Semin Thromb Hemost 2024; 50(03): 342-359
DOI: 10.1055/s-0043-1771270
Review Article

Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Gianluca Costamagna
1   Stroke Unit, Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
,
Babak B. Navi
2   Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medicine, New York, New York
3   Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
,
Morin Beyeler
4   Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
,
Andreas F. Hottinger
5   Services of Neurology and Oncology, Lundin Family Brain Tumor Research Center, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
,
Lorenzo Alberio
6   Division of Hematology and Hematology Central Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
,
Patrik Michel
7   Department of Clinical Neurosciences, Stroke Center, Neurology Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
› Author Affiliations

Abstract

Ischemic stroke is an important cause of morbidity and mortality in cancer patients. The underlying mechanisms linking cancer and stroke are not completely understood. Long-standing and more recent evidence suggests that cancer-associated prothrombotic states, along with treatment-related vascular toxicity, such as with chemotherapy and immunotherapy, contribute to an increased risk of ischemic stroke in cancer patients. Novel biomarkers, including coagulation, platelet and endothelial markers, cell-free DNA, and extracellular vesicles are being investigated for their potential to improve risk stratification and patient selection for clinical trials and to help guide personalized antithrombotic strategies. Treatment of cancer-related stroke poses unique challenges, including the need to balance the risk of recurrent stroke and other thromboembolic events with that of bleeding associated with antithrombotic therapy. In addition, how and when to restart cancer treatment after stroke remains unclear. In this review, we summarize current knowledge on the mechanisms underlying ischemic stroke in cancer, propose an etiological classification system unique to cancer-related stroke to help guide patient characterization, provide an overview of promising biomarkers and their clinical utility, and discuss the current state of evidence-based management strategies for cancer-related stroke. Ultimately, a personalized approach to stroke prevention and treatment is required in cancer patients, considering both the underlying cancer biology and the individual patient's risk profile.



Publication History

Article published online:
28 July 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Navi BB, Singer S, Merkler AE. et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014; 83 (01) 26-33
  • 2 Costamagna G, Hottinger A, Milionis H. et al. Clinical and demographic characteristics, mechanisms, and outcomes in patients with acute ischemic stroke and newly diagnosed or known active cancer. Neurology 2023; 100 (24) e2477-e2489
  • 3 Kim SG, Hong JM, Kim HY. et al. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke 2010; 41 (04) 798-801
  • 4 Schwarzbach CJ, Schaefer A, Ebert A. et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012; 43 (11) 3029-3034
  • 5 Gon Y, Okazaki S, Terasaki Y. et al. Characteristics of cryptogenic stroke in cancer patients. Ann Clin Transl Neurol 2016; 3 (04) 280-287
  • 6 Grazioli S, Paciaroni M, Agnelli G. et al. Cancer-associated ischemic stroke: a retrospective multicentre cohort study. Thromb Res 2018; 165: 33-37
  • 7 Dardiotis E, Aloizou AM, Markoula S. et al. Cancer-associated stroke: pathophysiology, detection and management (Review). Int J Oncol 2019; 54 (03) 779-796
