Pathophysiology of Trousseau’s syndrome

Summary

Clinically relevant clotting abnormalities in cancer patients are referred to as Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in every day’s practice, cancer patients may also experience severe bleeding symptoms due to complex systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The pathophysiology of Trousseau’s syndrome involves all aspects of Virchow’s triad, but previous basic research has mainly focused on the cellular and molecular mechanisms underlying blood hypercoagulability in solid cancers and haematological malignancies. In this regard, over-expression of tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, by primary tumour cells and increased shedding of TF-bearing plasma microparticles are critical to both thrombus formation and cancer progression. However, novel findings on intrinsic contact activation in vivo, such as the release of polyphosphates or DNA by activated platelets and neutrophils, respectively, have pointed to additional pathways in the complex pathophysiology of Trousseau’s syndrome.

Zusammenfassung

Klinisch relevante Gerinnungsstörungen bei Tumorpatienten werden unter dem Begriff Trousseau-Syndrom zusammengefasst. Während im Alltag thrombotische Komplikationen wie die venöse Thromboembolie im Vordergrund stehen, können als Folge komplexer Koagulopathien (z.B. DIC, hämolytische thrombotische Mikroangiopathie oder Hyperfibrinolyse) auch schwerste Blutungen auftreten. Die Pathophysiologie des TrousseauSyndroms betrifft zwar sämtliche Aspekte der Virchow-Trias; die Grundlagenforschung hat sich aber vor allem mit der Hyperkoagulabilität des Blutes bei soliden und hämatologischen Malignomen beschäftigt. Diesbezüglich sind die Expression von Tissue-Faktor (TF), dem Initiator der extrinsischen Gerinnungskaskade, durch die Tumorzellen und die Freisetzung von TF-positiven Mikropartikeln sowohl für die Thrombusentstehung als auch für die Tumorprogression von zentraler Bedeutung. Neue Erkenntnisse über die molekularen Grundlagen der Kontaktaktivierung in vivo (z. B. Freisetzung von Polyphosphaten oder DNA aus aktivierten Plättchen und neutrophilen Granulozyten) deuten auf weitere Mechanismen in der komplexen Pathophysiologie des Trousseau-Syndroms hin.

