Download PDF
Semin Thromb Hemost 2015; 41(07): 756-764
DOI: 10.1055/s-0035-1564040
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Cancer Tissue Procoagulant Mechanisms and the Hypercoagulable State of Patients with Cancer

Anna Falanga
1   Department of Immunohematology & Transfusion Medicine and the Hemostasis and Thrombosis Center, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Francesca Schieppati
2   Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy
,
Domenico Russo
2   Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, Brescia, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
26 September 2015 (online)

    Permissions and Reprints

Abstract

Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions.

Keywords

thrombosis - cancer - tissue factor - tumor cells - risk factors
 

  • References

  • 1 Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l'Hotel Dieu de Paris 1856; Vol. 3: 654-712
    PubMedSearch in Google Scholar
  • 2 Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11 (2) 223-233
    CrossrefPubMedSearch in Google Scholar
  • 3 Falanga A. Thrombophilia in cancer. Semin Thromb Hemost 2005; 31 (1) 104-110
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009; 22 (1) 49-60
    CrossrefPubMedSearch in Google Scholar
  • 5 Zwicker JI, Liebman HA, Bauer KA , et al. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol 2013; 160 (4) 530-537
    CrossrefPubMedSearch in Google Scholar
  • 6 Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res 2014; 133 (Suppl. 02) S35-S38
    CrossrefPubMedSearch in Google Scholar
  • 7 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 1996; 77 (9) 1877-1883
    CrossrefPubMedSearch in Google Scholar
  • 8 Takano S, Tsuboi K, Tomono Y, Mitsui Y, Nose T. Tissue factor, osteopontin, alphavbeta3 integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression. Br J Cancer 2000; 82 (12) 1967-1973
    CrossrefPubMedSearch in Google Scholar
  • 9 Guan M, Jin J, Su B, Liu WW, Lu Y. Tissue factor expression and angiogenesis in human glioma. Clin Biochem 2002; 35 (4) 321-325
    Search in Google Scholar
  • 10 Ishimaru K, Hirano H, Yamahata H, Takeshima H, Niiro M, Kuratsu J. The expression of tissue factor correlates with proliferative ability in meningioma. Oncol Rep 2003; 10 (5) 1133-1137
    PubMedSearch in Google Scholar
  • 11 Fernandes RS, Kirszberg C, Rumjanek VM, Monteiro RQ. On the molecular mechanisms for the highly procoagulant pattern of C6 glioma cells. J Thromb Haemost 2006; 4 (7) 1546-1552
    CrossrefPubMedSearch in Google Scholar
  • 12 Nadir Y, Brenner B. Heparanase multiple effects in cancer. Thromb Res 2014; 133 (Suppl. 02) S90-S94
    PubMedSearch in Google Scholar
  • 13 Elkin M, Ilan N, Ishai-Michaeli R , et al. Heparanase as mediator of angiogenesis: mode of action. FASEB J 2001; 15 (9) 1661-1663
    PubMedSearch in Google Scholar
  • 14 Fux L, Feibish N, Cohen-Kaplan V , et al. Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling. Cancer Res 2009; 69 (5) 1758-1767
    CrossrefPubMedSearch in Google Scholar
  • 15 Falanga A, Consonni R, Marchetti M , et al. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood 1998; 92 (1) 143-151
    PubMedSearch in Google Scholar
  • 16 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 (3) 1072-1081
    PubMedSearch in Google Scholar
  • 17 Falanga A, Toma S, Marchetti M , et al. Effect of all-trans-retinoic acid on the hypercoagulable state of patients with breast cancer. Am J Hematol 2002; 70 (1) 9-15
    CrossrefPubMedSearch in Google Scholar
  • 18 Ahn YS. Cell-derived microparticles: ‘Miniature envoys with many faces’. J Thromb Haemost 2005; 3 (5) 884-887
    CrossrefPubMedSearch in Google Scholar
  • 19 Horstman LL, Jy W, Jimenez JJ, Bidot C, Ahn YS. New horizons in the analysis of circulating cell-derived microparticles. Keio J Med 2004; 53 (4) 210-230
    CrossrefPubMedSearch in Google Scholar
  • 20 Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies. J Clin Oncol 2009; 27 (29) 4848-4857
    CrossrefPubMedSearch in Google Scholar
  • 21 Kim HK, Song KS, Park YS , et al. 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 2003; 39 (2) 184-191
    CrossrefPubMedSearch in Google Scholar
  • 22 Del Conde I, Bharwani LD, Dietzen DJ, Pendurthi U, Thiagarajan P, López JA. Microvesicle-associated tissue factor and Trousseau's syndrome. J Thromb Haemost 2007; 5 (1) 70-74
    Search in Google Scholar
  • 23 Tilley RE, Holscher T, Belani R, Nieva J, Mackman N. Tissue factor activity is increased in a combined platelet and microparticle sample from cancer patients. Thromb Res 2008; 122 (5) 604-609