  • 8 Moik F, Ay C. Venous and arterial thromboembolism in patients with cancer treated with targeted anti-cancer therapies. Thromb Res 2022; 213 (Suppl. 01) S58-S65
  • 9 Costamagna G, Hottinger AF, Milionis H. et al. Oral presentations. Eur J Neurol 2022; 29 (S1): 46-168
  • 10 Navi BB, Kasner SE, Elkind MSV, Cushman M, Bang OY, DeAngelis LM. Cancer and embolic stroke of undetermined source. Stroke 2021; 52 (03) 1121-1130
  • 11 Choi KH, Kim JH, Kim JM. et al. d-Dimer level as a predictor of recurrent stroke in patients with embolic stroke of undetermined source. Stroke 2021; 52 (07) 2292-2301
  • 12 Gon Y, Sakaguchi M, Takasugi J. et al. Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. Eur J Neurol 2017; 24 (03) 503-508
  • 13 Ohara T, Farhoudi M, Bang OY, Koga M, Demchuk AM. The emerging value of serum D-dimer measurement in the work-up and management of ischemic stroke. Int J Stroke 2020; 15 (02) 122-131
  • 14 Navi BB, Sherman CP, Genova R. et al. Mechanisms of ischemic stroke in patients with cancer: a prospective study. Ann Neurol 2021; 90 (01) 159-169
  • 15 Navi BB, Zhang C, Sherman CP. et al. Ischemic stroke with cancer: hematologic and embolic biomarkers and clinical outcomes. J Thromb Haemost 2022; 20 (09) 2046-2057
  • 16 Powers WJ, Rabinstein AA, Ackerson T. et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 (12) e344-e418
  • 17 Berge E, Whiteley W, Audebert H. et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6 (01) I-LXII
  • 18 Lee MJ, Chung JW, Ahn MJ. et al. Hypercoagulability and mortality of patients with stroke and active cancer: the OASIS-CANCER study. J Stroke 2017; 19 (01) 77-87
  • 19 Bang OY. Edoxaban for the treatment of coagulopathy in patients with active cancer and acute ischemic stroke: a pilot study. (ENCHASE Study). clinicaltrials.gov; 2018. Accessed March 07, 2023 at: https://clinicaltrials.gov/ct2/show/NCT03570281
  • 20 Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Ann Neurol 2018; 83 (05) 873-883
  • 21 Conen D, Wong JA, Sandhu RK. et al. Risk of malignant cancer among women with new-onset atrial fibrillation. JAMA Cardiol 2016; 1 (04) 389-396
  • 22 Santoro F, Tarantino N, Pellegrino PL. et al. Cardiovascular sequelae of radiation therapy. Clin Res Cardiol 2014; 103 (12) 955-967
  • 23 Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42 (09) 2410-2418
  • 24 Yamamoto A, Kikuchi Y, Homma K, O'uchi T, Furui S. Characteristics of intravascular large B-cell lymphoma on cerebral MR imaging. AJNR Am J Neuroradiol 2012; 33 (02) 292-296
  • 25 Navi BB, DeAngelis LM, Segal AZ. Multifocal strokes as the presentation of occult lung cancer. J Neurooncol 2007; 85 (03) 307-309
  • 26 Diener HC, Sacco RL, Easton JD. et al; RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019; 380 (20) 1906-1917
  • 27 Hart RG, Sharma M, Mundl H. et al; NAVIGATE ESUS Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378 (23) 2191-2201
  • 28 Kamel H, Longstreth Jr WT, Tirschwell DL. et al. The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods. Int J Stroke 2019; 14 (02) 207-214
  • 29 Ntaios G, Perlepe K, Lambrou D. et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. J Am Heart Assoc 2019; 8 (15) e012858
  • 30 Sanossian N, Djabiras C, Mack WJ, Ovbiagele B. Trends in cancer diagnoses among inpatients hospitalized with stroke. J Stroke Cerebrovasc Dis 2013; 22 (07) 1146-1150
  • 31 Kim SJ, Park JH, Lee MJ, Park YG, Ahn MJ, Bang OY. Clues to occult cancer in patients with ischemic stroke. PLoS One 2012; 7 (09) e44959
  • 32 Cocho D, Gendre J, Boltes A. et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 2015; 24 (06) 1324-1328
