Abstract
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau’s syndrome (i.e., cancer-associated thrombosis).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Falanga A, Marchetti M, Vignoli A (2013) Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 11:223–233
Lee AYY, Levine MN (2003) Venous thromboembolism and cancer: risks and outcomes. Circulation 107(Suppl 23)
Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC (2013) Epidemiology of venous thrombosis. Blood 122(10):1712–1723
Blom JW, Vanderschoot JPM, Oostindiër MJ, Osanto S, van der Meer FJM, Rosendaal FR (2006) Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 4(3):529–535
Blom J, Doggen C, Osanto S, Rosendaal F (2005) Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 9(293):715–722
Falanga A, Russo L (2012) Epidemiology, risk and outcomes of venous thromboembolism in cancer. Hamostaseologie 32:115–125
Falanga A, Russo L, Milesi V (2014) The coagulopathy of cancer. Curr Opin Hematol 21:423–429
Magnus N, D’Asti E, Meehan B, Garnier D, Rak J (2014) Oncogenes and the coagulation system—forces that modulate dormant and aggressive states in cancer. Thromb Res 133(Suppl 2):S1–S9
Khorana AA, McCrae KR (2014) Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res 133(Suppl 2):35–38
Falanga A, Marchetti M, Russo L (2015) The mechanisms of cancer-associated thrombosis. Thromb Res 135:S8–S11
Khorana AA, Francis CW, Culakova E, Lyman GH (2005) Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 104(12):2822–2829
Simanek R, Vormittag R, Ay C, Alguel G, Dunkler D, Schwarzinger I et al (2010) High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 8(1):114–120
Demers M, Wagner DD (2003) Neutrophil extracellular traps: a new link to cancer-associated thrombosis and potential implications for tumor progression. Oncoimmunology 2(2)
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW (2008) Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111(10):4902–4907
Ay C, Dunkler D, Marosi C, Chiriac A-L, Vormittag R, Simanek R et al (2010) Prediction of venous thromboembolism in cancer patients. Blood 116(24):5377–5382
Moore RA, Adel N, Riedel E, Bhutani M, Feldman DR, Tabbara NE et al (2011) High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: A large retrospective analysis. J Clin Oncol 29(25):3466–3473
Menter DG, Tucker SC, Kopetz S, Sood AK, Crissman JD, Honn KV (2014) Platelets and cancer: a casual or causal relationship: Revisited. Cancer Metastasis Rev 33(1):231–269
Gran OV, Braekkan SK, Hansen JB (2018) Prothrombotic genotypes and risk of venous thromboembolism in cancer. Thromb Res
Rosendaal F (1999) Venous thrombosis: a multicausal disease. Lancet 353(9159):1167–1173
Decousus H, Moulin N, Quenet S, Bost V, Rivron-Guillot K, Laporte S et al (2007) Thrombophilia and risk of venous thrombosis in patients with cancer. Thromb Res 120(Suppl 2):51–61
Pabinger I, Ay C, Dunkler D, Thaler J, Reitter EM, Marosi C et al (2015) Factor V Leiden mutation increases the risk for venous thromboembolism in cancer patients—results from the Vienna Cancer And Thrombosis Study (CATS). J Thromb Haemost 13(1):17–22
Gran OV, Smith EN, Brækkan SK, Jensvoll H, Solomon T, Hindberg K et al (2016) Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism. Haematologica 101(9):1046–1053
Dentali F, Gianni M, Agnelli G, Ageno W (2007) Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: results of the CAVECCAS study. J Thromb Haemost 6:70–75
Jick H, Slone D, Westerholm B, Inman W, Vessey M, Shapiro S et al (1969) Venous thromboembolic disease and ABO blood type. A cooperative study. Lancet 15(1):539–542
Sode BF, Allin KH, Dahl M, Gyntelberg F, Nordestgaard BG (2013) Risk of venous thromboembolism and myocardial infarction associated with factor V Leiden and prothrombin mutations and blood type. CMAJ 185(5):E229–E237
Wun T, White RH (2009) Epidemiology of cancer-related venous thromboembolism. Best Pr Res Clin Haematol 22(1):9–23
Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH (2007) Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 110(10):2339–2346
