Skip to main content

Advertisement

Log in

Cancer-related coagulopathy (Trousseau’s syndrome): review of the literature and experience of a single center of internal medicine

  • Review Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Venous thromboembolism (VTE) occurs roughly in one out of five cancer patients and is the second cause of death in this population. When all cancer patients are considered together, a sevenfold increased risk for VTE has been calculated. Over the last 20 years, a number of risk factors have been recognized. These have been used in several risk assessment models aimed at identifying high-risk patients who are therefore candidates for thromboprophylaxis. An easily applicable and reliable risk score is based on the cancer site, hemoglobin levels, pre-chemotherapy platelet and leukocyte counts as well as body mass index. The additional measurement of two biomarkers, namely D-dimer and soluble P-selectin, may improve estimates of the cumulative VTE probability. A variable incidence of VTE has been determined in patients with specific types of malignancy, with the highest odds in those with pancreatic cancer followed by head and neck tumors. In terms of histotype, the risk of VTE is significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma and in patients with high-grade versus low-grade tumors. Cancer therapy may also be responsible for VTE; specifically, the presence of an indwelling central venous catheter, immunomodulatory drugs such as thalidomide and lenalidomide, monoclonal antibodies, such as bevacizumab, erythropoiesis-stimulating agents and hormonal therapy with tamoxifen place patients at higher risk. The pathogenesis of cancer-related VTE is poorly understood but is likely to be multifactorial. “Virchow’s triad,” comprising stasis consequent to a decreased blood flow rate, an enhanced blood clotting tendency such as accompanies inflammation and growth factor expression, and structural modifications in blood vessel walls, is thought to play a central role in the induction of VTE. The prophylaxis and treatment of VTE are based on well-established drugs such as vitamin K antagonists and unfractionated and low-molecular-weight heparins as well as on an expanding group of new oral anticoagulants, including fondaparinux, rivaroxaban, apixaban and dabigatran. Furthermore, aspirin has been shown to prevent arterial thrombosis and to reduce the rate of major vascular events. Guidelines for the general management of VTE in cancer patients and in those with an indwelling central venous catheter have been recently developed with the aim of selecting the most rational therapeutic approach for each clinical situation. The main features of VTE based on our own observations of 92 cancer patients and 159 patients with non-neoplastic disease are briefly described herein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

APS:

Antiphospholipid syndrome

CI:

Confidence interval

CT:

Computed tomography

CVC:

Central venous catheter

DVT:

Deep-vein thrombosis

ESAs:

Erythropoiesis-stimulating agents

IMiD:

Immunomodulatory drug

LMWH:

Low-molecular-weight heparins

NETs:

Neutrophil extracellular traps

PE:

Pulmonary embolism

SIR:

Standardized incidence ratio

β2GPI:

Beta-2 glycoprotein I

TS:

Trousseau’s syndrome

VEGF:

Vascular endothelial growth factor

VKA:

Vitamin K antagonists

VTE:

Venous thromboembolism

References

  1. Trousseau A (1865) Phlegmasia alba dolens. Clinique Mèdicale de l’Hôtel-Dieu de Paris 3:654–712

  2. Bouillard JB, Bouillaud S (1823) De l’obliteration des veines et de son influence sur la formation des hydropisies partielles: consideration sur la hydropisies passive et general. Arch Gen Med 1:188–204

    Google Scholar 

  3. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158:585–593

    Article  PubMed  CAS  Google Scholar 

  4. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ (2006) The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 21:722–727

    Article  PubMed  Google Scholar 

  5. Lee CH, Cheng CL, Lin LJ, Tsai LM, Yang YH (2011) Epidemiology and predictors of short-term mortality in symptomatic venous thromboembolism. Circ J 75:1998–2004

    Article  PubMed  Google Scholar 

  6. Ahlbrecht J, Dickmann B, Ay C, Dunkler D, Thaler J, Schmidinger M, Quehenberger P, Haitel A, Zielinski C, Pabinger I (2012) Tumor grade is associated with venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 30:3870–3875

    Article  PubMed  Google Scholar 

  7. Noble S, Pasi J (2010) Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer 102(Suppl 1):S2–S9

    Article  PubMed  Google Scholar 

  8. Caruso V, Di Castelnuovo A, Meschengieser S, Lazzari MA, de Gaetano G, Storti S, Iacoviello L, Donati MB (2010) Thrombotic complications in adult patients with lymphoma: a meta-analysis of 29 independent cohorts including 18 018 patients and 1149 events. Blood 115:5322–5328

    Article  PubMed  CAS  Google Scholar 

  9. Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA (1999) Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 78:285–291

    Article  CAS  Google Scholar 

  10. Verso M, Agnelli G (2003) Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665–3675

    Article  PubMed  Google Scholar 

  11. Ioannou Y, Zhang JY, Qi M, Gao L, Qi JC, Yu DM, Lau H, Sturgess AD, Vlachoyiannopoulos PG, Moutsopoulos HM, Rahman A, Pericleous C, Atsumi T, Koike T, Heritier S, Giannakopoulos B, Krilis SA (2011) Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen beta2-glycoprotein I. Arthritis Rheum 63:2774–2782