  • 33 Selvik HA, Bjerkreim AT, Thomassen L, Waje-Andreassen U, Naess H, Kvistad CE. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018; 45 (1–2): 42-47
  • 34 Navi BB, Singer S, Merkler AE. et al. Cryptogenic subtype predicts reduced survival among cancer patients with ischemic stroke. Stroke 2014; 45 (08) 2292-2297
  • 35 Uemura J, Kimura K, Sibazaki K, Inoue T, Iguchi Y, Yamashita S. Acute stroke patients have occult malignancy more often than expected. Eur Neurol 2010; 64 (03) 140-144
  • 36 Beyeler M, Birner B, Branca M. et al. Development of a score for prediction of occult malignancy in stroke patients (Occult-5 score). J Stroke Cerebrovasc Dis 2022; 31 (08) 106609
  • 37 Bang OY, Chung JW, Lee MJ, Seo WK, Kim GM, Ahn MJ. OASIS-Cancer Study Investigators. Cancer-related stroke: an emerging subtype of ischemic stroke with unique pathomechanisms. J Stroke 2020; 22 (01) 1-10
  • 38 Lun R, Siegal D, Ramsay T, Dowlatshahi D. Cancer and stroke: what do we know and where do we go?. Thromb Res 2022; 219: 133-140
  • 39 Seok JM, Kim SG, Kim JW. et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010; 68 (02) 213-219
  • 40 Refaai MA, Riley P, Mardovina T, Bell PD. The clinical significance of fibrin monomers. Thromb Haemost 2018; 118 (11) 1856-1866
  • 41 Nahab F, Sharashidze V, Liu M. et al. Markers of coagulation and hemostatic activation aid in identifying causes of cryptogenic stroke. Neurology 2020; 94 (18) e1892-e1899
  • 42 Costamagna G, Hottinger AF, Milionis H. et al. Clinical and demographic characteristics, mechanisms, and clinical in patients with acute ischemic stroke and newly diagnosed or known active cancer. Neurology 2023; 100 (24) e2477-e2489
  • 43 Fujinami J, Ohara T, Kitani-Morii F. et al. Cancer-associated hypercoagulation increases the risk of early recurrent stroke in patients with active cancer. Cerebrovasc Dis 2018; 46 (1-2): 46-51
  • 44 Nam KW, Kim CK, Kim TJ. et al. D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. Eur J Neurol 2017; 24 (01) 205-211
  • 45 Ay C, Dunkler D, Pirker R. et al. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97 (08) 1158-1164
  • 46 Chen PC, Muo CH, Lee YT, Yu YH, Sung FC. Lung cancer and incidence of stroke: a population-based cohort study. Stroke 2011; 42 (11) 3034-3039
  • 47 Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun 2019; 10 (01) 5172
  • 48 Hashem H, Muhsen BA. Hyperleukocytosis-induced stroke and tonsillar herniation: case report. Ann Med Surg (Lond) 2021; 70: 102776
  • 49 Arboix A, Besses C, Acín P. et al. Ischemic stroke as first manifestation of essential thrombocythemia. Report of six cases. Stroke 1995; 26 (08) 1463-1466
  • 50 Abdel-Rahman I, Murphy C. Recurrent ischaemic stroke unveils polycythaemia vera. BMJ Case Rep 2015; 2015: bcr2014207625
  • 51 Navi BB, Kawaguchi K, Hriljac I, Lavi E, DeAngelis LM, Jamieson DG. Multifocal stroke from tumor emboli. Arch Neurol 2009; 66 (09) 1174-1175
  • 52 Aoki N, Sakai T, Oikawa A, Takizawa T, Koike M. Dissection of the middle cerebral artery caused by invasion of malignant glioma presenting as acute onset of hemiplegia. Acta Neurochir (Wien) 1999; 141 (09) 1005-1008
  • 53 Pina S, Carneiro Â, Rodrigues T. et al. Acute ischemic stroke secondary to glioblastoma. A case report. Neuroradiol J 2014; 27 (01) 85-90
  • 54 Gutiérrez ML, Carrasco-Moro R, Ruz-Caracuel I, San Millán JSM. Stroke secondary to leptomeningeal carcinomatosis with radiologic signs of arterial invasion. Surg Neurol Int 2022; 13: 290
  • 55 Klein P, Haley EC, Wooten GF, VandenBerg SR. Focal cerebral infarctions associated with perivascular tumor infiltrates in carcinomatous leptomeningeal metastases. Arch Neurol 1989; 46 (10) 1149-1152