Keywords

Cancer - thrombosis - tissue factor - factor VII - microparticles

SchlüsselWörter

Tumor - Thrombose - Tissue-Faktor - Faktor VII - Mikropartikel

• References

• 1 Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l’Hotel-Dieu de Paris 1865; 03: 654-712.
• 2 Sack Jr GH, 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: 1-37.
• 3 Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723-1729.
• 4 Dammacco F, Vacca A, Procaccio P. et al. Cancerrelated coagulopathy (Trousseau’s syndrome): review of the literature and experience of a single center of internal medicine. Clin Exp Med 2013; 13: 85-97.
• 5 Lechner D, Kollars M, Gleiss A. et al. Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity. J Thromb Haemost 2007; 05: 2445-2452.
• 6 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: 3466-3473.
• 7 Seng S, Liu Z, Chiu SK. et al. Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis. J Clin Oncol 2012; 30: 4416-4426.
• 8 Honecker F, Koychev D, Luhmann AD. et al. Venous thromboembolic events in germ cell cancer patients undergoing platinum-based chemotherapy. Onkologie 2013; 36: 663-668.
• 9 Langer F, Bokemeyer C. Crosstalk between cancer and haemostasis. Implications for cancer biology and cancer-associated thrombosis with focus on tissue factor. Hämostaseologie 2012; 32: 95-104.
• 10 Chaturvedi S, Sidana S, Elson P, Khorana AA, McCrae KR. Symptomatic and incidental venous thromboembolic disease are both associated with mortality in patients with prostate cancer. PLoS One 2014; 09: e94048.
• 11 Hyman DM, Soff GA, Kampel LJ. Disseminated intravascular coagulation with excessive fibrinolysis in prostate cancer: a case series and review of the literature. Oncology 2011; 81: 119-125.
• 12 Langer F, Spath B, Haubold K. et al. Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation. Ann Hematol 2008; 87: 451-457.
• 13 Lechner D, Weltermann A. Pathophysiology of chemotherapy-associated thrombosis. Hämostaseologie 2009; 29: 112-120.
• 14 Petersen I. The morphological and molecular diagnosis of lung cancer. Dtsch Arztebl Int 2011; 108: 525-531.
• 15 Rak J, Yu JL, Luyendyk J, Mackman N. Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans. Cancer Res 2006; 66: 10643-10646.
• 16 Svendsen E, Karwinski B. Prevalence of pulmonary embolism at necropsy in patients with cancer. J Clin Pathol 1989; 42: 805-809.
• 17 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: 648-655.
• 18 Thaler J, Preusser M, Ay C. et al. Intratumoral tissue factor expression and risk of venous thromboembolism in brain tumor patients. Thromb Res 2013; 131: 162-165.
• 19 Thaler J, Ay C, Mackman N. et al. Microparticle-associated tissue factor activity in patients with pancreatic cancer: correlation with clinicopathological features. Eur J Clin Invest 2013; 43: 277-285.
• 20 Goldin-Lang P, Tran QV, Fichtner I. et al. Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis. Oncol Rep 2008; 20: 123-128.
• 21 Khorana AA, Ahrendt SA, Ryan CK. et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res 2007; 13: 2870-2875.
• 22 Lo L, Valentine H, Harrison J. et al. Tissue factor expression in the metaplasia-adenoma-carcinoma sequence of gastric cancer in a European population. Br J Cancer 2012; 107: 1125-1130.
• 23 Uno K, Homma S, Satoh T. et al. Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer. Br J Cancer 2007; 96: 290-295.
• 24 Borsig L, Wong R, Feramisco J. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA 2001; 98: 3352-3357.
• 25 Wahrenbrock M, Borsig L, Wahrenbrock M, Le D. et al. Selectinmucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003; 112: 853-862.
• 26 Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013; 122: 1873-1880.
• 27 Hernández C, Orbe J, Roncal C. et al. Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients. Thromb Haemost 2013; 110: 598-608.
• 28 Thaler J, Ay C, Mackman N. et al. Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients. J Thromb Haemost 2012; 10: 1363-1370.
• 29 Bharthuar A, Khorana AA, Hutson A. et al. Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res 2013; 132: 180-184.
• 30 Thomas GM, Panicot-Dubois L, Lacroix R. et al. Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo. J Exp Med 2009; 206: 1913-1927.
• 31 Wang JG, Geddings JE, Aleman MM. et al. Tumorderived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. Blood 2012; 119: 5543-5552.
• 32 Davila M, Robles-Carrillo L, Unruh D. et al. Microparticle association and heterogeneity of tumor-derived tissue factor in plasma: is it important for coagulation activation?. J Thromb Haemost 2014; 12: 186-196.
• 33 Bogdanov VY, Balasubramanian V, Hathcock J. et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003; 09: 458-462.
• 34 van den Berg YW, Versteeg HH. Alternatively spliced tissue factor. A crippled protein in coagulation or a key player in non-haemostatic processes? Hamostaseologie 2010; 30: 144-149.
• 35 Kocatürk B, Versteeg HH. Tissue factor isoforms in cancer and coagulation: may the best isoform win. Thromb Res 2012; 129: S69-S75.
• 36 Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro Oncol 2012; 14: iv73-80.
• 37 Thaler J, Ay C, Kaider A. et al. Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas. Neuro Oncol 2014; 16: 1645-1651.
• 38 Sartori MT, Della APuppa, Ballin A. et al. Prothrombotic state in glioblastoma multiforme: an evaluation of the procoagulant activity of circulating microparticles. J Neurooncol 2011; 104: 225-231.
• 39 Sartori MT, Della APuppa, 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: 378-385.
