{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:11:56Z","timestamp":1791555116011,"version":"4.3.4"},"reference-count":51,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T00:00:00Z","timestamp":1697760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Transthyretin amyloidosis (ATTR) is a group of diseases caused by the deposition of insoluble fibrils derived from misfolded transthyretin, which compromises the structure and function of various organs, including the heart. Thromboembolic events and increased bleeding risk are among the most important complications of ATTR, though the underlying mechanisms are not yet fully understood. Transthyretin plays a complex role in the coagulation cascade, contributing to the activation and regulation of the coagulation and fibrinolytic systems. The prevalence of atrial fibrillation, cardiac mechanical dysfunction, and atrial myopathy in patients with ATTR may contribute to thrombosis, though such events may also occur in patients with a normal sinus rhythm and rarely in properly anticoagulated patients. Haemorrhagic events are modest and mainly linked to perivascular amyloid deposits with consequent capillary fragility and coagulation anomalies, such as labile international-normalised ratio during anticoagulant therapy. Therefore, it is paramount to carefully stratify the thrombotic and haemorrhagic risks, especially when initiating anticoagulant therapy. Our review aims to ascertain the prevalence of thromboembolic and haemorrhagic events in ATTR and identify potential risk factors and predictors and their impact on antithrombotic therapy.<\/jats:p>","DOI":"10.3390\/jcm12206640","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T07:25:22Z","timestamp":1697786722000},"page":"6640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Thromboembolic and Bleeding Events in Transthyretin Amyloidosis and Coagulation System Abnormalities: A Review"],"prefix":"10.3390","volume":"12","author":[{"given":"Angela","family":"Napolitano","sequence":"first","affiliation":[{"name":"General Internal Medicine & Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0574-4052","authenticated-orcid":false,"given":"Laura","family":"De Michieli","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Sciences & Public Health, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Sinigiani","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Sciences & Public Health, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Berno","sequence":"additional","affiliation":[{"name":"Haematology Unit, Department of Medicine, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-6202","authenticated-orcid":false,"given":"Alberto","family":"Cipriani","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Sciences & Public Health, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4339-8525","authenticated-orcid":false,"given":"Luca","family":"Spiezia","sequence":"additional","affiliation":[{"name":"General Internal Medicine & Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine, Padova University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/joim.13169","article-title":"Systemic amyloidosis from A (AA) to T (ATTR): A review","volume":"289","author":"Muchtar","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1161\/CIRCULATIONAHA.108.843334","article-title":"Systemic cardiac amyloidoses: Disease profiles and clinical courses of the 3 main types","volume":"120","author":"Rapezzi","year":"2009","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41572-018-0034-3","article-title":"Systemic immunoglobulin light chain amyloidosis","volume":"4","author":"Merlini","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Stelmach-Go\u0142dy\u015b, A., Zaborek-\u0141yczba, M., \u0141yczba, J., Garus, B., Pasiarski, M., Mertowska, P., Ma\u0142kowska, P., Hrynkiewicz, R., Nied\u017awiedzka-Rystwej, P., and Grywalska, E. (2022). Physiology, Diagnosis and Treatment of Cardiac Light Chain Amyloidosis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11040911"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3517","DOI":"10.1093\/cvr\/cvac119","article-title":"Transthyretin cardiac amyloidosis","volume":"118","author":"Porcari","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1056\/NEJM199709253371306","article-title":"The systemic amyloidoses","volume":"337","author":"Falk","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e178","DOI":"10.1161\/CIRCULATIONAHA.111.069195","article-title":"Cardiac Amyloidosis","volume":"126","author":"Quarta","year":"2012","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1093\/eurheartj\/ehv338","article-title":"Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction","volume":"36","author":"Robles","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Laptseva, N., Rossi, V.A., Sudano, I., Schwotzer, R., Ruschitzka, F., Flammer, A.J., and Duru, F. (2023). Arrhythmic Manifestations of Cardiac Amyloidosis: Challenges in Risk Stratification and Clinical Management. J. Clin. Med., 12.","DOI":"10.3390\/jcm12072581"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Frustaci, A., Verardo, R., Russo, M.A., Caldarulo, M., Alfarano, M., Galea, N., Miraldi, F., and Chimenti, C. (2023). Infiltration of Conduction Tissue Is a Major Cause of Electrical Instability in Cardiac