Falanga A, Marchetti M (2012) Anticancer treatment and thrombosis. Thromb Res 129(3):353–359
Lechner D, Weltermann A (2008) Chemotherapy-induced thrombosis: a role for microparticles and tissue factor? Semin Thromb Hemost 34(2):199–203
Kakkar A, Lemoine N, Scully M, Tebbutt S, Williamson R (1995) Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg 82(8):1101–1104
Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y (1996) Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 77:1877–1883
Takano S, Tsuboi K, Tomono Y, Mitsui Y, Nose T (2000) Tissue factor, osteopontin, alphavbeta3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression. Br J Cancer 82(12):1967–1973
Guan M, Jin J, Su B, Liu W, Lu Y (2002) Tissue factor expression and angiogenesis in human glioma. Clin Biochem 35(4):321–325
Ishimaru K, Hirano H, Yamahata H, Takeshima H, Niiro M, Kuratsu J (2003) The expression of tissue factor correlates with proliferative ability in meningioma. Oncol Rep 10:1133–1137
Fernandes RS, Kirszbeg C, Rumjanek M, Monteiro RQ (2006) On the molecular mechanisms for the highly procoagulant pattern of C6 glioma cells. J Thromb Haemost 4:1546–1552
Yu JL, May L, Lhotak V, Shahrzad S, Shirasawa S, Weitz JI et al (2005) Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 105(4):1734–1742
Davila M, Amirkhosravi A, Coll E, Desai H, Robles L, Colon J et al (2008) Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost 6:1517–1524
Magnus N, Garnier D, Meehan B, Mcgraw S, Hoon T, Caron M (2014) Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. PNAS 111(9):3544–3549
Falanga A, Russo L, Milesi V, Vignoli A (2017) Mechanisms and risk factors of thrombosis in cancer. Crit Rev Oncol Hematol 118:79–83
Falanga A, Consonni R, Marchetti M, Locatelli G, Garattini E, Gambacorti Passerini C et al (1998) Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood 92(1):143–151
Falanga A, Iacoviello L, Evangelista V, Belotti D, Consonni R, D’Orazio A et al (1995) Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid. Blood 86(3):1072–1081
Falanga A, Toma S, Marchetti M, Palumbo R, Raffo P, Consonni R et al (2002) Effect of all-trans-retinoic acid on the hypercoagulable state of patients with breast cancer. Am J Hematol 70:9–15
Nadir Y, Brenner B (2014) Heparanase multiple effects in cancer. Thromb Res. Elsevier Masson SAS 133:S90–S94
Xu X, Quiros RM, Maxhimer JB, Jiang P, Marcinek R, Ain KB et al (2003) Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: a potential role in tumor metastasis. Clin Cancer Res 9:5968–5979
El-assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N (2001) The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res 7(May):1299–1305
Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I (1988) A heparin-binding angiogenic protein-basic fibroblast growth factor is stored within basement membrane. Am J Pathol 130(2):393–400
Vlodavsky I, Folkmantt J, Sullivant R, Fridman R, Ishai-michaeli R, Sasset J et al (1987) Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Nati Acad Sci USA 84(April):2292–2296
Friedmann Y, Vlodavsky I, Aingorn H, Aviv A, Peretz T, Pecker I, et al (2000) Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma. evidence for its role in colonic tumorigenesis. Am J Pathol 157(4):1167–1175
Elkin M, Ilan N, Ishai-Michaeli R, Friedmann Y, Papo O, Pecker I et al (2001) Heparanase as mediator of angiogenesis: mode of action. FASEB J 15(9):1661–1663
Nadir Y, Brenner B (2016) Heparanase procoagulant activity in cancer progression. Thromb Res 140:S44–S48
Ahn YS (2005) Cell-derived microparticles: “Miniature envoys with many faces”. J Thromb Haemost 3:884–887
Horstman LL, Jy W, Jimenez JJ, Bidot C, Ahn YS (2004) New horizons in the analysis of circulating cell-derived microparticles. Keio J Med 53(4):210–230
Nomura S, Suzuki M, Katsura K, Xie GL, Miyazaki Y, Miyake T et al (1995) Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 116:235–240
Mallat Z, Benamer H (2000) Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood. Circulation 101:841–843
Nieuwland R, Berckmans J, Mcgregor S, Bo AN, Romijn FPHTM, Westendorp RGJ, et al (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95(3):930–936
