Semin Thromb Hemost 2021; 47(08): 931-941
DOI: 10.1055/s-0040-1722607
Review Article

Cancer-Associated Splanchnic Vein Thrombosis

Omri Cohen
1   National Hemophilia Center, Institute of Thrombosis and Hemostasis and the Amalia Biron Research Institute, Sheba Medical Center, Tel-HaShomer, Israel
2   Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
3   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Lucia Maria Caiano
3   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Antonella Tufano
4   Regional Reference Centre for Coagulation Disorders, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
,
Walter Ageno
3   Department of Medicine and Surgery, University of Insubria, Varese, Italy
› Author Affiliations

Abstract

Splanchnic vein thrombosis (SVT), which includes portal, mesenteric, and splenic vein thrombosis and the Budd–Chiari syndrome, is an infrequent manifestation of venous thromboembolism (VTE). Like typical site VTE, SVT is also frequently associated with cancer, particularly intra-abdominal solid malignancies and myeloproliferative neoplasms (MPNs). The clinical presentation of SVT is nonspecific. Symptoms may be related to the underlying malignancy, and thrombosis is incidentally diagnosed by imaging studies for cancer staging or follow-up in a substantial proportion of cases. The occurrence of SVT predicts worse prognosis in patients with liver or pancreatic cancer and, not uncommonly, SVT may precede the diagnosis of cancer. Therefore, the occurrence of an apparently unprovoked SVT should prompt careful patient evaluation for the presence of an underlying malignancy or MPN. Cancer patients carry a high risk of VTE extension and recurrence and long-term anticoagulant treatment is suggested in the absence of high risk of bleeding. Either LMWH or direct oral anticoagulants (DOACs) are suggested for the treatment of patients with cancer-related SVT, although limited experience is available on the use of DOACs in these settings. Vitamin K antagonists (VKAs) are suggested for the short and long-term treatment of SVT associated with MPN. This review outlines the epidemiological aspects, pathogenesis, risk factors, and diagnosis of cancer-associated SVT, and addresses questions regarding the management of this challenging condition.



Publication History

Article published online:
11 June 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Eichinger S. Cancer associated thrombosis: risk factors and outcomes. Thromb Res 2016; 140 (Suppl. 01) S12-S17
  • 2 Abdol Razak NB, Jones G, Bhandari M, Berndt MC, Metharom P. Cancer-associated thrombosis: an overview of mechanisms, risk factors, and treatment. Cancers (Basel) 2018; 10 (10) 380
  • 3 Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 3-14
  • 4 Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985-2009). Am J Med 2014; 127 (09) 829-39.e5
  • 5 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) advisory panel. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
  • 6 Riva N, Ageno W. Clinical manifestations and imaging tools in the diagnosis of splanchnic and cerebral vein thromboses. Thromb Res 2018; 163: 252-259
  • 7 Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood 2014; 124 (25) 3685-3691
  • 8 Ageno W, Riva N, Schulman S. et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med 2015; 175 (09) 1474-1480
  • 9 Riva N, Ageno W, Schulman S. et al; International Registry on Splanchnic Vein Thrombosis (IRSVT) study group. Clinical history and antithrombotic treatment of incidentally detected splanchnic vein thrombosis: a multicentre, international prospective registry. Lancet Haematol 2016; 3 (06) e267-e275
  • 10 Thatipelli MR, McBane RD, Hodge DO, Wysokinski WE. Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol 2010; 8 (02) 200-205
