Thrombocardiology: Novel Insights from Clinical Experience Cardiology DOI: 10.1159/000506925 Received: October 21, 2019 Accepted after revision: March 2, 2020 Published online: April 29, 2020 Left Ventricular Thrombi and Embolic Events in Takotsubo Syndrome despite Therapeutic Anticoagulation Claudia Stöllberger a Josef Finsterer a Birke Schneider b a Krankenanstalt Rudolfstiftung, Wien, Austria; b Sana Kliniken Lübeck, Lübeck, Germany Established Facts • Left-ventricular (LV) thrombi in patients with takotsubo syndrome (TTS) differ from LV thrombi in acute myocardial infarction. In patients with a TTS-related thrombus, the rapid improvement of contractility promotes the discharge of emboli by causing detachment of the thrombus from the LV wall resulting in embolic events despite optimal anticoagulation. At present, the management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Novel Insights • Until these studies are available, we suggest the following approach: patients with TTS-related ventricular thrombi should be monitored by echocardiography while receiving anticoagulation. In case of highly mobile LV thrombi, cardiac surgery to prevent systemic embolism may be considered. Abstract Introduction: Takotsubo syndrome (TTS) may be complicated by left-ventricular (LV) thrombus formation in 1.3–5.3% of patients. Risk factors for thrombi comprise apical TTS, elevated levels of C-reactive protein and troponine, thrombocytosis, persisting ST segment elevation and right-ventricular involvement. Embolic risk appears high, and anticoagulation is recommended. Case Presentation: We present 3 females, aged 60– 82 years, with TTS-associated LV thrombi and cerebral embo- karger@karger.com www.karger.com/crd © 2020 S. Karger AG, Basel lism despite therapeutic anticoagulation. Two patients showed apical and 1 patient midventricular ballooning. In 2 patients LV thrombi had not been present at the first echocardiographic examination. LV thrombi were multiple and highly mobile in 2 patients; 1 patient had a single immobile thrombus associated with spontaneous echocardiographic contrast (SEC). In each case, 3 of the described risk factors for LV thrombus formation were identified. The embolic stroke occurred 41–120 h after TTS symptom onset and 21–93 h after the initiation of therapeutic anticoagulation. Two patients were discharged with a neurological deficit, and 1 of them eventually died as a consequence of the stroke. LV thrombectomy to prevent embolism, which has been reported in a small number of cases, had not been considered in our patients. Conclusion: At present, the Prof. Dr. Claudia Stöllberger Steingasse 31/18 AT–1030 Wien (Austria) claudia.stoellberger @ chello.at Downloaded by: Université de Paris 193.51.85.197 - 5/1/2020 3:29:08 AM Keywords Anticoagulation · Apical ballooning · Embolic stroke · Takotsubo syndrome · Thrombus management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Until these studies are available, we suggest the following approach: patients with a TTS-related thrombus should be monitored by echocardiography while receiving anticoagulation. In case of highly mobile LV thrombi, the heart team may consider cardiac surgery to prevent systemic embolism. The role of SEC in TTS remains to be determined. © 2020 S. Karger AG, Basel Introduction Formation of a left-ventricular (LV) thrombus is an infrequent complication of takotsubo syndrome (TTS) with a prevalence ranging from 1.3 to 5.3% (Table 1) [1– 8]. Several risk factors for LV thrombus formation have been described: apical TTS, significantly elevated levels of C-reactive protein and troponine, thrombocytosis, persisting ST segment elevation and right-ventricular involvement [3, 4, 7, 9]. It has been recommended to treat Table 1. Prevalence, embolic risk and factors associated with left-ventricular thrombus formation in takotsubo syndrome (TTS) Author, year Patients Setting Prevalence of LV thrombi Embolic events with LV thrombi TTS type with LV