Chirinos JA, Heresi GA, Velasquez H, Jy W, Jimenez JJ, Ahn E, et al (2005) Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol. Elsevier Masson SAS 45(9):1467–1471
Piccioli A, Falanga A, Baccaglini U, Marchetti M, Prandoni P (2006) Cancer and venous thromboembolism. Semin Thromb Hemost 32(7):694–699
Falanga A, Marchetti M (2009) Venous thromboembolism in the hematologic malignancies. J Clin Oncol 27(29):4848–4857
Kim H, Song K, Park Y, Kang Y, Lee Y, Lee K et al (2003) Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 39(2):184–191
Del Conde I, Bharwani LD, Dietzen DJ, Pendurthi U, Thiagarajan P, LóPez JA (2007) Microvesicle-associated tissue factor and Trousseau’s syndrome. J Thromb Haemost 5(1):70–74
Tilley RE, Holscher T, Belani R, Nieva J, Mackman J (2008) Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients. Thromb Res 122(5):604–609
Falanga A, Barbui T, Rickles FR (2008) Hypercoagulability and tissue factor gene upregulation in hematologic malignancies. Semin Thromb Hemost 34(2):204–210
Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, et al (1981) Tumor shedding and coagulation. Science 212(4497):923–924
Bastida E, Ordinas A, Escolar G, Jamieson GA (1984) Tissue factor in microvescicles shed from U87MG human glioblastoma cells induces coagulation, platelet aggregation, and thrombogenesis. Blood 64(1):177–184
Yu JL, Rak JW (2004) Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells. J Thromb Haemost 2(11):2065–2067
Tesselaar MET, Romijn FPHTM, Van Der Linden IK, Prins FA, Bertina RM, Osanto S (2006) Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 5:520–527
Manly DA, Wang J, Glover SL, Kasthuri R, Liebman HA, Key S et al (2010) Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb Res 125(6):511–512
Kwaan HC, Magalha E (2010) Role of microparticles in the hemostatic dysfunction in acute promyelocytic leukemia. Semin Thromb Hemost 36(8):917–924
van Aalderen MC, Trappenburg MC, van Schilfgaarde M, Molenaar PJ (2011) Procoagulant myeloblast-derived microparticles in AML patients: changes in numbers and thrombin generation potential during chemotherapy. J Thromb Haemost 9:223–234
Auwerda JJ, Yuana Y, Osanto S, de Maat MP, Sonneveld P, Bertina RM et al (2011) Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma. Thromb Haemost 105(1):14–20
Trappenburg MC, Van Schilfgaarde M, Marchetti M, Spronk HM, Cate H, Leyte A et al (2009) Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 94(7):911–998
Martinez MC, Andriantsitohaina R (2011) Microparticles in angiogenesis: therapeutic potential. Circ Res 109:110–119
Kim HK, Song KS, Chung J, Lee KR, Lee S (2004) Platelet microparticles induce angiogenesis in vitro. Br J Haematol 124:376–384
Janowska-wieczorek A, Wysoczynski M, Kijowski J, Marquez-curtis L, Machalinski B, Ratajczak J et al (2004) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760
Falanga A, Marchetti M, Vignoli A, Balducci D (2003) Clotting mechanisms and cancer: implications in thrombus formation and tumor progression. Clin Adv Hematol Oncol 1(11):673–678
Ruf W, Yokota N, Schaffner F (2010) Tissue factor in cancer progression and angiogenesis. Thromb Res 2018(125):S36–S38
Milsom CC, Yu JL, Mackman N, Micallef J, Anderson GM, Guha A et al (2008) Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis. Cancer Res 68(24):10068–10077
Zwicker JI (2010) Predictive value of tissue factor bearing microparticles in cancer associated thrombosis. Thromb Res. Elsevier Ltd 125:S89–S91
Erdmann D, Heim J (1995) Orphan nuclear receptor HNF-4 binds to the human coagulation factor VII promoter. J Biol Chem 270(39):22988–22996
Tsao BYBP, Fair DS, Curtiss LK, Edgington TS (1984) Monocytes can be induced by lipopolysaccharide-triggered T lymphocytes to express functional factor VII/VIIa protease activity. J Exp Med 159:1042–1057
Chapman HA Jr, Allen CL, Stone OL, Fair DS. Human alveolar macrophages synthesize factor VII in vitro. Possible role in interstitial lung disease. J Clin Invest 75:2030–2037
Neaud V, Hisaka T, Monvoisin A, Bedin C, Balabaud C, Foster DC et al (2000) Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells. J Biol Chem 275(45):35565–35569