  • 11 Robin P, Carrier M. Revisiting occult cancer screening in patients with unprovoked venous thromboembolism. Thromb Res 2018; 164 (Suppl. 01) S7-S11
  • 12 Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost 2011; 9 (Suppl. 01) 316-324
  • 13 Derman BA, Kwaan HC. Risk factors, diagnosis, management, and outcome of splanchnic vein thrombosis: a retrospective analysis. Semin Thromb Hemost 2015; 41 (05) 503-513
  • 14 Søgaard KK, Farkas DK, Pedersen L, Sørensen HT. Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival. Blood 2015; 126 (08) 957-963
  • 15 Falanga A, Marchetti M, Russo L. The mechanisms of cancer-associated thrombosis. Thromb Res 2015; 135 (Suppl. 01) S8-S11
  • 16 Gerotziafas GT, Galea V, Mbemba E. et al. Tissue factor over-expression by human pancreatic cancer cells BXPC3 is related to higher prothrombotic potential as compared to breast cancer cells MCF7. Thromb Res 2012; 129 (06) 779-786
  • 17 Rak J, Milsom C, Magnus N, Yu J. Tissue factor in tumour progression. Best Pract Res Clin Haematol 2009; 22 (01) 71-83
  • 18 Ruiz-Tovar J, Priego P. Portal vein thrombosis after splenic and pancreatic surgery. Adv Exp Med Biol 2017; 906: 241-251
  • 19 Janssen HL, Meinardi JR, Vleggaar FP. et al. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood 2000; 96 (07) 2364-2368
  • 20 Mutreja D, Kotru M, Sazawal S. et al. Hereditary and acquired thrombophilia in splanchnic vein thrombosis: a single-center experience. Clin Appl Thromb Hemost 2015; 21 (06) 521-526
  • 21 Zarrouk M, Salim S, Elf J, Gottsäter A, Acosta S. Testing for thrombophilia in mesenteric venous thrombosis - retrospective original study and systematic review. Best Pract Res Clin Gastroenterol 2017; 31 (01) 39-48
  • 22 Fitzmaurice C, Abate D, Abbasi N. et al; Global Burden of Disease Cancer Collaboration. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol 2019; 5 (12) 1749-1768
  • 23 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
  • 24 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69 (01) 7-34
  • 25 Arber DA, Orazi A, Hasserjian R. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20) 2391-2405
  • 26 Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017; 129 (06) 680-692
  • 27 Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013; 122 (13) 2176-2184
  • 28 Arachchillage DR, Laffan M. Pathogenesis and management of thrombotic disease in myeloproliferative neoplasms. Semin Thromb Hemost 2019; 45 (06) 604-611
  • 29 De Stefano V, Finazzi G, Barbui T. Antithrombotic therapy for venous thromboembolism in myeloproliferative neoplasms. Blood Cancer J 2018; 8 (07) 65
  • 30 Kiladjian JJ, Cervantes F, Leebeek FW. et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008; 111 (10) 4922-4929
  • 31 Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013; 162 (06) 730-747
  • 32 De Stefano V, Qi X, Betti S, Rossi E. Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment. Thromb Haemost 2016; 115 (02) 240-249
  • 33 Sant'Antonio E, Guglielmelli P, Pieri L. et al. Splanchnic vein thromboses associated with myeloproliferative neoplasms: an international, retrospective study on 518 cases. Am J Hematol 2020; 95 (02) 156-166
  • 34 Naymagon L, Tremblay D, Zubizarreta N, Moshier E, Schiano T, Mascarenhas J. Portal vein thrombosis patients harboring JAK2V617F have poor long-term outcomes despite anticoagulation. J Thromb Thrombolysis 2020; 50 (03) 652-660
  • 35 Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 2006; 91 (02) 169-175
  • 36 Robertson B, Urquhart C, Ford I. et al. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J Thromb Haemost 2007; 5 (08) 1679-1685
  • 37 Bertozzi I, Bogoni G, Biagetti G. et al. Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. Ann Hematol 2017; 96 (08) 1297-1302