    Article  PubMed  CAS  Google Scholar 

  12. Gavish I, Brenner B (2011) Air travel and the risk of thromboembolism. Intern Emerg Med 6:113–116

    Article  PubMed  Google Scholar 

  13. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III (2000) Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 160:809–815

    Article  PubMed  CAS  Google Scholar 

  14. Young A, Chapman O, Connor C, Poole C, Rose P, Kakkar AK (2012) Thrombosis and cancer. Nat Rev Clin Oncol 9:437–449

    Article  PubMed  CAS  Google Scholar 

  15. White RH, Chew HK, Zhou H, Parikh-Patel A, Harris D, Harvey D, Wun T (2005) Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med 165:1782–1787

    Article  PubMed  Google Scholar 

  16. Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov B, Goldhaber SZ (2005) Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 352:969–977

    Article  PubMed  CAS  Google Scholar 

  17. Chopard P, Spirk D, Bounameaux H (2006) Identifying acutely ill medical patients requiring thromboprophylaxis. J Thromb Haemost 4:915–916

    Article  PubMed  CAS  Google Scholar 

  18. Ay C, Simanek R, Vormittag R, Dunkler D, Alguel G, Koder S, Kornek G, Marosi C, Wagner O, Zielinski C, Pabinger I (2008) 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 112:2703–2708

    Article  PubMed  CAS  Google Scholar 

  19. Kucher N, Spirk D, Baumgartner I, Mazzolai L, Korte W, Nobel D, Banyai M, Bounameaux H (2010) Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the SWIss Venous ThromboEmbolism Registry (SWIVTER). Ann Oncol 21:931–935

    Article  PubMed  CAS  Google Scholar 

  20. Woller SC, Stevens SM, Jones JP, Lloyd JF, Evans RS, Aston VT, Elliott CG (2011) Derivation and validation of a simple model to identify venous thromboembolism risk in medical patients. Am J Med 124:947–954

    Article  PubMed  Google Scholar 

  21. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ III (2000) Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 160:761–768

    Article  PubMed  CAS  Google Scholar 

  22. Franchini M, Mannucci PM (2012) Association between venous and arterial thrombosis: clinical implications. Eur J Intern Med 23:333–337

    Article  PubMed  Google Scholar 

  23. Prandoni P, Piovella C, Pesavento R (2012) Venous thromboembolism and arterial complications. Semin Respir Crit Care Med 33:205–210

    Article  PubMed  Google Scholar 

  24. Matsui H, Nishinaka K, Oda M, Kubori T, Udaka F (2007) Trousseau syndrome due to pleural mesothelioma. Neurologist 13:205–208

    Article  PubMed  Google Scholar 

  25. Rizzo D, Barone G, Ruggiero A, Maurizi P, Furfaro IF, Castagneto M, Riccardi R (2011) Massive venous thrombosis of inferior vena cava as primary manifestation of renal Ewing’s sarcoma. Clin Nephrol 75:560–564

    PubMed  CAS  Google Scholar 

  26. Paneesha S, McManus A, Arya R, Scriven N, Farren T, Nokes T, Bacon S, Nieland A, Cooper D, Smith H, O’Shaughnessy D, Rose P (2010) Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics. Thromb Haemost 103:338–343

    Article  PubMed  CAS  Google Scholar 

  27. Blom JW, Osanto S, Rosendaal FR (2004) The risk of a venous thrombotic event in lung cancer patients: higher risk for adenocarcinoma than squamous cell carcinoma. J Thromb Haemost 2:1760–1765

    Article  PubMed  CAS  Google Scholar 

  28. Manzoni M, Bencardino K, Piovella F, Chatzileontiadou S, Delfanti S, Riccardi A, Danova M, Corazza GR (2007) New agents in medical oncology and the risk of venous thromboembolism. J Exp Clin Cancer Res 26:185–194

    PubMed  CAS  Google Scholar 

  29. Prandoni P, Falanga A, Piccioli A (2005) Cancer and venous thromboembolism. Lancet Oncol 6:401–410

    Article  PubMed  Google Scholar 

  30. Khosravi-Shahi P, Perez-Manga G (2009) International recommendations for the prevention and treatment of venous thromboembolism associated with cancer. Clin Drug Investig 29:625–633

    Article  PubMed  CAS  Google Scholar 

  31. Merchionne F, Perosa F, Dammacco F (2007) New therapies in multiple myeloma. Clin Exp Med 7:83–97

    Article  PubMed  CAS  Google Scholar 

  32. van Marion AM, Auwerda JJ, Lisman T, Sonneveld P, de Maat MP, Lokhorst HM, Leebeek FW (2008) Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens. Leuk Res 32:1078–1084

    Article  PubMed  Google Scholar 

  33. Cives M, Milano A, Dammacco F, Silvestris F (2012) Lenalidomide in multiple myeloma: current experimental and clinical data. Eur J Haematol 88:279–291

    Article  PubMed  CAS  Google Scholar 

  34. Larocca A, Cavallo F, Mina R, Boccadoro M, Palumbo A (2012) Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. Future Oncol 8:1223–1238