Fischer EG, Riewald M, Huang HY, Miyagi Y, Kubota Y, Mueller BM et al (1999) Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J Clin Invest 104(9):1213–1221
Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ (1993) Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. J Natl Cancer Inst 85(15):1225–1230
Wojtukiewicz MZ, Zacharski LR, Ruciñska M, Zimnoch L, Jaromin J, Rózañska-Kudelska M, et al (1999) Expression of tissue factor and tissue factor pathway inhibitor in situ in laryngeal carcinoma. Thromb Haemost 82:1659–1662
Koizume S, Jin M-S, Miyagi E, Hirahara F, Nakamura Y, Piao J-H et al (2006) Activation of cancer cell migration and invasion by ectopic synthesis of coagulation factor VII. Cancer Res 66(19):9453–9460
Tang J, Fan Q, Wu W, Jia Z, Li H, Yang Y et al (2010) Extrahepatic synthesis of coagulation factor VII by colorectal cancer cells promotes tumor invasion and metastasis. Chin Med J 123(24):3559–3565
Yokota N, Koizume S, Miyagi E, Hirahara F, Nakamura Y, Kikuchi K et al (2009) Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells. Br J Cancer 101(12):2023–2029
Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B et al (2000) High plasma levels of factor VIII and the Risk of recurrent venous thromboembolism. N Engl J Med 343(7):457–462
Legnani C, Cosmi B, Cini M, Frascaro M, Giuliana G, Palareti G (2004) High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 124(4):504–510
Auwerda JJA, Sonneveld P, De Maat MPM, Leebeek FWG (2007) Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma. Haematologica 92(2):279–280
Yigit E, Gönüllü G, Yücel I, Turgut M, Erdem D, Çakar B (2008) Relation between hemostatic parameters and prognostic/predictive factors in breast cancer. Eur J Intern Med 19(8):602–607
Battistelli S, Stefanoni M, Lorenzi B, Dell’Avanzato R, Varrone F, Pascucci A et al (2008) Coagulation factor levels in non-metastatic colorectal cancer patients. Int J Biol Markers 23(1):36–41
Dogan M, Demirkazik A, Konuk N, Yalcin, Buyukcelik A, Utkan G, et al (2006) The effect of venous thromboembolism on survival of cancer patients and its relationship with serum level of factor VIII and vascular endothelial growth factor: a prospective matched-paired study. Int J Biol Markers 21(4):206–210
Vormittag R, Simanek R, Ay C, Dunkler D, Quehenberger P, Marosi C et al (2009) High factor VIII levels independently predict venous thromboembolism in cancer patients: The cancer and thrombosis study. Arterioscler Thromb Vasc Biol 29(12):2176–2181
Andrén-Sandberg A, Lecander I, Martinsson G, Astedt B (1992) Peaks in plasma plasminogen activator inhibitor-1 concentration may explain thrombotic events in cases of pancreatic carcinoma. Cancer 69(12):2884–2887
Sciacca FL, Ciusani E, Silvani A, Corsini E, Frigerio S, Pogliani S et al (2004) Genetic and plasma markers of venous thromboembolism in patients with high grade glioma. Clin Cancer Res 10(4):1312–1317
Chen N, Ren M, Li R, Deng X, Li Y, Yan K et al (2015) Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma. Mol Cancer 14(1):1–7
Liu Y, Wang Z, Jiang M, Dai L, Zhang W, Wu D et al (2011) The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia. Leuk Res 35(7):879–884
Connolly GC, Phipps RP, Francis CW (2014) Platelets and cancer-associated thrombosis. Semin Oncol. Elsevier 41(3):302–310
Falanga A, Russo L, Verzeroli C (2013) Mechanisms of thrombosis in cancer. Thromb Res. Elsevier Ltd 131:S59–S62
Lee EC, Cameron SJ (2017) Cancer and thrombotic risk: the platelet paradigm. Front Cardiovasc Med. 4(November):1–6
Läubli H, Borsig L (2010) Selectins promote tumor metastasis. Semin Cancer Biol 20(3):169–177
Chen M, Geng JG (2006) P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 54(2):75–84
Stegner D, Dütting S, Nieswandt B (2014) Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 133(Suppl 2):149–157
Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW (2005) Platelets and fibrin (ogen) increase metastatic potential by impeding natural killer cell—mediated elimination of tumor cells. Blood J 105(1):178–185
