Predicting VTE in Cancer Patients: Candidate Biomarkers and Risk Assessment Models

Silvia Riondino, Patrizia Ferroni, Fabio Massimo Zanzotto, Mario Roselli, Fiorella Guadagni, Silvia Riondino, Patrizia Ferroni, Fabio Massimo Zanzotto, Mario Roselli, Fiorella Guadagni

Abstract

Risk prediction of chemotherapy-associated venous thromboembolism (VTE) is a compelling challenge in contemporary oncology, as VTE may result in treatment delays, impaired quality of life, and increased mortality. Current guidelines do not recommend thromboprophylaxis for primary prevention, but assessment of the patient's individual risk of VTE prior to chemotherapy is generally advocated. In recent years, efforts have been devoted to building accurate predictive tools for VTE risk assessment in cancer patients. This review focuses on candidate biomarkers and prediction models currently under investigation, considering their advantages and disadvantages, and discussing their diagnostic performance and potential pitfalls.

Keywords: biomarkers; clinical decision systems; machine learning; risk assessment models; venous thromboembolism.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Graphical summary of the mechanism of tumor-induced coagulation cascade and relevant biomarkers at various stages of the pro-coagulant processes. Tumor cells express tissue factor (TF) and “cancer pro-coagulant” (CP). TF binds to activated factor VII (VIIa), forming a complex (TF/VIIa) that initiates coagulation cascade by activating factor IX and X, with consequent thrombin generation and fibrin formation. CP directly activates factor X. Thrombin, in turn, triggers platelet (PLT) activation with subsequent release of platelet granule content and amplification of the whole activatory process. Tumor cells may also interact with vascular cells (monocytes, platelets, endothelial cells) either directly (through membrane interactions) or indirectly (through cytokine release, prompted by activation of redox sensitive genes). Activated vascular cells release microparticles (MPs) with pro-coagulant activity in the circulation. Candidate biomarkers for VTE prediction are highlighted in red. aPCR: resistance to activated Protein C; F1+2: Prothrombin fragment; IL-1: interleukin-1; NLR: neutrophil/lymphocyte ratio; PLR: platelet/lymphocyte ratio; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor; WBC: white blood cells.
Figure 2
Figure 2
Effects of chemotherapy on coagulation activation. Chemotherapy may cause incongruous activation of hemostasis through various mechanisms: direct endothelial cell toxicity and apoptosis; vascular cell activation, resulting in tissue factor (TF) exposure; production of reactive oxygen species (ROS); unbalance of factors involved in the control of the coagulation cascade, with an impairment of the protein C (PC)/protein S (PS) anticoagulant pathway; activation of the monocyte/macrophage system and platelets. aPC: activated Protein C; (O2•−): superoxide anion; (OH•): radical hydroxyl radical; (NO•): nitric oxide; TF: tissue factor.
Figure 3
Figure 3
Kaplan–Meier curves of VTE-free survival time of chemotherapy-treated ambulatory cancer patients in the training (Panel A, n = 825), testing (Panel B, n = 354) and validation set (Panel C, n = 255). Comparison between patients with low (Group: 0; solid black line) or high (Group: 1; dotted red line) risk of VTE based on the combined model predictor. Patients stratification based on the Khorana score ≥2 is also given for comparison (Panel D).