  • 56 Anbil S, Fenerty K, Feng Z, Doughty R, El-Farra NS. Intravascular large B cell lymphoma as a cause of multifocal cryptogenic stroke. Am J Med 2021; 134 (10) 1236-1237
  • 57 Rota E, Pitino A, Pastorino R, Gallesio I, Morelli N. Intravascular large B-cell lymphoma: a forgotten stroke “mimic”. Acta Neurol Belg 2020; 120 (03) 745-746
  • 58 Vinter N, Christesen AMS, Fenger-Grøn M, Tjønneland A, Frost L. Atrial fibrillation and risk of cancer: a Danish population-based cohort study. J Am Heart Assoc 2018; 7 (17) e009543
  • 59 Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11 (02) 223-233
  • 60 Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985; 64 (01) 16-35
  • 61 Marto JP, Strambo D, Livio F, Michel P. Drugs associated with ischemic stroke: a review for clinicians. Stroke 2021; 52 (10) e646-e659
  • 62 Home - electronic medicines compendium (emc). Accessed October 19, 2022 at: https://www.medicines.org.uk/emc
  • 63 Meyler's Side Effects of Drugs. 16th ed. Accessed May 11, 2022 at: https://www.elsevier.com/books/meylers-side-effects-of-drugs/aronson/978-0-444-53717-1
  • 64 Lysov Z, Dwivedi DJ, Gould TJ, Liaw PC. Procoagulant effects of lung cancer chemotherapy: impact on microparticles and cell-free DNA. Blood Coagul Fibrinolysis 2017; 28 (01) 72-82
  • 65 Li SH, Chen WH, Tang Y. et al. Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10,963 patients. Clin Neurol Neurosurg 2006; 108 (02) 150-156
  • 66 Barceló R, Muñoz A, López-Vivanco G. Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine. Cancer 2005; 104 (05) 1110-1111 , author reply 1111
  • 67 Zuo PY, Chen XL, Liu YW, Xiao CL, Liu CY. Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: a meta-analysis. PLoS One 2014; 9 (07) e102484
  • 68 Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1. J Am Coll Cardiol 2017; 70 (20) 2536-2551
  • 69 Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica (Buchar) 2013; 8 (01) 59-67
  • 70 Yoon GJ, Telli ML, Kao DP, Matsuda KY, Carlson RW, Witteles RM. Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies are clinicians responding optimally?. J Am Coll Cardiol 2010; 56 (20) 1644-1650
  • 71 Belzile-Dugas E, Eisenberg MJ. Radiation-induced cardiovascular disease: review of an underrecognized pathology. J Am Heart Assoc 2021; 10 (18) e021686
  • 72 Kucuk O, Kwaan HC, Gunnar W, Vazquez RM. Thromboembolic complications associated with L-asparaginase therapy. Etiologic role of low antithrombin III and plasminogen levels and therapeutic correction by fresh frozen plasma. Cancer 1985; 55 (04) 702-706
  • 73 Grover SP, Hisada YM, Kasthuri RS, Reeves BN, Mackman N. Cancer therapy-associated thrombosis. Arterioscler Thromb Vasc Biol 2021; 41 (04) 1291-1305
  • 74 Kitano T, Sasaki T, Gon Y. et al. The effect of chemotherapy on stroke risk in cancer patients. Thromb Haemost 2020; 120 (04) 714-723
  • 75 Drobni ZD, Alvi RM, Taron J. et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020; 142 (24) 2299-2311
  • 76 Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102 (01) 39-46
  • 77 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991; 9 (02) 286-294
  • 78 Pemberton KD, Melissari E, Kakkar VV. The influence of tamoxifen in vivo on the main natural anticoagulants and fibrinolysis. Blood Coagul Fibrinolysis 1993; 4 (06) 935-942
  • 79 Cosman F, Baz-Hecht M, Cushman M. et al. Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116 (01) 1-13
  • 80 Eilertsen AL, Liestøl S, Mowinckel MC, Hemker HC, Sandset PM. Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007; 97 (06) 938-943
  • 81 Rühl H, Schröder L, Müller J. et al. Tamoxifen induces resistance to activated protein C. Thromb Res 2014; 133 (05) 886-891