thrombi Factors associated with LV thrombi Sharkey et al. [1], 2010 136 SC 5 (3.7%) 2/5 (40%) –NR NR Kurisu et al. [2], 2011 95 SC 5 (5.3%) 1/5 (20%) Apical n = 5 –NR Schneider et al. [3], 2014 209 MC 7* (3.3%) 2/7 (29%) Apical n = 6 Midventricular n = 1 RV involvement El-Battrawy et al. [4], 2016 114 SC 6 (5.2%) 1/6 (17%) Apical n = 3 Midventricular n = 3 Elevated CRP ST segment elevation RV involvement Dias et al. [5], 2016 206 MC 6 (3%) 1/6 (17%) NR –NR Ghadri et al. [6], 2016 1,750 MC 23 (1.3%) NR Apical n = 22 Midventricular n = 1 –NR Santoro et al. [7], 2017 541 MC 12 (2.2%) 2/12 (17%) Apical n = 12 Troponin level >20× ULN, apical ballooning ST segment elevation >48 h Almendro-Delia et al. [8], 2018 711 MC 20 (2.9%) –NR NR –NR CRP, C-reactive protein; LV, left ventricular; MC, multicenter; NR, not reported; RV, right ventricular; SC, single-center; ULN, upper limit of normal. Table 2. Embolic events under anticoagulation therapy in patients with takotsubo syndrome and left-ventricular thrombi Author, year Age/ sex TTS type LV EF, % Thrombus morphology Anticoagulation Embolic event Interval: initiation of AC and embolic event Outcome Schmidt et al. [15], 2007 70/f apical – P “effective,” drug not mentioned Transient ischemic attack NR Discharged Nerella [13], et al. 2008 43/f apical 45 F/S Heparin, VKA Renal embolism 3 days Discharged Kurisu et al. [2], 2011 82/f apical 45 P/M “AC,” drug not mentioned Ischemic stroke 1 day Discharged Valbusa et al. [12], 2013 75/f apical 40 F/S → P/M Heparin, VKA Brachial artery embolism 6 days Discharged Porta et al. [14], 2013 78/f apical 35 ASA, heparin Ischemic stroke, mesenteric 1 and 7 days artery embolism F/S → P/M Died 2 Cardiology DOI: 10.1159/000506925 Stöllberger/Finsterer/Schneider Downloaded by: Université de Paris 193.51.85.197 - 5/1/2020 3:29:08 AM AC, Anticoagulation; ASA, acetylsalicylic acid; F, flat; LV EF, left-ventricular ejection fraction; M, mobile; NR, not reported; P, protruding; S, sessile; TTS, takotsubo syndrome; VKA, vitamin K antagonist. patients with TTS-related LV thrombi with anticoagulation for up to 3 months until LV function has completely normalized [7, 10, 11]. However, embolic events in patients with TTS-related thrombi despite therapeutic anticoagulation have been reported in the literature (Table 2) [2, 12–15]. We present further 3 patients with TTS-associated thrombi who developed cerebral embolism under therapeutic anticoagulation and discuss the therapeutic options in this clinical scenario. Case Report Discussion This case series and the published cases listed in Table 2 demonstrate that therapeutic anticoagulation in TTS-related LV thrombi may not completely protect from embolic events in every case. It has been recommended that patients with TTS-related ventricular thrombi should be treated with anticoagulant therapy for 3 months, since usually the wall motion abnormality resolves within this period of time Thrombi in Takotsubo Syndrome Fig. 1. Echocardiographic modified apical 4-chamber view showing ballooning of the left ventricular apex with 2 protruding thrombi measuring 10 mm (*) and 15 mm (+). [7, 10, 11]. This recommendation derives from data on LV thrombi associated with acute myocardial infarction, most frequently anterior ST elevation myocardial infarction (STEMI) [16, 17]. There are, however, no randomized controlled trials which have assessed safety and efficacy of anticoagulation in TTS-related thrombi. Possible mechanisms for thrombus formation in TTS are transient LV regional wall motion abnormalities resulting in the local activation of hemostasis, endocardial injury with regional exposure or release of thrombogenic substances and influence of catecholamines on nucleotide-induced platelet aggregation [10]. In the literature, most of the thrombi have been described in patients with apical TTS; however, in contrast to the assumption of Santoro et al. [7, 9], midventricular TTS may equally be associated with thrombus