Review of Trousseau phenomenon - pathomechanism, diagnosis, treatment and risk of cancer
DOI:
https://doi.org/10.12775/JEHS.2025.79.57865Keywords
Trousseau's syndrome, thrombosis, cancer-associated thrombosis, cancerAbstract
Introduction: Trousseau's phenomenon, also referred to as malignancy-associated thrombosis, represents a hypercoagulable state commonly encountered in oncology patients, contributing substantially to morbidity and mortality. This review examines the underlying mechanisms of Trousseau’s phenomenon, including the release of tumor-derived procoagulants and immune-inflammatory interactions, alongside contemporary diagnostic methodologies and emerging biomarker candidates. Additionally, therapeutic strategies, with a focus on anticoagulation management, are discussed, highlighting the clinical and prognostic significance of Trousseau’s phenomenon in evaluating cancer progression and risk stratification. The evolving understanding of this condition underscores the necessity of interdisciplinary collaboration in its clinical management and ongoing research efforts.
Aim of these study: The aim of this study was to explore the issue of hypercoagulability in the cancer patient population and to investigate the underlying mechanisms contributing to its development.
State of knowledge: It is well-established in scientific literature that oncology patients are at a significantly increased risk for thromboembolic events. Neoplasms promote a hypercoagulable state and its associated complications through diverse and complex pathophysiological mechanisms.
Conclusions: Cancer-associated thrombosis is a significant clinical challenge in oncology patients. Understanding the underlying mechanisms, identifying specific risk factors, and ensuring early diagnosis are essential for improving prognosis and optimizing therapeutic outcomes.
References
1.Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110(6):1723-1729. doi:10.1182/blood-2006-10-053736
2.Khorana AA. Malignancy, thrombosis and Trousseau: the case for an eponym. J Thromb Haemost. 2003;1(12):2463-2465. doi:10.1111/j.1538-7836.2003.00501.x
3.Goad KE, Gralnick HR. Coagulation disorders in cancer. Hematol Oncol Clin North Am. 1996;10(2):457-484. doi:10.1016/s0889-8588(05)70347-6
4.Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore). 1977;56(1):1-37.
5.Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state. Lancet Oncol. 2002;3(1):27-34. doi:10.1016/s1470-2045(01)00619-2
6.Falanga A, Marchetti M, Russo L. The mechanisms of cancer-associated thrombosis. Thromb Res. 2015;135 Suppl 1:S8-S11. doi:10.1016/S0049-3848(15)50432-5
7.Zhen C, Wang Y, Wang H, Li D, Wang X. Multiple cerebral infarction linked to underlying cancer: a review of Trousseau syndrome-related cerebral infarction. Br J Hosp Med (Lond). 2021;82(5):1-7. doi:10.12968/hmed.2020.0696
8.Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334(11):677-681. doi:10.1056/NEJM199603143341101
9.Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999;78(5):285-291. doi:10.1097/00005792-199909000-00001
10.Svendsen E, Karwinski B. Prevalence of pulmonary embolism at necropsy in patients with cancer. J Clin Pathol. 1989;42(8):805-809. doi:10.1136/jcp.42.8.805
11.Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634. doi:10.1111/j.1538-7836.2007.02374.x
12.Lee AY. Management of thrombosis in cancer: primary prevention and secondary prophylaxis. Br J Haematol. 2005;128(3):291-302. doi:10.1111/j.1365-2141.2004.05292.x
13.Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haematol. 2009;22(1):9-23. doi:10.1016/j.beha.2008.12.001
14.Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore). 1977;56(1):1-37.
15.Ikushima S, Ono R, Fukuda K, Sakayori M, Awano N, Kondo K. Trousseau's syndrome: cancer-associated thrombosis. Jpn J Clin Oncol. 2016;46(3):204-208. doi:10.1093/jjco/hyv165
16.Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore). 1977;56(1):1-37.