  • 82 Wang TF, Khorana AA, Carrier M. Thrombotic complications associated with immune checkpoint inhibitors. Cancers (Basel) 2021; 13 (18) 4606
  • 83 Moik F, Chan WE, Wiedemann S. et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood 2021; 137 (12) 1669-1678
  • 84 Ando Y, Hayashi T, Sugimoto R. et al. Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors. Invest New Drugs 2020; 38 (04) 1200-1206
  • 85 Sussman TA, Li H, Hobbs B, Funchain P, McCrae KR, Khorana AA. Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. J Immunother Cancer 2021; 9 (01) e001719
  • 86 Scott AS, Parr LA, Johnstone PAS. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol 2009; 90 (02) 163-165
  • 87 Jiang Z, Elkind M, Lucky M, Fekete Z. Stroke in a young man: a late complication of radiation therapy. BMJ Case Rep 2019; 12 (02) e228029
  • 88 Donnellan E, Griffin BP, Johnston DR. et al. Rate of progression of aortic stenosis and its impact on outcomes in patients with radiation-associated cardiac disease: a matched cohort study. JACC Cardiovasc Imaging 2018; 11 (08) 1072-1080
  • 89 Xu J, Cao Y. Radiation-induced carotid artery stenosis: a comprehensive review of the literature. Intervent Neurol 2014; 2 (04) 183-192
  • 90 Campen CJ, Kranick SM, Kasner SE. et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 2012; 43 (11) 3035-3040
  • 91 Fullerton HJ, Stratton K, Mueller S. et al. Recurrent stroke in childhood cancer survivors. Neurology 2015; 85 (12) 1056-1064
  • 92 Apostolakis E, Koletsis EN, Panagopoulos N, Prokakis C, Dougenis D. Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy. J Cardiothorac Surg 2006; 1 (01) 25
  • 93 Kamiya-Matsuoka C, Cachia D, Yust-Katz S. et al; Anderson Cancer Center. Ischemic stroke in patients with gliomas at the University of Texas-M.D. J Neurooncol 2015; 125 (01) 143-148
  • 94 Jacob L, Kostev K. Cancer is associated with intraoperative and postprocedural complications and disorders. J Cancer Res Clin Oncol 2016; 142 (04) 777-781
  • 95 Schwarzbach CJ, Fatar M, Eisele P, Ebert AD, Hennerici MG, Szabo K. DWI lesion patterns in cancer-related stroke–specifying the phenotype. Cerebrovasc Dis Extra 2015; 5 (03) 139-145
  • 96 Nouh AM, Staff I, Finelli PF. Three territory sign: an MRI marker of malignancy-related ischemic stroke (Trousseau syndrome). Neurol Clin Pract 2019; 9 (02) 124-128
  • 97 Guo L, Wang L, Liu W. Ability of the number of territories involved on DWI-MRI to predict occult systemic malignancy in cryptogenic stroke patients. J Stroke Cerebrovasc Dis 2020; 29 (07) 104823
  • 98 Park MG, Oh SJ, Baik SK, Jung DS, Park KP. Susceptibility-weighted imaging for detection of thrombus in acute cardioembolic stroke. J Stroke 2016; 18 (01) 73-79
  • 99 Ikeda H, Ishibashi R, Kinosada M. et al. Factors related to white thrombi in acute ischemic stroke in cancer patients. Neuroradiol J 2023; 36 (04) 453-459
  • 100 Beyeler M, Belachew NF, Kielkopf M. et al. Absence of susceptibility vessel sign in patients with malignancy-related acute ischemic stroke treated with mechanical thrombectomy. Front Neurol 2022; 13: 930635
  • 101 Chen J, Zhang Z, Nie X. et al. Predictive value of thrombus susceptibility for cardioembolic stroke by quantitative susceptibility mapping. Quant Imaging Med Surg 2022; 12 (01) 550-557
  • 102 Yoo J, Choi JK, Kim YD. et al. Outcome of stroke patients with cancer and nonbacterial thrombotic endocarditis. J Stroke 2020; 22 (02) 245-253
  • 103 Zmaili MA, Alzubi JM, Kocyigit D. et al. A contemporary 20-year cleveland clinic experience of nonbacterial thrombotic endocarditis: etiology, echocardiographic imaging, management, and outcomes. Am J Med 2021; 134 (03) 361-369