formation, as seen in one of our patients [4, 6, 18, 19]. Risk factors for LV thrombus formation in TTS, identified from several case series, comprise an apical type of TTS [7], significantly elevated C-reactive protein levels [4, 18], thrombocytosis [18], elevated troponine levels (>20 times the upper limit of normal) [7], ST segment elevation [4, 7], persisting for more than 48 h [9] and rightventricular involvement [3, 4]. The predictive value of these risk factors, however, has so far not been prospectively tested. In each of our cases, a combination of 3 previously described risk factors was identified. The prevalence of TTS-associated thrombi in large multicenter registries appears lower than in single-center Cardiology DOI: 10.1159/000506925 3 Downloaded by: Université de Paris 193.51.85.197 - 5/1/2020 3:29:08 AM The clinical characteristics, laboratory findings and course of the patients are listed in Table 3. Two of these 3 patients had been included in a multicenter registry [3]. All 3 patients were postmenopausal females with an age range from 60 to 82 years. Regarding laboratory findings, 1 patient had an elevated thrombocyte count, 2 patients showed elevated D-dimer levels, and all patients had elevated C-reactive protein levels. The ECG on admission showed ST segment elevation in 2 patients and widespread negative T waves with a prolonged QTc interval >500 ms in all patients. LV ejection fraction was moderately reduced (45–56%). One patient suffered from midventricular ballooning with right-ventricular involvement whereas the other 2 patients showed an apical ballooning pattern of the LV. In 2 patients, LV thrombi had not been present at the first echocardiographic examination and were detected 21–76 h after initiation of anticoagulation for stroke and paroxysmal atrial fibrillation. LV thrombi were multiple and highly mobile in 2 patients (Fig. 1), 1 patient had a single immobile thrombus and dense spontaneous echocardiographic contrast (SEC) extending from the LV apical akinesia into the LV cavity. All embolic events were ischemic strokes, occurring 41–120 h after symptom onset and 21–93 h after initiation of anticoagulation. At the time of embolism, all patients were under therapeutic levels of anticoagulant therapy, either controlled by anti-factor Xa activity or by aPTT. Two patients had additionally received acetylsalicylic acid 100 mg/ day and a clopidogrel loading dose because of an initially suspected acute coronary syndrome. All patients had a combination of 3 of the previously described risk factors for LV thrombus formation. One patient developed paroxysmal atrial fibrillation after admission as an additional risk factor for cerebral embolism. Two of the 3 patients were discharged with a neurological deficit, and 1 of them eventually died as a consequence of the disabling stroke. Table 3. Characteristics and course of patients with takotsubo syndrome, left-ventricular thrombi and embolic events despite anticoagulation Patient 1 Patient 2 Patient 3 Age, years/sex 60/f 82/f 82/f Cardiovascular risk factors Hypertension Diabetes Hypercholesterolemia Smoking BMI + 0 + + 26 0 0 0 0 18.4 0 + 0 0 31.3 Pulmonary tuberculosis 30 years previously; ankylosing spondylitis for 15 years; cervical spinal canal stenosis, dorsal surgical decompression 3 months previously Parkinson’s disease; osteoporosis Hypothyroidism; pneumonia Trazodone 50 mg/day Pregabalin 150 mg/day Diltiazem 90 mg/day Pantoprazol 40 mg/day Tizanidine 4 mg/day Dexibuprofen 400 mg/day Adalimumab 40 mg every second week, last injection 6 days previously Conflicts within the family Pramipexol 3 × 0.18 mg/day Levothyroxine 50 µg/day Alendronic acid 70 mg/week Levothyroxine 75 µg/day Fall at home, lying on the floor for 20 h Malaise Pneumonia SR, ST segment elevation V2, negative T waves I, II, aVL, V2–V6 27 0 0 565 SR, ST segment elevation I, aVL, V2, V3, negative T waves aVL, V2–V6 21 0 + 585 12.3 1.88 14.7 – 3.1 267 54 3.61 2.5 2.7 – normal 