicated cases.Early surgical management of pedunculated LV thrombi is the management of choice and it should be considered to avoid the failure rates of anticoagulation and thrombolytic medications.A clear diagnostic algorithm should be adopted for early diagnosis and for avoiding embolic presentations.Similarly, screening algorithms should also be developed for patients with non-ischemic cardiomyopathies and those liable to LV thrombosis with normal LV function -inflammatory bowel disease, and hypercoagulable states, for example.Furthermore, large clinical trials of the efficacy of prophylactic anticoagulation following acute MI, specifically anterior/LAD MI, are needed.

Figure 1 .
Figure 1.Electrocardiogram of the patient five years before his recent presentation showing ST-segment elevation myocardial infarction in leads V1-6 after receiving thrombolysis (streptokinase), which failed.

Figure 2 .
Figure 2. Transthoracic echocardiography; a four-chamber view of the heart after the bilateral mechanical thrombectomy and fasciotomy showing a pedunculated mass (thrombus) measuring 4.32*2.82cm.

Figure 3 .
Figure 3.A four-chamber view of the patient' s heart a few days after admission showing enlarging thrombus size (4.7*3.9 cm).

Figure 4 .
Figure 4. Flowchart of selection and screening of relevant studies.