  • 104 Deppisch LM, Fayemi AO. Non-bacterial thrombotic endocarditis: clinicopathologic correlations. Am Heart J 1976; 92 (06) 723-729
  • 105 Llenas-García J, Guerra-Vales JM, Montes-Moreno S, López-Ríos F, Castelbón-Fernández FJ, Chimeno-García J. Nonbacterial thrombotic endocarditis: clinicopathologic study of a necropsy series [in Spanish]. Rev Esp Cardiol 2007; 60 (05) 493-500
  • 106 Steiner I. Nonbacterial thrombotic endocarditis–a study of 171 case reports [in Czech]. Cesk Patol 1993; 29 (02) 58-60
  • 107 Hisada Y, Mackman N. Tissue factor and cancer: regulation, tumor growth, and metastasis. Semin Thromb Hemost 2019; 45 (04) 385-395
  • 108 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
  • 109 Eichinger S. Cancer associated thrombosis: risk factors and outcomes. Thromb Res 2016; 140 (Suppl. 01) S12-S17
  • 110 Ha J, Lee MJ, Kim SJ. et al. Prevalence and impact of venous and arterial thromboembolism in patients with embolic stroke of undetermined source with or without active cancer. J Am Heart Assoc 2019; 8 (21) e013215
  • 111 Blann AD, Dunmore S. Arterial and venous thrombosis in cancer patients. Cardiol Res Pract 2011; 2011: 394740
  • 112 Kawano T, Sasaki T, Gon Y. et al. High neutrophil/lymphocyte ratio at cancer diagnosis predicts incidence of stroke in cancer patients. Brain Commun 2021; 3 (02) fcab071
  • 113 Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91 (03) 181-184
  • 114 Kang MH, Go SI, Song HN. et al. The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer 2014; 111 (03) 452-460
  • 115 Goyal N, Tsivgoulis G, Chang JJ. et al. Admission neutrophil-to-lymphocyte ratio as a prognostic biomarker of outcomes in large vessel occlusion strokes. Stroke 2018; 49 (08) 1985-1987
  • 116 Nam KW, Kim TJ, Kim CK. et al. Temporal changes in the neutrophil to lymphocyte ratio and the neurological progression in cryptogenic stroke with active cancer. PLoS One 2018; 13 (03) e0194286
  • 117 Sarejloo S, Kheradjoo H, Haghi SE. et al. Neutrophil-to-lymphocyte ratio and early neurological deterioration in stroke patients: a systematic review and meta-analysis. BioMed Res Int 2022; 2022: 8656864
  • 118 Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 2019; 8 (07) 727
  • 119 Bang OY, Chung JW, Lee MJ. et al. Cancer cell-derived extracellular vesicles are associated with coagulopathy causing ischemic stroke via tissue factor-independent way: the OASIS-CANCER study. PLoS One 2016; 11 (07) e0159170
  • 120 Chung JW, Cho YH, Ahn MJ. et al. Association of cancer cell type and extracellular vesicles with coagulopathy in patients with lung cancer and stroke. Stroke 2018; 49 (05) 1282-1285
  • 121 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
  • 122 Almeida VH, Rondon AMR, Gomes T, Monteiro RQ. Novel aspects of extracellular vesicles as mediators of cancer-associated thrombosis. Cells 2019; 8 (07) 716
  • 123 Thålin C, Demers M, Blomgren B. et al. NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. Thromb Res 2016; 139: 56-64
  • 124 Bang OY, Chung JW, Cho YH. et al. Circulating DNAs, a marker of neutrophil extracellular traposis and cancer-related stroke: the OASIS-Cancer study. Stroke 2019; 50 (10) 2944-2947
  • 125 Maezono-Kandori K, Ohara T, Fujinami J, Makita N, Tanaka E, Mizuno T. Elevated CA125 is related to stroke due to cancer- associated hypercoagulation. J Stroke Cerebrovasc Dis 2021; 30 (12) 106126
  • 126 Long H, Qin K, Chen J. et al. Biomarkers of gastric cancer-related ischemic stroke and its underlying pathogenesis. Medicine (Baltimore) 2018; 97 (17) e0493