17.Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275. doi:10.1371/journal.pmed.1001275
18.Khorana AA. Targeted prophylaxis in cancer: the evidence accumulates. Intern Emerg Med. 2013;8(3):187-189. doi:10.1007/s11739-012-0883-9
19.Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol. 2014;8:129-137. Published 2014 Dec 4. doi:10.4137/CMO.S18991
20.Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best Pract Res Clin Haematol. 2009;22(1):9-23. doi:10.1016/j.beha.2008.12.001
21.Walker AJ, Card TR, West J, Crooks C, Grainge MJ. Incidence of venous thromboembolism in patients with cancer - a cohort study using linked United Kingdom databases. Eur J Cancer. 2013;49(6):1404-1413. doi:10.1016/j.ejca.2012.10.021
22.Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006;119(1):60-68. doi:10.1016/j.amjmed.2005.06.058
23.Khorana AA, Ahrendt SA, Ryan CK, et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res. 2007;13(10):2870-2875. doi:10.1158/1078-0432.CCR-06-2351
24.Wang JG, Geddings JE, Aleman MM, et al. Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood. 2012;119(23):5543-5552. doi:10.1182/blood-2012-01-402156
25.Ruf W, Edgington TS. Structural biology of tissue factor, the initiator of thrombogenesis in vivo. FASEB J. 1994;8(6):385-390.
26.Garg SK, Niemetz J. Tissue factor activity of normal and leukemic cells. Blood 1973;42(05):729–735
27.Gouault Heilmann M, Chardon E, Sultan C, Josso F. The procoagulant factor of leukaemic promyelocytes: demonstration of immunologic cross reactivity with human brain tissue factor. Br J Haematol. 1975;30(2):151-158. doi:10.1111/j.1365-2141.1975.tb00529.x
28.Cesarman-Maus G, Braggio E, Lome-Maldonado C, Morales-Leyte AL, Fonseca R. Absence of tissue factor is characteristic of lymphoid malignancies of both T- and B-cell origin. Thromb Res. 2014;133(4):606-609. doi:10.1016/j.thromres.2014.01.020
29.Carty N, Taylor I, Roath OS, el-Baruni K, Francis JL. Urinary tissue factor activity in colorectal disease. Br J Surg. 1990;77(10):1091-1094. doi:10.1002/bjs.1800771005
30.Yu JL, May L, Lhotak V, et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood. 2005;105(4):1734-1741. doi:10.1182/blood-2004-05-2042
31.Rong Y, Belozerov VE, Tucker-Burden C, et al. Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res. 2009;69(6):2540-2549. doi:10.1158/0008-5472.CAN-08-1547
32.Provençal M, Labbé D, Veitch R, et al. c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration. Carcinogenesis. 2009;30(7):1089-1096. doi:10.1093/carcin/bgp085
33.Yu JL, Xing R, Milsom C, Rak J. Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1. Thromb Res. 2010;126(1):e6-e10. doi:10.1016/j.thromres.2010.04.014
34.Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer. 2000;83(2):164-170. doi:10.1054/bjoc.2000.1272
35.Förster Y, Meye A, Albrecht S, et al. Tissue specific expression and serum levels of human tissue factor in patients with urological cancer. Cancer Lett. 2003;193(1):65-73. doi:10.1016/s0304-3835(02)00687-0
36.Shigemori C, Wada H, Matsumoto K, Shiku H, Nakamura S, Suzuki H. Tissue factor expression and metastatic potential of colorectal cancer. Thromb Haemost. 1998;80(6):894-898.