  • 38 Kekre N, Connors JM. Venous thromboembolism incidence in hematologic malignancies. Blood Rev 2019; 33: 24-32
  • 39 Colombo R, Gallipoli P, Castelli R. Thrombosis and hemostatic abnormalities in hematological malignancies. Clin Lymphoma Myeloma Leuk 2014; 14 (06) 441-450
  • 40 Elice F, Rodeghiero F. Hematologic malignancies and thrombosis. Thromb Res 2012; 129 (03) 360-366
  • 41 Rashidi A, Silverberg ML, Conkling PR, Fisher SI. Thrombosis in acute promyelocytic leukemia. Thromb Res 2013; 131 (04) 281-289
  • 42 Castaman G, Rodeghiero F, Dini E. Thrombotic complications during L-asparaginase treatment for acute lymphocytic leukemia. Haematologica 1990; 75 (06) 567-569
  • 43 Truelove E, Fielding AK, Hunt BJ. The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia 2013; 27 (03) 553-559
  • 44 Carrier M, Le Gal G, Tay J, Wu C, Lee AY. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 2011; 9 (04) 653-663
  • 45 Ageno W, Riva N, Schulman S. et al; IRSVT study group. Antithrombotic treatment of splanchnic vein thrombosis: results of an international registry. Semin Thromb Hemost 2014; 40 (01) 99-105
  • 46 Colović M, Miljić P, Colović N, Janković G, Stojković M. Reversible portal vein thrombosis complicating induction therapy of acute promyelocytic leukemia. Thromb Res 2001; 101 (02) 101-103
  • 47 Bandyopadhyay S, Bandyopadhyay D. Acute Budd-Chiari syndrome as an initial presentation of acute promyelocytic leukemia. J Cancer Res Ther 2010; 6 (04) 567-569
  • 48 Choudhry A, DeLoughery TG. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol 2012; 87 (06) 596-603
  • 49 Acosta S, Alhadad A, Svensson P, Ekberg O. Epidemiology, risk and prognostic factors in mesenteric venous thrombosis. Br J Surg 2008; 95 (10) 1245-1251
  • 50 De Stefano V, Martinelli I. Splanchnic vein thrombosis: clinical presentation, risk factors and treatment. Intern Emerg Med 2010; 5 (06) 487-494
  • 51 Darwish Murad S, Plessier A, Hernandez-Guerra M. et al; EN-Vie (European Network for Vascular Disorders of the Liver). Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Intern Med 2009; 151 (03) 167-175
  • 52 Rajani R, Melin T, Björnsson E. et al. Budd-Chiari syndrome in Sweden: epidemiology, clinical characteristics and survival - an 18-year experience. Liver Int 2009; 29 (02) 253-259
  • 53 Tufano A, Ageno W, Di Micco P. et al; RIETE Investigators. Outcomes during anticoagulation in patients with symptomatic vs. incidental splanchnic vein thrombosis. Thromb Res 2018; 164: 69-74
  • 54 Kumar A, Sharma P, Arora A. Review article: portal vein obstruction--epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther 2015; 41 (03) 276-292
  • 55 Rajesh S, Mukund A, Arora A. Imaging diagnosis of splanchnic venous thrombosis. Gastroenterol Res Pract 2015; 2015: 101029
  • 56 Rossi S, Rosa L, Ravetta V. et al. Contrast-enhanced versus conventional and color Doppler sonography for the detection of thrombosis of the portal and hepatic venous systems. AJR Am J Roentgenol 2006; 186 (03) 763-773
  • 57 Bradbury MS, Kavanagh PV, Chen MY, Weber TM, Bechtold RE. Noninvasive assessment of portomesenteric venous thrombosis: current concepts and imaging strategies. J Comput Assist Tomogr 2002; 26 (03) 392-404
  • 58 Harnik IG, Brandt LJ. Mesenteric venous thrombosis. Vasc Med 2010; 15 (05) 407-418
  • 59 Acosta S, Alhadad A, Ekberg O. Findings in multi-detector row CT with portal phase enhancement in patients with mesenteric venous thrombosis. Emerg Radiol 2009; 16 (06) 477-482
  • 60 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e419S-e496S
  • 61 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 (05) 496-520
  • 62 Senzolo M, Riva N, Dentali F. et al; IRSVT study investigators. Long-term outcome of splanchnic vein thrombosis in cirrhosis. Clin Transl Gastroenterol 2018; 9 (08) 176