References

    1. Heit J.A., Spencer F.A., White R.H. The epidemiology of venous thromboembolism. J. Thromb. Thrombolysis. 2016;41:3–14. doi: 10.1007/s11239-015-1311-6.
    1. Crous-Bou M., Harrington L.B., Kabrhel C. Environmental and genetic risk factors associated with venous thromboembolism. Semin. Thromb. Hemost. 2016;42:808–820. doi: 10.1055/s-0036-1592333.
    1. Geerts W.H., Bergqvist D., Pineo G.F., Heit J.A., Samama C.M., Lassen M.R., Colwell C.W. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest. 2008;133:381S–453S. doi: 10.1378/chest.08-0656.
    1. Alikhan R., Cohen A.T., Combe S., Samama M.M., Desjardins L., Eldor A., Janbon C., Leizorovicz A., Olsson C.G., Turpie A.G., et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: Analysis of the MEDENOX Study. Arch. Intern. Med. 2004;164:963–968. doi: 10.1001/archinte.164.9.963.
    1. Rickles F.R., Levine M., Edwards R.L. Hemostatic alterations in cancer patients. Cancer Metastasis Rev. 1992;11:237–248. doi: 10.1007/BF01307180.
    1. Heit J.A., O’Fallon W.M., Petterson T.M., Lohse C.M., Silverstein M.D., Mohr D.N., Melton L.J., 3rd Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: A population-based study. Arch. Intern. Med. 2002;162:1245–1248. doi: 10.1001/archinte.162.11.1245.
    1. Dentali F., Ageno W., Becattini C., Galli L., Gianni M., Riva N., Imberti D., Squizzato A., Venco A., Agnelli G. Prevalence and clinical history of incidental, asymptomatic pulmonary embolism: A meta-analysis. Thromb. Res. 2010;125:518–522. doi: 10.1016/j.thromres.2010.03.016.
    1. Moore R.A., Adel N., Riedel E., Bhutani M., Feldman D.R., Tabbara N.E., Soff G., Parameswaran R., Hassoun H. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: A large retrospective analysis. J. Clin. Oncol. 2011;29:3466–3473. doi: 10.1200/JCO.2011.35.5669.
    1. Barni S., Labianca R., Agnelli G., Bonizzoni E., Verso M., Mandalà M., Brighenti M., Petrelli F., Bianchini C., Perrone T., et al. Chemiotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: Results of a retrospective analysis of the PROTECHT study. J. Transl. Med. 2011;9:179. doi: 10.1186/1479-5876-9-179.
    1. Lyman G.H., Eckert L., Wang Y., Wang H., Cohen A. Venous thromboembolism risk in patients with cancer receiving chemotherapy: A real-world analysis. Oncologist. 2013;18:1321–1329. doi: 10.1634/theoncologist.2013-0226.
    1. Roselli M., Riondino S., Mariotti S., La Farina F., Ferroni P., Guadagni F. Clinical models and biochemical predictors of VTE in lung cancer. Cancer Metastasis Rev. 2014;33:771–789. doi: 10.1007/s10555-014-9500-x.
    1. Riondino S., Del Monte G., Fratangeli F., Guadagni F., Roselli M., Ferroni P. Anti angiogenic drugs, vascular toxicity and thromboembolism in solid cancer. Cardiovasc. Hematol. Agents Med. Chem. 2017;15:3–16. doi: 10.2174/1871525715666170127101605.
    1. Riondino S., Guadagni F., Formica V., Ferroni P., Roselli M. Gender differences in cancer-associated venous thromboembolism. Curr. Med. Chem. 2017;24:2589–2601. doi: 10.2174/0929867323666161018144505.
    1. Prandoni P., Lensing A.W., Piccioli A., Bernardi E., Simioni P., Girolami B., Marchiori A., Sabbion P., Prins M.H., Noventa F., et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–3488. doi: 10.1182/blood-2002-01-0108.
    1. Mandalà M., Falanga A., Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann. Oncol. 2011;22:85–92. doi: 10.1093/annonc/mdr392.
    1. Siragusa S., Armani U., Carpenedo M., Falanga A., Fulfaro F., Imberti D., Laurora R., Molinari A.C., Prisco D., Silingardi M., et al. Prevention of venous thromboembolism in patients with cancer: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET) Thromb. Res. 2011;129:e171–e176. doi: 10.1016/j.thromres.2011.09.002.
    1. Guyatt G.H., Akl E.A., Crowther M., Gutterman D.D., Schuünemann H.J., American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:7S–47S. doi: 10.1378/chest.1412S3.