37.Yamashita H, Kitayama J, Ishikawa M, Nagawa H. Tissue factor expression is a clinical indicator of lymphatic metastasis and poor prognosis in gastric cancer with intestinal phenotype. J Surg Oncol. 2007;95(4):324-331. doi:10.1002/jso.20680
38.Maciel EO, Carvalhal GF, da Silva VD, Batista EL Jr, Garicochea B. Increased tissue factor expression and poor nephroblastoma prognosis. J Urol. 2009;182(4):1594-1599. doi:10.1016/j.juro.2009.06.011
39.Han LY, Landen CN Jr, Kamat AA, et al. Preoperative serum tissue factor levels are an independent prognostic factor in patients with ovarian carcinoma. J Clin Oncol. 2006;24(5):755-761. doi:10.1200/JCO.2005.02.9181
40.Sawada M, Miyake S, Ohdama S, et al. Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis. Br J Cancer. 1999;79(3-4):472-477. doi:10.1038/sj.bjc.6690073
41.Nitori N, Ino Y, Nakanishi Y, et al. Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2005;11(7):2531-2539. doi:10.1158/1078-0432.CCR-04-0866
42.Akashi T, Furuya Y, Ohta S, Fuse H. Tissue factor expression and prognosis in patients with metastatic prostate cancer. Urology. 2003;62(6):1078-1082. doi:10.1016/s0090-4295(03)00768-4
43.Freyssinet JM. Cellular microparticles: what are they bad or good for?. J Thromb Haemost. 2003;1(7):1655-1662. doi:10.1046/j.1538-7836.2003.00309.x
44.Sinauridze EI, Kireev DA, Popenko NY, et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost. 2007;97(3):425-434.
45.Lechner D, Weltermann A. Chemotherapy-induced thrombosis: a role for microparticles and tissue factor?. Semin Thromb Hemost. 2008;34(2):199-203. doi:10.1055/s-2008-1079261
46.Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8:83. Published 2015 Jul 10. doi:10.1186/s13045-015-0181-x
47.Campello E, Spiezia L, Radu CM, et al. Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb Res. 2011;127(5):473-477. doi:10.1016/j.thromres.2011.01.002
48.Sartori MT, Della Puppa A, Ballin A, et al. Circulating microparticles of glial origin and tissue factor bearing in high-grade glioma: a potential prothrombotic role. Thromb Haemost. 2013;110(2):378-385. doi:10.1160/TH12-12-0957
49.Zhao L, Bi Y, Kou J, Shi J, Piao D. Phosphatidylserine exposing-platelets and microparticles promote procoagulant activity in colon cancer patients. J Exp Clin Cancer Res. 2016;35:54. Published 2016 Mar 25. doi:10.1186/s13046-016-0328-9
50.Mezouar S, Mege D, Darbousset R, et al. Involvement of platelet-derived microparticles in tumor progression and thrombosis. Semin Oncol. 2014;41(3):346-358. doi:10.1053/j.seminoncol.2014.04.010
51.Geddings JE, Hisada Y, Boulaftali Y, et al. Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice [published correction appears in J Thromb Haemost. 2016 Dec;14(12):2566. doi: 10.1111/jth.13540]. J Thromb Haemost. 2016;14(1):153-166. doi:10.1111/jth.13181
52.Muhsin-Sharafaldine MR, Saunderson SC, Dunn AC, Faed JM, Kleffmann T, McLellan AD. Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles. Oncotarget. 2016;7(35):56279-56294. doi:10.18632/oncotarget.10783
53.Leal AC, Mizurini DM, Gomes T, et al. Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis. Sci Rep. 2017;7(1):6438. Published 2017 Jul 25. doi:10.1038/s41598-017-06893-7
54.Nickel KF, Ronquist G, Langer F, et al. The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis. Blood. 2015;126(11):1379-1389. doi:10.1182/blood-2015-01-622811
55.Mandalà M, Barni S, Prins M, et al. Acquired and inherited risk factors for developing venous thromboembolism in cancer patients receiving adjuvant chemotherapy: a prospective trial. Ann Oncol. 2010;21(4):871-876. doi:10.1093/annonc/mdp354
56.Simanek R, Vormittag R, Ay C, et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost. 2010;8(1):114-120. doi:10.1111/j.1538-7836.2009.03680.x
57.Moore RA, Adel N, Riedel E, et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol. 2011;29(25):3466-3473. doi:10.1200/JCO.2011.35.5669