    CrossrefPubMedSearch in Google Scholar
  • 24 Garnier D, Magnus N, Lee TH , et al. Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. J Biol Chem 2012; 287 (52) 43565-43572
    CrossrefPubMedSearch in Google Scholar
  • 25 Davila M, Amirkhosravi A, Coll E , et al. Tissue factor-bearing microparticles derived from tumor cells: impact on coagulation activation. J Thromb Haemost 2008; 6 (9) 1517-1524
    CrossrefPubMedSearch in Google Scholar
  • 26 Manly DA, Wang J, Glover SL , et al. Increased microparticle tissue factor activity in cancer patients with Venous Thromboembolism. Thromb Res 2010; 125 (6) 511-512
    CrossrefPubMedSearch in Google Scholar
  • 27 Kwaan HC, Rego EM. Role of microparticles in the hemostatic dysfunction in acute promyelocytic leukemia. Semin Thromb Hemost 2010; 36 (8) 917-924
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Van Aalderen MC, Trappenburg MC, Van Schilfgaarde M , et al. Procoagulant myeloblast-derived microparticles in AML patients: changes in numbers and thrombin generation potential during chemotherapy. J Thromb Haemost 2011; 9 (1) 223-226
    CrossrefPubMedSearch in Google Scholar
  • 29 Auwerda JJ, Yuana Y, Osanto S , et al. Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma. Thromb Haemost 2011; 105 (1) 14-20
    PubMedSearch in Google Scholar
  • 30 Trappenburg MC, van Schilfgaarde M, Marchetti M , et al. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica 2009; 94 (7) 911-918
    CrossrefPubMedSearch in Google Scholar
  • 31 Liu Y, Wang Z, Jiang M , et al. The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia. Leuk Res 2011; 35 (7) 879-884
    CrossrefPubMedSearch in Google Scholar
  • 32 van Hinsbergh VW, Bauer KA, Kooistra T , et al. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 1990; 76 (11) 2284-2289
    PubMedSearch in Google Scholar
  • 33 Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24 (8) 1374-1383
    CrossrefPubMedSearch in Google Scholar
  • 34 Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102 (6) V215-V224
    CrossrefPubMedSearch in Google Scholar
  • 35 Falanga A, Marchetti M, Vignoli A, Balducci D. Clotting mechanisms and cancer: implications in thrombus formation and tumor progression. Clin Adv Hematol Oncol 2003; 1 (11) 673-678
    PubMedSearch in Google Scholar
  • 36 Demers M, Wagner DD. Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression. OncoImmunology 2013; 2 (2) e22946
    CrossrefPubMedSearch in Google Scholar
  • 37 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 U S A 2012; 109 (32) 13076-13081
    CrossrefPubMedSearch in Google Scholar
  • 38 Brinkmann V, Reichard U, Goosmann C , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
    CrossrefPubMedSearch in Google Scholar
  • 39 Fuchs TA, Brill A, Duerschmied D , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
    CrossrefPubMedSearch in Google Scholar
  • 40 Massberg S, Grahl L, von Bruehl ML , et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (8) 887-896
    CrossrefPubMedSearch in Google Scholar
  • 41 Snyder KM, Kessler CM. The pivotal role of thrombin in cancer biology and tumorigenesis. Semin Thromb Hemost 2008; 34 (8) 734-741
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Bastida E, Ordinas A, Giardina SL, Jamieson GA. Differentiation of platelet-aggregating effects of human tumor cell lines based on inhibition studies with apyrase, hirudin, and phospholipase. Cancer Res 1982; 42 (11) 4348-4352
    PubMedSearch in Google Scholar
  • 43 Pinto S, Gori L, Gallo O, Boccuzzi S, Paniccia R, Abbate R. Increased thromboxane A2 production at primary tumor site in metastasizing squamous cell carcinoma of the larynx. Prostaglandins Leukot Essent Fatty Acids 1993; 49 (1) 527-530
    CrossrefPubMedSearch in Google Scholar
  • 44 Zucchella M, Dezza L, Pacchiarini L , et al. Human tumor cells cultured “in vitro” activate platelet function by producing ADP or thrombin. Haematologica 1989; 74 (6) 541-545
    PubMedSearch in Google Scholar
  • 45 Grignani G, Pacchiarini L, Ricetti MM , et al. Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. Invasion Metastasis 1989; 9 (5) 298-309
    PubMedSearch in Google Scholar
  • 46 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U S A 1968; 61 (1) 46-52
    CrossrefPubMedSearch in Google Scholar
  • 47 Stegner D, Dütting S, Nieswandt B. Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 2014; 133 (Suppl. 02) S149-S157
    CrossrefPubMedSearch in Google Scholar
  • 48 Honn KV, Tang DG, Crissman JD. Platelets and cancer metastasis: a causal relationship?. Cancer Metastasis Rev 1992; 11 (3–4) 325-351
    CrossrefPubMedSearch in Google Scholar