236 303 Midventricular hypoakinesia 68 Apical akinesia 20 68 Multiple, mobile 0 Midventricular 48 + 94 Single, sessile, dense spontaneous echo contrast 0 Apical 56 0 89 No additional heparin Normal LAD 20 No additional heparin Nonsignificant plaque 0 TTS Medication at admission Triggering event Symptoms Epigastric pain, radiating into neck; paresthesia in fingertips and tongue SR, negative T waves I, II, III, aVF; V2–V6 ECG on admission Hours after OOS Q wave Persisting ST elevation QTc (Bazett), ms 16 0 0 505 Laboratory findings Creatine kinase × ULN 1.52 Creatine kinase MB × ULN NM Troponine × ULN 5.6 NT-pro-BNP × ULN 5.6 D-dimer × ULN 2.0 Thrombocyte count, GPT/L 527 C-reactive protein, mg/L 8.4 Echocardiography Thickened myocardium, apical akinesia Hours after OOS 18 Detection of LV thrombus, hours after OOS 41 Thrombus morphology Multiple, mobile LVOTO LV ballooning pattern LV ejection fraction, % RV involvement 0 Apical 45 0 Coronary angiography Hours after OOS 88 Unfractionated heparin, IU 5,000 Coronary arteries Nonsignificant plaque Myocardial bridging 0 4 Cardiology DOI: 10.1159/000506925 Angina, dyspnea Stöllberger/Finsterer/Schneider Downloaded by: Université de Paris 193.51.85.197 - 5/1/2020 3:29:08 AM Extracardiac comorbidities Table 3 (continued) Pharmacotherapy Acetylsalicylic acid, mg Started hours after OOS Clopidogrel, mg Started hours after OOS Anticoagulation Started hours after OOS Patient 1 Patient 2 Patient 3 250 33, once 0 0 Enoxaparin 120 mg/day s.c. 100 27 300 loading dose 40, once Certoparin 3,000 IU, followed by unfractionated heparin i.v. in therapeutic dose according to PTT 27 250 loading dose 18, once 300 loading dose 20, once Unfractionated heparin i.v. in therapeutic dose according to PTT 18 20 Embolism Clinical signs Assessed as Hours after OOS Confirmed by Therapy Right-sided weakness Stroke 41 MRI, CT Enoxaparin continued Left-sided hemiparesis Stroke 120 CT Unfractionated heparin continued Left-sided weakness Stroke 92 CT Unfractionated heparin continued Additional adverse event 0 Sinoatrial block Paroxysmal atrial fibrillation Outcome Discharge after Neurological deficit Ventricular function Thrombus visible Anticoagulant therapy 26 days 0 Normal 0 0 27 days Left-sided hemiparesis Normal 0 Acetylsalicylic acid 100 mg/day, certoparin 3,000 IU/day Died after 45 days from aspiration pneumonia due to the disabling stroke 11 days Left-sided weakness Apical hypokinesia Small thrombus reduced in size Acetylsalicylic acid 100 mg/day, enoxaparin 100 mg/day Surgery for rectal carcinoma after 27 months Follow-up No cardiac event after 5 months series (Table 1). The detection rate of thrombi depends largely on the time interval between onset of TTS and the echocardiographic examination which has not been standardized in any of the registries. Furthermore, the frequency of echocardiographic examinations might be higher in single-center studies dedicated to the detection of thrombus formation than in large registries. By using cardiac magnetic resonance imaging instead of echocardiography as a diagnostic tool, the detection rate of TTSassociated thrombi is reported to be even higher [1, 3]. The clinical course of LV thrombi in TTS and STEMI in the primary percutaneous coronary intervention era seems to differ substantially. The prevalence of LV thrombi in anterior STEMI is higher than in TTS, ranging from 9.1% by echocardiography [16] to 12.2% by cardiac magnetic resonance imaging [20]. With anticoagulant therapy, LV thrombi in anterior STEMI resolve in 80–90% of the cases within 3–6 months [17, 20]; however, new late LV thrombus formation may occur during follow-up since the wall motion abnormality usually persists [20]. The embolic complication rate in patients with anterior STEMI and LV thrombi appears to be low (1.5–6.5%) [17, 20, 21]. In contrast, in patients with TTS, the wall motion abnormalities disappear within a few days to weeks, and LV thrombi are no longer present after 2–3 months [7, 10, 18]. Embolic events, however, have been observed in 17– 40% of patients with TTS-associated LV thrombi (Table 1) [1–5, 7]. Overall, in 6 large TTS registries the embolic event rate of LV thrombi was 22% (9 out of 41 patients with thrombi). It has been hypothesized that the improvement of contractility in TTS promotes the discharge of emboli by causing detachment of the thrombus from the ventricular wall, thereby transforming a mural thrombus into a protruding, floating one with embolic compli- Thrombi in Takotsubo Syndrome Cardiology DOI: 10.1159/000506925 5 Downloaded by: Université de Paris 193.51.85.197 - 5/1/2020 3:29:08 AM BMI, body mass index; CT, computed tomography; GPT, glutamic pyruvic transaminase; i.v., intravenous infusion; LAD, left anterior descending coronary artery; LV, left-ventricular; LVOTO, left ventricular outflow obstruction; MRI, magnetic resonance imaging; NM, normal muscle; NT-pro BNP, N-terminal probrain natriuretic peptide; OOS, onset of symptoms; PTT, partial thromboplastin time; RV, right-ventricular; s.c., subcutaneous injection; TTS, takotsubo syndrome; ULN, upper limit of normal. cations despite optimal anticoagulation therapy [2, 12, 19, 22]. This evolution makes LV thrombi in TTS extremely dangerous. The pathogenetic assumption is supported by the finding that the LV systolic function was not severely depressed, neither in our patients nor in the patients reported in the literature (Tables 2 and 3). By transthoracic echocardiography, one of our patients showed extensive SEC in the left ventricle. SEC is related to thromboembolic events and indicates an interaction between erythrocytes and plasma proteins [23]. SEC in TTS has, to our knowledge, only been described once; however, in this case with atrial fibrillation, SEC was seen originating from the left atrium [24]. Thrombolytic therapy with urokinase has been reported to be successful and without complications in a patient with TTS-associated LV thrombus and renal infarction [25]. This therapy, however, may be associated with the risk of thrombolysis-induced fragmentation and embolization. Cardiac surgery represents another therapeutic option for these patients. In a small number of patients aged 48–68 years, surgical thrombectomy by use of different techniques has been shown to safely remove the thrombus from the left ventricle [26–30]. Considering the high rate of embolic events in TTS-related LV thrombi and the failure of anticoagulant therapy in preventing systemic embolism in the presented 3 cases and in previous case reports, involvement of the heart team may be considered in order to discuss surgical removal of mobile TTS-related LV thrombi. Conclusion At present, the management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Until these studies are available, we suggest the following approach: patients with TTSrelated LV thrombi should be monitored by echocardiography every day while receiving anticoagulation. If changes in mobility and morphology of the thrombi are observed, cardiac surgery to prevent embolism may be considered by the heart team. The role of SEC as a marker for embolic events in TTS is largely unknown and should be investigated in future studies. Statement of Ethics The subjects have given their written informed consent to publish their case (including publication of images). Disclosure Statement The authors have no conflicts of interest to declare. Sources of Funding No grants, no funding. Author Contribution Claudia Stöllberger: treatment of the patients, drafting of the manuscript, literature research, corresponding author. Josef Finsterer: treatment of the patients, drafting of the manuscript, literature research. Birke Schneider: treatment of the patients, drafting of the manuscript, literature research. References 6 Cardiology DOI: 10.1159/000506925 4 El-Battrawy I, Behnes M, Hillenbrand D, Haghi D, Hoffmann U, Papavassiliu T, et al. 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