58.Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. doi:10.1182/blood-2007-10-116327
59.Simanek R, Vormittag R, Ay C, et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost. 2010;8(1):114-120. doi:10.1111/j.1538-7836.2009.03680.x
60.Ay C, Simanek R, Vormittag R, et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood. 2008;112(7):2703-2708. doi:10.1182/blood-2008-02-142422
61.Ay C, Vormittag R, Dunkler D, et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol. 2009;27(25):4124-4129. doi:10.1200/JCO.2008.21.7752
62.Lupu-Meiri M, Geras-Raaka E, Lupu R, et al. Knock-down of plasminogen-activator inhibitor-1 enhances expression of E-cadherin and promotes epithelial differentiation of human pancreatic adenocarcinoma cells. J Cell Physiol. 2012;227(11):3621-3628. doi:10.1002/jcp.24068
63.Westrick RJ, Eitzman DT. Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets. 2007;8(9):966-1002. doi:10.2174/138945007781662328
64.Andrén-Sandberg A, Lecander I, Martinsson G, Astedt B. Peaks in plasma plasminogen activator inhibitor-1 concentration may explain thrombotic events in cases of pancreatic carcinoma. Cancer. 1992;69(12):2884-2887. doi:10.1002/1097-0142(19920615)69:12<2884::aid-cncr2820691204>3.0.co;2-s
65.Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484-3488. doi:10.1182/blood-2002-01-0108
66.Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol. 2000;18(17):3078-3083. doi:10.1200/JCO.2000.18.17.3078
67.Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report [published correction appears in Chest. 2016 Oct;150(4):988. doi: 10.1016/j.chest.2016.08.1442]. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026
68.Lyman GH, Bohlke K, Falanga A; American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Oncol Pract. 2015;11(3):e442-e444. doi:10.1200/JOP.2015.004473
69.Mandalà M, Labianca R; European Society for Medical Oncology. Venous thromboembolism (VTE) in cancer patients. ESMO clinical recommendations for prevention and management. Thromb Res. 2010;125 Suppl 2:S117-S119. doi:10.1016/S0049-3848(10)70028-1
70.Streiff MB, Holmstrom B, Angelini D, et al. Cancer-Associated Venous Thromboembolic Disease, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024;22(7):483-506. doi:10.6004/jnccn.2024.0046
71.Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-2204. doi:10.1200/JCO.2013.49.1118
72.Khorana AA, Otten HM, Zwicker JI, et al. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost. 2014;12(11):1928-1931. doi:10.1111/jth.12725
73.Kaur S, Kumar S, Momi N, Sasson AR, Batra SK. Mucins in pancreatic cancer and its microenvironment. Nat Rev Gastroenterol Hepatol. 2013;10(10):607-620. doi:10.1038/nrgastro.2013.120
74.Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45-60. doi:10.1038/nrc1251
75.Kaźmierczak M, Lewandowski K, Wojtukiewicz MZ, et al. Cancer procoagulant in patients with adenocarcinomas. Blood Coagul Fibrinolysis. 2005;16(8):543-547. doi:10.1097/01.mbc.0000188413.32859.b2
76.Kröger K, Weiland D, Ose C, et al. Risk factors for venous thromboembolic events in cancer patients. Ann Oncol. 2006;17(2):297-303. doi:10.1093/annonc/mdj068
77.Connolly GC, Dalal M, Lin J, Khorana AA. Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer. Lung Cancer. 2012;78(3):253-258. doi:10.1016/j.lungcan.2012.09.007
78.Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer. 2013;119(3):648-655. doi:10.1002/cncr.27772
79.Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166(4):458-464. doi:10.1001/archinte.166.4.458
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Copyright (c) 2025 Paula Majewska, Alicja Staszek, Wiktoria Łoskot, Jan Szwech, Mateusz Matczak, Karol Jasiński, Aleksandra Broda, Kacper Hoksa, Krzysztof Jodłowski, Ewa Dubniewicz
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