  • 49 Karpatkin S, Pearlstein E, Ambrogio C, Coller BS. Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 1988; 81 (4) 1012-1019
    CrossrefPubMedSearch in Google Scholar
  • 50 Palumbo JS, Talmage KE, Massari JV , et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105 (1) 178-185
    CrossrefPubMedSearch in Google Scholar
  • 51 Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59 (6) 1295-1300
    PubMedSearch in Google Scholar
  • 52 Shau H, Roth MD, Golub SH. Regulation of natural killer function by nonlymphoid cells. Nat Immun 1993; 12 (4–5) 235-249
    PubMedSearch in Google Scholar
  • 53 Placke T, Örgel M, Schaller M , et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res 2012; 72 (2) 440-448
    CrossrefPubMedSearch in Google Scholar
  • 54 Möhle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci U S A 1997; 94 (2) 663-668
    CrossrefPubMedSearch in Google Scholar
  • 55 Yang L, Carbone DP. Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 2004; 92: 13-27
    PubMedSearch in Google Scholar
  • 56 Tímár J, Tóvári J, Rásó E, Mészáros L, Bereczky B, Lapis K. Platelet-mimicry of cancer cells: epiphenomenon with clinical significance. Oncology 2005; 69 (3) 185-201
    CrossrefPubMedSearch in Google Scholar
  • 57 Rice GE, Bevilacqua MP. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 1989; 246 (4935) 1303-1306
    CrossrefPubMedSearch in Google Scholar
  • 58 Giavazzi R, Foppolo M, Dossi R, Remuzzi A. Rolling and adhesion of human tumor cells on vascular endothelium under physiological flow conditions. J Clin Invest 1993; 92 (6) 3038-3044
    CrossrefPubMedSearch in Google Scholar
  • 59 Chen M, Geng JG. P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 2006; 54 (2) 75-84
    CrossrefPubMedSearch in Google Scholar
  • 60 Coppinger JA, Cagney G, Toomey S , et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 2004; 103 (6) 2096-2104
    CrossrefPubMedSearch in Google Scholar
  • 61 David M, Wannecq E, Descotes F , et al. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts. PLoS ONE 2010; 5 (3) e9741
    CrossrefPubMedSearch in Google Scholar
  • 62 Reed GL. Platelet secretory mechanisms. Semin Thromb Hemost 2004; 30 (4) 441-450
    Thieme ConnectPubMedSearch in Google Scholar
  • 63 Ren Q, Ye S, Whiteheart SW. The platelet release reaction: just when you thought platelet secretion was simple. Curr Opin Hematol 2008; 15 (5) 537-541
    CrossrefPubMedSearch in Google Scholar
  • 64 Bendas G, Borsig L. Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012; 2012: 676731
    PubMedSearch in Google Scholar
  • 65 Nomura S, Suzuki M, Katsura K , et al. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 1995; 116 (2) 235-240
    CrossrefPubMedSearch in Google Scholar
  • 66 Mallat Z, Benamer H, Hugel B , et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101 (8) 841-843
    CrossrefPubMedSearch in Google Scholar
  • 67 Nieuwland R, Berckmans RJ, McGregor S , et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95 (3) 930-935
    PubMedSearch in Google Scholar
  • 68 Chirinos JA, Heresi GA, Velasquez H , et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45 (9) 1467-1471
    CrossrefPubMedSearch in Google Scholar
  • 69 Weitz IC, Israel VK, Waisman JR, Presant CA, Rochanda L, Liebman HA. Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation. Thromb Haemost 2002; 88 (2) 213-220
    PubMedSearch in Google Scholar
  • 70 Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104 (12) 2822-2829
    CrossrefPubMedSearch in Google Scholar
  • 71 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
    CrossrefPubMedSearch in Google Scholar
  • 72 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
    CrossrefPubMedSearch in Google Scholar
  • 73 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
    CrossrefPubMedSearch in Google Scholar
  • 74 Ay C, Dunkler D, Marosi C , et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
    CrossrefPubMedSearch in Google Scholar
  • 75 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
    CrossrefPubMedSearch in Google Scholar
  • 76 Mandala M, Clerici M, Corradino I , et al. Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the context of phase I studies: the ‘SENDO experience’. Ann Oncol 2012; 23 (6) 1416-1421
    CrossrefPubMedSearch in Google Scholar
  • 77 Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern Emerg Med 2012; 7 (3) 291-292
    PubMedSearch in Google Scholar
  • 78 Palumbo A, Rajkumar SV, Dimopoulos MA , et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22 (2) 414-423
    CrossrefPubMedSearch in Google Scholar