Amyloidosis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12051798"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1378\/chest.102.1.304","article-title":"Amyloid heart disease manifested by systemic arterial thromboemboli","volume":"102","author":"Browne","year":"1992","journal-title":"Chest"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14192","DOI":"10.1074\/jbc.RA118.003990","article-title":"Plasminogen activation triggers transthyretin amyloidogenesis in vitro","volume":"293","author":"Mangione","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1111\/j.1538-7836.2007.02457.x","article-title":"Increased plasmin-\u03b12-antiplasmin levels indicate activation of the fibrinolytic system in systemic amyloidoses","volume":"5","author":"Bouma","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wieczorek, E., and O\u017cyhar, A. (2021). Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases. Cells, 10.","DOI":"10.3390\/cells10071768"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1161\/STROKEAHA.120.033107","article-title":"Cerebral Amyloid Angiopathy and the Fibrinolytic System: Is Plasmin a Therapeutic Target?","volume":"52","author":"Mutimer","year":"2021","journal-title":"Stroke"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1182\/blood-2016-03-705228","article-title":"Biochemical and structural analysis of the interaction between \u03b2-amyloid and fibrinogen","volume":"128","author":"Zamolodchikov","year":"2016","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.jds.2018.08.004","article-title":"Abundant proteins in platelet-rich fibrin and their potential contribution to wound healing: An explorative proteomics study and review of the literature","volume":"13","author":"Yaprak","year":"2018","journal-title":"J. Dent. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1111\/jth.14220","article-title":"Discovery of novel plasma biomarkers for future incident venous thromboembolism by untargeted synchronous precursor selection mass spectrometry proteomics","volume":"16","author":"Jensen","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"638529","DOI":"10.3389\/fmed.2021.638529","article-title":"Serum Prealbumin Concentrations, COVID-19 Severity, and Mortality: A Systematic Review and Meta-Analysis","volume":"8","author":"Zinellu","year":"2021","journal-title":"Front. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3109\/13506129.2012.691918","article-title":"Coagulation and fibrinolysis abnormalities in familial amyloid polyneuropathy","volume":"19","author":"Takahashi","year":"2012","journal-title":"Amyloid"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/ehf2.13701","article-title":"Thromboembolism and bleeding in systemic amyloidosis: A review","volume":"9","author":"Nicol","year":"2022","journal-title":"ESC Heart Fail."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/ejhf.2566","article-title":"Systemic embolism in amyloid transthyretin cardiomyopathy","volume":"24","author":"Vilches","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Martini, N., Sinigiani, G., De Michieli, L., Mussinelli, R., Perazzolo Marra, M., Iliceto, S., Zorzi, A., Perlini, S., Corrado, D., and Cipriani, A. (2023). Electrocardiographic features and rhythm disorders in cardiac amyloidosis. Trends Cardiovasc. Med., S1050-1738(23)00024-5.","DOI":"10.1016\/j.tcm.2023.02.006"},{"key":"ref_24","first-page":"17","article-title":"Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis","volume":"15","author":"Bandera","year":"2022","journal-title":"Cardiovasc. Imaging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1136\/hrt.74.5.541","article-title":"Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: Evidence for atrial electromechanical dissociation","volume":"74","author":"Dubrey","year":"1995","journal-title":"Heart"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1093\/eurheartj\/ehab072","article-title":"Diagnosis and treatment of cardiac amyloidosis: A position statement of the ESC working group on myocardial and pericardial diseases","volume":"42","author":"Rapezzi","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Versteylen, M.O., Brons, M., Teske, A.J., and Oerlemans, M.I.F.J. (2022). Restrictive Atrial Dysfunction in Cardiac Amyloidosis: Differences between Immunoglobulin Light Chain and Transthyretin Cardiac Amyloidosis Patients. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081768"},{"key":"ref_28","first-page":"1128","article-title":"Left atrial structure and function in cardiac amyloidosis","volume":"18","author":"Nochioka","year":"2017","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1161\/CIRCULATIONAHA.107.697763","article-title":"Intracardiac thrombosis and embolism in patients with cardiac amyloidosis","volume":"116","author":"Feng","year":"2007","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1161\/CIRCULATIONAHA.108.785014","article-title":"Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis","volume":"119","author":"Feng","year":"2009","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/j.jacc.2019.01.035","article-title":"High prevalence of intracardiac thrombi in cardiac amyloidosis","volume":"73","author":"Corovic","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.jacc.2018.10.079","article-title":"Direct current cardioversion of atrial arrhythmias in adults with