  • 63 Amitrano L, Guardascione MA, Menchise A. et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010; 44 (06) 448-451
  • 64 Condat B, Pessione F, Hillaire S. et al. Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology 2001; 120 (02) 490-497
  • 65 Amitrano L, Guardascione MA, Scaglione M. et al. Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 2007; 102 (11) 2464-2470
  • 66 Plessier A, Darwish-Murad S, Hernandez-Guerra M. et al; European Network for Vascular Disorders of the Liver (EN-Vie). Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study. Hepatology 2010; 51 (01) 210-218
  • 67 Spaander MC, Hoekstra J, Hansen BE, Van Buuren HR, Leebeek FW, Janssen HL. Anticoagulant therapy in patients with non-cirrhotic portal vein thrombosis: effect on new thrombotic events and gastrointestinal bleeding. J Thromb Haemost 2013; 11 (03) 452-459
  • 68 Dentali F, Ageno W, Witt D. et al; WARPED consortium. Natural history of mesenteric venous thrombosis in patients treated with vitamin K antagonists: a multi-centre, retrospective cohort study. Thromb Haemost 2009; 102 (03) 501-504
  • 69 Di Nisio M, Valeriani E, Riva N, Schulman S, Beyer-Westendorf J, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J Thromb Haemost 2020; 18 (07) 1562-1568
  • 70 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
  • 71 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
  • 72 Young AM, Marshall A, Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
  • 73 Khorana AA, Noble S, Lee AYY. et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1891-1894
  • 74 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
  • 75 Janczak DT, Mimier MK, McBane RD. et al. Rivaroxaban and apixaban for initial treatment of acute venous thromboembolism of atypical location. Mayo Clin Proc 2018; 93 (01) 40-47
  • 76 Nagaoki Y, Aikata H, Daijyo K. et al. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res 2018; 48 (01) 51-58
  • 77 De Stefano V, Za T, Rossi E. et al; GIMEMA CMD-Working Party. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93 (03) 372-380
  • 78 Hernández-Boluda JC, Arellano-Rodrigo E, Cervantes F. et al; Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN). Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia. Ann Hematol 2015; 94 (06) 911-918
  • 79 De Stefano V, Ruggeri M, Cervantes F. et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia 2016; 30 (10) 2032-2038
  • 80 Finazzi G, De Stefano V, Barbui T. Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018. Blood Cancer J 2018; 8 (07) 64
  • 81 Kaifie A, Kirschner M, Wolf D. et al; Study Alliance Leukemia (SAL). Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry. J Hematol Oncol 2016; 9: 18
  • 82 Martin K. Risk factors for and management of MPN-associated bleeding and thrombosis. Curr Hematol Malig Rep 2017; 12 (05) 389-396
  • 83 Barbui T, De Stefano V, Falanga A. et al. Addressing and proposing solutions for unmet clinical needs in the management of myeloproliferative neoplasm-associated thrombosis: a consensus-based position paper. Blood Cancer J 2019; 9 (08) 61
  • 84 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol 2019; 94 (01) 133-143
  • 85 Samuelson Bannow BR, Lee AYY, Khorana AA. et al. Management of anticoagulation for cancer-associated thrombosis in patients with thrombocytopenia: a systematic review. Res Pract Thromb Haemost 2018; 2 (04) 664-669
  • 86 Samuelson Bannow BT, Lee A, Khorana AA. et al. Management of cancer-associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (06) 1246-1249
  • 87 Szuber N, Vallapureddy RR, Penna D. et al. Myeloproliferative neoplasms in the young: Mayo Clinic experience with 361 patients age 40 years or younger. Am J Hematol 2018; 93 (12) 1474-1484