Raica M, Cimpean AM, Ribatti D (2008) The role of podoplanin in tumor progression and metastasis. Anticancer Res 28(5B):2997–3006
Riedl J, Preusser M, Nazari PMS, Posch F, Panzer S, Marosi C et al (2017) Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood 129(13):1831–1839
Chang Y-W, Hsieh P, Chang Y, Lu M, Huang T-F, Chong K-Y et al (2015) Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis. Oncotarget 6(40):42733–42748
Shao B, Wahrenbrock MG, Yao L, David T, Coughlin SR, Xia L et al (2011) Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118(15):4015–4023
Brill A, Fuchs T a, Chauhan AK, Yang JJ, Meyer SF De, Ko M, et al (2011) von Willebrand factor—mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 117(4):1400–1407
Vanschoonbeek K, Feijge MAH, Van Kampen RJW, Kenis H, Hemker HC, Giesen PLA et al (2004) Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: Subject-dependent variation in thrombogram characteristics. J Thromb Haemost 2(3):476–484
Falanga A, Marchetti M, Evangelista V, Vignoli A, Licini M, Balicco M et al (2000) Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 96(13):4261–4266
Barbui T, Finazzi G, Falanga A (2013) Myeloproliferative neoplasms and thrombosis. Blood 122(13):2176–2184
Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al (2012) Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 109(32):13076–13081
Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD et al (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 107(36):15880–15885
Clark S, Ma A, Tavener S, McDonald B, Goodarzi Z, Kelly M et al (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13(4):463–469
Snyder KM, Kessler CM (2008) The pivotal role of thrombin in cancer biology and tumorigenesis. Semin Thromb Hemost 34(8):734–741
Edwards R, Rickles F (1984) Macrophage procoagulants. Prog Hemost Thromb 7:183–209
Semeraro N (1988) Different expression of procoagulant activity in macrophages associated with experimental and human tumors. Haemostasis 18:47–54
Semeraro N, Montemurro P, Conese M, Giordano D, Stella M, Restaino A et al (1990) Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynecological malignancies. Int J Cancer 45(2):251–254
Pabinger I, Posch F (2014) Flamethrowers: blood cells and cancer thrombosis risk. Hematol Am Soc Hematol Educ Program 2014 2014(1):410–417
Granger V, Faille D, Marani V, Noël B, Gallais Y, Szely N et al (2017) Human blood monocytes are able to form extracellular traps. J Leukoc Biol 102(3):775–781
Go S, Kim R, Song H, Kang M, Lee U, Choi H et al (2015) Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism. Tumour Biol 36(10):7631–7639
Tas F, Duranyildiz D, Argon A, Og H (2005) Serum levels of leptin and proinflammatory cytokines in advanced-stage non-small cell lung cancer. Med Oncol 22(4):353–354
Zwicker JI, Furie BC, Furie B (2007) Cancer-associated thrombosis. Crit Rev Oncol Hematol 62:126–136
Falanga A, Marchetti M, Giovanelli S, Barbui T (1996) All-trans-retinoic acid counteracts endothelial cell procoagulant activity induced by a human promyelocytic leukemia-derived cell line (NB4). Blood 87(2):613–618
Van de Wouwer M, Collen D, Conway EM (2004) Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 24(8):1374–1383
Lindahl AK, Boffa MC, Abildgaard U (1993) Increased plasma thrombomodulin in cancer patients. Thromb Haemost 69(2):112–114
Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U (2005) Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res 96(12):1233–1239
Friedenberg WR, Roberts RC, Alonso-Escolano D (1992) Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative. Am J Hematol 40(4):283–289
Karakantza M, Giannakoulas NC, Zikos P, Sakellaropoulos G, Kouraklis A, Aktypi A et al (2004) Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera. Int J Hematol 79(3):253–259
Gogali A, Charalabopoulos K, Zampira I, Konstantinidis AK, Tachmazoglou F, Daskalopoulos G et al (2010) Soluble adhesion molecules E-cadherin, intercellular adhesion molecule-1, and E-selectin as lung cancer biomarkers. Chest 138(5):1173–1179