• 40 Müller C, Holtschmidt J, Auer M. et al. Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med 2014; 06: 247ra101.
• 41 Chen H, Shah AS, Girgis RE, Grossman SA. Transmission of glioblastoma multiforme after bilateral lung transplantation. J Clin Oncol 2008; 26: 3284-3285.
• 42 Fatt MA, Horton KM, Fishman EK. Transmission of metastatic glioblastoma multiforme from donor to lung transplant recipient. J Comput Assist Tomogr 2008; 32: 407-409.
• 43 Zhao P, Strohl A, Gonzalez C. et al. Donor transmission of pineoblastoma in a two-yr-old male recipient of a multivisceral transplant: a case report. Pediatr Transplant 2012; 16: E110-E114.
• 44 Tanaka M, Yamanishi H. The expression of tissue factor antigen and activity on the surface of leukemic cells. Leuk Res 1993; 17: 103-111.
• 45 Nadir Y, Katz T, Sarig G. et al. Hemostatic balance on the surface of leukemic cells: the role of tissue factor and urokinase plasminogen activator receptor. Haematologica 2005; 90: 1549-1556.
• 46 De Stefano V, Teofili L, Sica S. et al. Effect of alltrans retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia. Blood 1995; 86: 3535-3541.
• 47 Falanga A, Iacoviello L, Evangelista V. et al. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid. Blood 1995; 86: 1072-1081.
• 48 Spath B, Amirkhosravi A, Davila M. et al. Role of protein disulfide isomerase (PDI) in the expression of tissue factor (TF) procoagulant activity on apoptotic myeloblasts. Blood 2010; 116: A152.
• 49 Gheldof D, Mullier F, Bailly N. et al. Microparticle bearing tissue factor: a link between promyelocytic cells and hypercoagulable state. Thromb Res 2014; 133: 433-439.
• 50 Thaler J, Pabinger I, Sperr WR, Ay C. Clinical evidence for a link between microparticle-associated tissue factor activity and overt disseminated intravascular coagulation in patients with acute myelocytic leukemia. Thromb Res 2014; 133: 303-305.
• 51 Kwaan HC, Cull EH. The coagulopathy in acute promyelocytic leukaemia – what have we learned in the past twenty years. Best Pract Res Clin Haematol 2014; 27: 11-18.
• 52 Basavaraj MG, Olsen JO, Österud B, Hansen JB. Differential ability of tissue factor antibody clones on detection of tissue factor in blood cells and microparticles. Thromb Res 2012; 130: 538-546.
• 53 Cesarman-Maus G, Braggio E, Maldonado H, Fonseca R. Absence of tissue factor expression by neoplastic plasma cells in multiple myeloma. Leukemia 2012; 26: 1671-1674.
• 54 Colombo R, Gallipoli P, Castelli R. Thrombosis and hemostatic abnormalities in hematological malignancies. Clin Lymphoma Myeloma Leuk. 2014 doi: 10.1016/j.clml.2014.05.003.
• 55 Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2012; 2012: 571-581.
• 56 Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC. et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 2006; 91: 169-175.
• 57 Panova-Noeva M, Marchetti M, Buoro S. et al. JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients. Blood 2011; 118: 2599-2601.
• 58 Rumi E, Pietra D, Ferretti V. et al. Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2014; 123: 1544-1551.
• 59 Falanga A, Marchetti M, Vignoli A. et al. V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. Exp Hematol. 2007 35. 702-711 Erratum in: Exp Hematol 2007; 35: 1476.
• 60 Trappenburg MC, van Schilfgaarde M, Marchetti M. et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 2009; 94: 911-918.
• 61 Marchetti M, Tartari CJ, Russo L. et al. Phospholipid-dependent procoagulant activity is highly expressed by circulating microparticles in patients with essential thrombocythemia. Am J Hematol 2014; 89: 68-73.
• 62 Kreher S, Ochsenreither S, Trappe RU. et al. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). Ann Hematol 2014; 93: 1953-1963.
• 63 Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012; 122: 2331-2336.
• 64 Demers M, Krause DS, Schatzberg D. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 2012; 109: 13076-13081.
• 65 Demers M, Wagner DD. NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost 2014; 40: 277-283.
• 66 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123: 2768-2776.
• 67 Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777-1783.
• 68 Fuchs TA, Kremer JAHovinga, Schatzberg D. et al. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120: 1157-1164.
• 69 Khorana AA. Risk assessment for cancer-associated thrombosis: what is the best approach?. Thromb Res 2012; 129: S10-S15.
• 70 Van Montfoort ML, Stephan F, Lauw MN. et al. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. Arterioscler Thromb Vasc Biol 2013; 33: 147-151.
• 71 Piccioli A, Lensing AW, Prins MH. et al. SOMIT Investigators Group. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004; 02: 884-889.
• 72 Van Doormaal FF, Terpstra W, Van Der Griend R. et al. Is extensive screening for cancer in idiopathic venous thromboembolism warranted?. J Thromb Haemost 2011; 09: 79-84.
• 73 Rosovsky R, Lee AY. Evidence-based mini-review: should all patients with idiopathic venous thromboembolic events be screened extensively for occult malignancy?. Hematology Am Soc Hematol Educ Program 2010; 2010: 150-152.
• 74 Trujillo-Santos J, Prandoni P, Rivron-Guillot K. et al. RIETE Investigators. Clinical outcome in patients with venous thromboembolism and hidden cancer: findings from the RIETE Registry. J Thromb Haemost 2008; 06: 251-255.
• 75 Claussen C, Rausch AV, Spath B. et al. Clinical significance of hemostatic activation markers in women with suspected ovarian cancer. Oncol Res Treat 2014; 37: V669.