  • 127 Okazaki K, Oka F, Ishihara H, Suzuki M. Cerebral infarction associated with benign mucin-producing adenomyosis: report of two cases. BMC Neurol 2018; 18 (01) 166
  • 128 Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110 (06) 1723-1729
  • 129 Park H, Kim J, Ha J. et al. Histological features of intracranial thrombi in stroke patients with cancer. Ann Neurol 2019; 86 (01) 143-149
  • 130 Huang S, Lu X, Tang LV, Hu Y. Efficacy and safety of intravenous thrombolysis for acute ischemic stroke in cancer patients: a systemic review and meta-analysis. Am J Transl Res 2020; 12 (08) 4795-4806
  • 131 Eun MY, Jeon ET, Seo KD, Lee D, Jung JM. Reperfusion therapy in acute ischemic stroke with active cancer: a meta-analysis aided by machine learning. J Stroke Cerebrovasc Dis 2021; 30 (06) 105742
  • 132 Murthy SB, Karanth S, Shah S. et al. Thrombolysis for acute ischemic stroke in patients with cancer: a population study. Stroke 2013; 44 (12) 3573-3576
  • 133 Inohara T, Liang L, Kosinski AS. et al. Thrombolytic therapy in older acute ischemic stroke patients with gastrointestinal malignancy or recent bleeding. Eur Stroke J 2020; 5 (01) 47-55
  • 134 Singh K, Mowla A, Mehla S. et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients with preexisting intracranial neoplasms: a case series. Int J Stroke 2015; 10 (03) E29-E30
  • 135 Rubinshtein R, Jaffe R, Flugelman MY, Karkabi B, Lewis BS. Thrombolysis in patients with a brain tumour. Heart 2004; 90 (12) 1476
  • 136 Dafer RM, Paleologos N, Lynch D. Intravenous thrombolysis for ischemic stroke in recurrent oligodendroglioma: a case report. J Stroke Cerebrovasc Dis 2014; 23 (05) 1235-1238
  • 137 Schwarzbach CJ, Ebert A, Hennerici MG, Neumaier-Probst E, Platten M, Fatar M. Off-label use of IV t-PA in patients with intracranial neoplasm and cavernoma. Ther Adv Neurol Disord 2018; 11: 1756285617753423
  • 138 Neil W, Ovbiagele B. Intravenous thrombolysis in ischemic stroke patients with intracranial neoplasms: two cases and a literature review. Case Rep Med 2011; 2011: 503758
  • 139 Etgen T, Steinich I, Gsottschneider L. Thrombolysis for ischemic stroke in patients with brain tumors. J Stroke Cerebrovasc Dis 2014; 23 (02) 361-366
  • 140 Turc G, Tsivgoulis G, Audebert HJ. et al. European Stroke Organisation (ESO)-European Society for Minimally Invasive Neurological Therapy (ESMINT) expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischemic stroke and anterior circulation large vessel occlusion. J Neurointerv Surg 2022; 14 (03) 209-227
  • 141 Cho BH, Yoon W, Kim JT. et al. Outcomes of endovascular treatment in acute ischemic stroke patients with current malignancy. Neurol Sci 2020; 41 (02) 379-385
  • 142 Lee EJ, Bae J, Jeong HB, Lee EJ, Jeong HY, Yoon BW. Effectiveness of mechanical thrombectomy in cancer-related stroke and associated factors with unfavorable outcome. BMC Neurol 2021; 21 (01) 57
  • 143 Jolugbo P, Ariëns RAS. Thrombus composition and efficacy of thrombolysis and thrombectomy in acute ischemic stroke. Stroke 2021; 52 (03) 1131-1142
  • 144 Jung S, Jung C, Hyoung Kim J. et al. Procedural and clinical outcomes of endovascular recanalization therapy in patients with cancer-related stroke. Interv Neuroradiol 2018; 24 (05) 520-528
  • 145 Staessens S, Denorme F, Francois O. et al. Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance. Haematologica 2020; 105 (02) 498-507
  • 146 Denorme F, Langhauser F, Desender L. et al. ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice. Blood 2016; 127 (19) 2337-2345
  • 147 Gauberti M, Martinez de Lizarrondo S, Vivien D. Thrombolytic strategies for ischemic stroke in the thrombectomy era. J Thromb Haemost 2021; 19 (07) 1618-1628