Silva HC, Garcao F, Coutinho EG, De Oliveira CF, Regateiro FJ (2006) Soluble VCAM-1 and E-selectin in breast cancer: relationship with staging and with the detection of circulating cancer cells. Neoplasma. 53(6):538–543
Cella G, Marchetti M, Vianello F, Panova-Noeva M, Vignoli A, Russo L et al (2010) Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb Haemost 104(1):151–156
Goon PKY, Lip GYH, Boos CJ, Stonelake PS, Blann AD (2006) Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia 8(2):79–88
Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F (2001) Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97(11):3658–3662
Fleitas T, Martínez-Sales V, Vila V, Reganon E, Mesado D, Martín M et al (2012) Circulating endothelial cells and microparticles as prognostic markers in advanced non-small cell lung cancer. PLoS ONE 7(10):1–6
Rak J, Klement G (2000) Impact of oncogenes and tumor suppressor genes on deregulation of hemostasis and angiogenesis in cancer. Cancer Metastasis Rev 19(1–2):93–96
Magnus N, Gerges N, Jabado N, Rak J (2013) Coagulation-related gene expression profile in glioblastoma is defined by molecular disease subtype. J Thromb Haemost 11(6):1197–1200
Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T et al (1995) Advances in brief mutant ras oncogenes upregulate VEGFIVPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580
Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6(5):447–458
Phan VT, Wu X, Cheng JH, Sheng RX, Chung AS, Zhuang G et al (2013) Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc Natl Acad Sci USA 110(15):6079–6084
Rickles FR (2009) Cancer and thrombosis in women—molecular mechanisms. Thromb Res 123(Suppl 2):16–20
Koizume S, Yokota N, Miyagi E, Hirahara F, Nakamura Y, Sakuma Y et al (2009) Hepatocyte nuclear factor-4-independent synthesis of coagulation factor VII in breast cancer cells and its inhibition by targeting selective histone acetyltransferases. Mol Cancer Res 7(12):1928–1936
Magnus N, Garnier D, Rak J (2010) Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells sure to FVIIa and PAR1- or PAR2-activat-. Blood 116(5):815–819
Garnier D, Magnus N, Lee TH, Bentley V, Meehan B, Milsom C et al (2012) Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. J Biol Chem 287(52):43565–43572
Provençal M, Berger-Thibaul N, Labbé D, Veitch R, Boivin D, Rivard G et al (2010) Tissue factor mediates the HGF/Met-induced anti-apoptotic pathway in DAOY medulloblastoma cells. J Neurooncol 97(3):365–372
Rong Y, Belozerov VE, Tucker-Burden C, Chen G, Durden DL, Olson JJ et al (2009) Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res 69(6):2540–2549
Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D (2011) MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer Res 71(3):645–654
Chu HW, Cheng CW, Chou WC, Hu LY, Wang HW, Hsiung CN et al (2014) A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis. Hum Mol Genet 23(2):355–367
Botla SK, Savant S, Jandaghi P, Bauer AS, Mucke O, Moskalev EA et al (2016) Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression. Cancer Res 76(14):4149–4159
Wu X-L (2013) MicroRNA-143 suppresses gastric cancer cell growth and induces apoptosis by targeting COX-2. World J Gastroenterol 19(43):7758
D’Asti E, Rak J (2016) Biological basis of personalized anticoagulation in cancer: oncogene and oncomir networks as putative regulators of coagulopathy. Thromb Res 140(Suppl 1):37–43
Karpatkin S (2004) Does hypercoagulability awaken dormant tumor cells in the host? J Thromb Haemost 2(12):2103–2106
Vossen CY, Hoffmeister M, Chang-Claude JC, Rosendaal FR, Brenner H (2011) Clotting factor gene polymorphisms and colorectal cancer risk. J Clin Oncol 29(13):1722–1727
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Falanga, A., Schieppati, F., Russo, L. (2019). Pathophysiology 1. Mechanisms of Thrombosis in Cancer Patients. In: Soff, G. (eds) Thrombosis and Hemostasis in Cancer. Cancer Treatment and Research, vol 179. Springer, Cham. https://doi.org/10.1007/978-3-030-20315-3_2
Download citation
DOI: https://doi.org/10.1007/978-3-030-20315-3_2
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-20314-6
Online ISBN: 978-3-030-20315-3
eBook Packages: MedicineMedicine (R0)