cardiac amyloidosis","volume":"73","author":"Dispenzieri","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/13506129.2020.1810010","article-title":"Anticoagulation with warfarin compared to novel oral anticoagulants for atrial fibrillation in adults with transthyretin cardiac amyloidosis: Comparison of thromboembolic events and major bleeding","volume":"28","author":"Mitrani","year":"2020","journal-title":"Amyloid"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.jacep.2020.04.019","article-title":"Atrial fibrillation in transthyretin cardiac amyloidosis: Predictors, prevalence, and efficacy of rhythm control strategies","volume":"6","author":"Donnellan","year":"2020","journal-title":"Clin. Electrophysiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1080\/13506129.2020.1798922","article-title":"Arterial thrombo-embolic events in cardiac amyloidosis: A look beyond atrial fibrillation","volume":"28","author":"Cappelli","year":"2020","journal-title":"Amyloid"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1161\/CIRCULATIONAHA.120.052136","article-title":"Prevalence of Atrial Fibrillation and Thromboembolic Risk in Wild-Type Transthyretin Amyloid Cardiomyopathy","volume":"143","author":"Bukhari","year":"2021","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1046\/j.1365-2141.2000.02183.x","article-title":"Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis","volume":"110","author":"Mumford","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1093\/ehjci\/ehaa946.2122","article-title":"Bleeding events in patients with cardiac amyloidosis","volume":"41","author":"Schrutka","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e242614","DOI":"10.1136\/bcr-2021-242614","article-title":"Periorbital ecchymosis and shoulder pad sign in transthyretin amyloidosis","volume":"14","author":"Ono","year":"2021","journal-title":"BMJ Case Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"ytad108","DOI":"10.1093\/ehjcr\/ytad108","article-title":"Hereditary transthyretin amyloidosis presenting with spontaneous periorbital purpura: A case report","volume":"7","author":"Jhawar","year":"2023","journal-title":"Eur. Heart J. Case Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s12328-021-01551-y","article-title":"Intra-abdominal bleeding caused by amyloid transthyretin amyloidosis in the gastrointestinal tract: A case report","volume":"15","author":"Yumoto","year":"2022","journal-title":"Clin. J. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5892707","DOI":"10.1155\/2020\/5892707","article-title":"Senile Systemic Amyloidosis Presenting as Hematuria: A Rare Presentation and Review of Literature","volume":"2020","author":"Jayakrishnan","year":"2020","journal-title":"Case Rep. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"128","DOI":"10.18240\/ijo.2023.01.19","article-title":"Clinical features of retinal amyloid angiopathy with transthyretin Gly83Arg variant","volume":"16","author":"Su","year":"2023","journal-title":"Int. J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1097\/ICB.0000000000001318","article-title":"An 82-year-old woman with retinal vascular sheathing and vitreous hemorrhage","volume":"17","author":"Hudson","year":"2023","journal-title":"Retin. Cases Brief Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"742428","DOI":"10.3389\/fcvm.2021.742428","article-title":"New Oral Anticoagulants vs. Vitamin K Antagonists Among Patients With Cardiac Amyloidosis: Prognostic Impact","volume":"8","author":"Cariou","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ijcard.2022.01.036","article-title":"Cardiac microcalcifications in transthyretin (ATTR) amyloidosis","volume":"352","author":"Thelander","year":"2022","journal-title":"Int. J. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1161\/STROKEAHA.118.021872","article-title":"Cerebral Amyloid Angiopathy With Vascular Iron Accumulation and Calcification","volume":"49","author":"Bulk","year":"2018","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1111\/bpa.12721","article-title":"Osteopontin and phospho-SMAD2\/3 are associated with calcification of vessels in D-CAA, an hereditary cerebral amyloid angiopathy","volume":"29","author":"Bulk","year":"2019","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/s41569-022-00818-2","article-title":"The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis","volume":"20","author":"Sud","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Writing Committee, Kittleson, M.M., Ruberg, F.L., Ambardekar, A.V., Brannagan, T.H., Cheng, R.K., Clarke, J.O., Dember, L.M., Frantz, J.G., and Hershberger, R.E. (2023). 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J. Am. Coll Cardiol., 81, 1076\u20131126.","DOI":"10.1016\/j.jacc.2022.11.022"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Tsch\u00f6pe, C., and Elsanhoury, A. (2022). Treatment of Transthyretin Amyloid Cardiomyopathy: The Current Options, the Future, and the Challenges. J. Clin. Med., 11.","DOI":"10.3390\/jcm11082148"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:10:17Z","timestamp":1760130617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,20]]},"references-count":51,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12206640"],"URL":"https:\/\/doi.org\/10.3390\/jcm12206640","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,20]]}}}