    Article  PubMed  CAS  Google Scholar 

  35. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300:2277–2285

    Article  PubMed  CAS  Google Scholar 

  36. Hurwitz HI, Saltz LB, Van CE, Cassidy J, Wiedemann J, Sirzen F, Lyman GH, Rohr UP (2011) Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 29:1757–1764

    Article  PubMed  CAS  Google Scholar 

  37. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M (2008) Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914–924

    Article  PubMed  CAS  Google Scholar 

  38. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A (2006) Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708–714

    Article  PubMed  CAS  Google Scholar 

  39. Aapro M, Jelkmann W, Constantinescu SN, Leyland-Jones B (2012) Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br J Cancer 106:1249–1258

    Article  PubMed  CAS  Google Scholar 

  40. Onitilo AA, Doi SA, Engel JM, Glurich I, Johnson J, Berg R (2012) Clustering of venous thrombosis events at the start of tamoxifen therapy in breast cancer: a population-based experience. Thromb Res 130:27–31

    Article  PubMed  CAS  Google Scholar 

  41. Deitcher SR, Gomes MP (2004) The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma: a systematic review. Cancer 101:439–449

    Article  PubMed  Google Scholar 

  42. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

    Article  PubMed  CAS  Google Scholar 

  43. Rott H (2012) Thrombotic risks of oral contraceptives. Curr Opin Obstet Gynecol 24:235–240

    Article  PubMed  Google Scholar 

  44. Patel A, Schwarz EB (2012) Cancer and contraception. Release date May 2012. SFP Guideline #20121. Contraception 86:191–198

    Article  PubMed  Google Scholar 

  45. Kvolik S, Jukic M, Matijevic M, Marjanovic K, Glavas-Obrovac L (2010) An overview of coagulation disorders in cancer patients. Surg Oncol 19:e33–e46

    Article  PubMed  Google Scholar 

  46. Rak J, Milsom C, May L, Klement P, Yu J (2006) Tissue factor in cancer and angiogenesis: the molecular link between genetic tumor progression, tumor neovascularization, and cancer coagulopathy. Semin Thromb Hemost 32:54–70

    Article  PubMed  CAS  Google Scholar 

  47. Chi JT, Chang HY, Haraldsen G, Jahnsen FL, Troyanskaya OG, Chang DS, Wang Z, Rockson SG, van de Rijn M, Botstein D, Brown PO (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 100:10623–10628

    Article  PubMed  CAS  Google Scholar 

  48. Brooks EG, Trotman W, Wadsworth MP, Taatjes DJ, Evans MF, Ittleman FP, Callas PW, Esmon CT, Bovill EG (2009) Valves of the deep venous system: an overlooked risk factor. Blood 114:1276–1279

    Article  PubMed  CAS  Google Scholar 

  49. Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD (2012) Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 109:13076–13081

    Article  PubMed  CAS  Google Scholar 

  50. Wolberg AS, Aleman MM, Leiderman K, Machlus KR (2012) Procoagulant activity in hemostasis and thrombosis: Virchow’s triad revisited. Anesth Analg 114:275–285

    Article  PubMed  CAS  Google Scholar 

  51. Buller HR, Prins MH (2003) Secondary prophylaxis with warfarin for venous thromboembolism. N Engl J Med 349:702–704

    Article  PubMed  Google Scholar 

  52. Kennedy B, Gargoum FS, Kennedy L, Khan F, Curran DR, O’Connor TM (2012) Emerging anticoagulants. Curr Med Chem 19:3388–3416

    Article  PubMed  CAS  Google Scholar 

  53. Mantha S, Ansell J (2012) An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost 108:476–484

    Article  PubMed  CAS  Google Scholar 

  54. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ (2012) Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 110:453–460

    Article  PubMed  CAS  Google Scholar 

  55. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368:699–708

    Google Scholar 

  56. Warkentin TE (2012) Aspirin for dual prevention of venous and arterial thrombosis. N Engl J Med 367:2039–2041

    Article  PubMed  CAS  Google Scholar 

  57. Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J (2012) Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 367:1979–1987

    Article  PubMed  CAS  Google Scholar 

  58. Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, Prins MH, Qari MH, Streiff MB, Syrigos K, Bounameaux H, Buller HR (2012) International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost

  59. Debourdeau P, Farge D, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, Prins MH, Qari MH, Streiff MB, Syrigos K, Buller HR, Bounameaux H (2013) International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost 11:71–80

    Google Scholar 

Download references

Acknowledgments

This study was supported in part by the ‘Associazione Italiana per la Ricerca sul Cancro’ (AIRC), the Italian Ministry of University and Scientific and Technologic Research and the Finalized Project of the Apulia Region “Biotecnoter.”

Conflict of interest

The authors have no conflicts of interests to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Franco Dammacco.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dammacco, F., Vacca, A., Procaccio, P. et al. Cancer-related coagulopathy (Trousseau’s syndrome): review of the literature and experience of a single center of internal medicine. Clin Exp Med 13, 85–97 (2013). https://doi.org/10.1007/s10238-013-0230-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-013-0230-0

Keywords

Navigation