  • 148 Stalder G, Chatte A, De Rossi N, Yerly P, Alberio L, Eeckhout E. Caplacizumab for treating subacute intra-stent thrombus occurring despite efficacious double anti-platelet treatment and anticoagulation: a case report. Eur Heart J Case Rep 2023; 7 (02) ytac497
  • 149 Caimano D, Letteri F, Capasso F. et al. Endovascular treatment in patients with acute ischemic stroke and cancer: systematic review and meta-analysis. Eur Stroke J 2022; 7 (03) 204-211
  • 150 Verschoof MA, Groot AE, de Bruijn SFTM. et al; MR CLEAN Registry Investigators. Clinical outcome after endovascular treatment in patients with active cancer and ischemic stroke: a MR CLEAN registry substudy. Neurology 2022; 98 (10) e993-e1001
  • 151 Letteri F, Pracucci G, Saia V. et al. Endovascular treatment in patients with acute ischemic stroke and comorbid cancer: analysis of the Italian Registry of Endovascular Treatment in Acute Stroke. Stroke Vasc Intervent Neurol 2023; 3: e000423
  • 152 Chatterjee A, Merkler AE, Murthy SB. et al. Temporal trends in the use of acute recanalization therapies for ischemic stroke in patients with cancer. J Stroke Cerebrovasc Dis 2019; 28 (08) 2255-2261
  • 153 Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-of-the-Art Review. JACC Cardiooncol 2021; 3 (02) 173-190
  • 154 De Stefano V. Arterial thrombosis and cancer: the neglected side of the coin of Trousseau syndrome. Haematologica 2018; 103 (09) 1419-1421
  • 155 Jang H, Lee JJ, Lee MJ. et al. Comparison of enoxaparin and warfarin for secondary prevention of cancer-associated stroke. J Oncol 2015; 2015: 502089
  • 156 Navi BB, Marshall RS, Bobrow D. et al. Enoxaparin vs aspirin in patients with cancer and ischemic stroke: the TEACH pilot randomized clinical trial. JAMA Neurol 2018; 75 (03) 379-381
  • 157 Nam KW, Kim CK, Kim TJ. et al. Treatment of cryptogenic stroke with active cancer with a new oral anticoagulant. J Stroke Cerebrovasc Dis 2017; 26 (12) 2976-2980
  • 158 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
  • 159 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
  • 160 Falanga A, Ay C, Di Nisio M. et al; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023; 34 (05) 452-467
  • 161 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
  • 162 Martinez-Majander N, Ntaios G, Liu YY. et al; NAVIGATE ESUS investigators. Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial. Eur J Neurol 2020; 27 (05) 841-848
  • 163 Mantia C, Uhlmann EJ, Puligandla M, Weber GM, Neuberg D, Zwicker JI. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood 2017; 129 (25) 3379-3385
  • 164 Kamphuisen PW, Beyer-Westendorf J. Bleeding complications during anticoagulant treatment in patients with cancer. Thromb Res 2014; 133 (Suppl. 02) S49-S55
  • 165 Angelini DE, Radivoyevitch T, McCrae KR, Khorana AA. Bleeding incidence and risk factors among cancer patients treated with anticoagulation. Am J Hematol 2019; 94 (07) 780-785
  • 166 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
  • 167 Falanga A, Leader A, Ambaglio C. et al. EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer. HemaSphere 2022; 6 (08) e750
  • 168 De Stefano V, Carobbio A, Di Lazzaro V. et al. Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms. Blood Cancer J 2018; 8 (03) 25
  • 169 ECOG-ACRIN Cancer Research Group. ECOG performance status scale. Accessed March 05, 2023 at: https://ecog-acrin.org/resources/ecog-performance-status/
  • 170 Weitz JI, Eikelboom JW. What is the future of factor XI inhibitors?. Circulation 2022; 146 (25) 1899-1902
  • 171 Grisold W, Oberndorfer S, Struhal W. Stroke and cancer: a review. Acta Neurol Scand 2009; 119 (01) 1-16