    1. Streiff M.B., Bockenstedt P.L., Cataland S.R., Chesney C., Eby C., Fanikos J., Fogerty A.E., Gao S., Goldhaber S.Z., Hassoun H., et al. Venous thromboembolic disease. J. Natl. Compr. Cancer Netw. 2013;11:1402–1429. doi: 10.6004/jnccn.2013.0163.
    1. Farge D., Debourdeau P., Beckers M., Baglin C., Bauersachs R.M., Brenner B., Brilhante D., Falanga A., Gerotzafias G.T., Haim N., et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J. Thromb. Haemost. 2013;11:56–70. doi: 10.1111/jth.12070.
    1. Lyman G.H., Bohlke K., Khorana A.A., Kuderer N.M., Lee A.Y., Arcelus J.I., Balaban E.P., Clarke J.M., Flowers C.R., Francis C.W., et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 2015;33:654–656. doi: 10.1200/JCO.2014.59.7351.
    1. Oo T.H. Outpatient thromboprophylaxis with low-molecular weight heparin in solid tumors: Where do we stand today? J. Thromb. Thrombolysis. 2016;41:539–540. doi: 10.1007/s11239-016-1346-3.
    1. Khorana A.A., Kuderer N.M., Culakova E., Lyman G.H., Francis C.W. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902–4907. doi: 10.1182/blood-2007-10-116327.
    1. Mansfield A.S., Tafur A.J., Wang C.E., Kourelis T.V., Wysokinska E.M., Yang P. Predictors of active cancer thromboembolic outcomes: Validation of the Khorana score among patients with lung cancer. J. Thromb. Haemost. 2016;14:1773–1778. doi: 10.1111/jth.13378.
    1. Noble S., Alikhan R., Robbins A., Macbeth F., Hood K. Predictors of active cancer thromboembolic outcomes: Validation of the Khorana score among patients with lung cancer: Comment. J. Thromb. Haemost. 2017;15:590–591. doi: 10.1111/jth.13594.
    1. Ay C., Dunkler D., Marosi C., Chiriac A.L., Vormittag R., Simanek R., Quehenberger P., Zielinski C., Pabinger I. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116:5377–5382. doi: 10.1182/blood-2010-02-270116.
    1. Pelzer U., Sinn M., Stieler J., Riess H. Primary pharmacological prevention of thromboembolic events in ambulatory patients with advanced pancreatic cancer treated with chemotherapy? Dtsch. Med. Wochenschr. 2013;138:2084–2088. doi: 10.1055/s-0033-1349608.
    1. 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;7:291–292. doi: 10.1007/s11739-012-0784-y.
    1. Chew H.K., Wun T., Harvey D., Zhou H., White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch. Intern. Med. 2006;166:458–464. doi: 10.1001/archinte.166.4.458.
    1. Blom J.W., Vanderschoot J.P., Oostindier M.J., Osanto S., van der Meer F.J., Rosendaal F.R. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: Results of a record linkage study. J. Thromb. Haemost. 2006;4:529–535. doi: 10.1111/j.1538-7836.2006.01804.x.
    1. Khorana A.A., Dalal M., Lin J., Connolly G.C. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer. 2013;119:648–655. doi: 10.1002/cncr.27772.
    1. Roselli M., Ferroni P., Riondino S., Mariotti S., Laudisi A., Vergati M., Cavaliere F., Palmirotta R., Guadagni F. Impact of chemotherapy on activated protein C-dependent thrombin generation--association with VTE occurrence. Int. J. Cancer. 2013;133:1253–1258. doi: 10.1002/ijc.28104.
    1. Guy J.B., Bertoletti L., Magné N., Rancoule C., Mahé I., Font C., Sanz O., Martín-Antorán J.M., Pace F., Vela J.R., et al. RIETE investigators. Venous thromboembolism in radiation therapy cancer patients: Findings from the RIETE registry. Crit. Rev. Oncol. Hematol. 2017;113:83–89. doi: 10.1016/j.critrevonc.2017.03.006.
    1. Strukova S. Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front. Biosci. 2006;11:59–80. doi: 10.2741/1780.
    1. Del Conde I., Bharwani L.D., Dietzen D.J., Pendurthi U., Thiagarajan P., López J.A. Microvesicle-associated tissue factor and Trousseau’s syndrome. J. Thromb. Haemost. 2007;5:70–74. doi: 10.1111/j.1538-7836.2006.02301.x.
    1. Tesselaar M.E., Romijn F.P., van der Linden I.K., Bertina R.M., Osanto S. Microparticle-associated tissue factor activity in cancer patients with and without thrombosis. J. Thromb. Haemost. 2009;7:1421–1423. doi: 10.1111/j.1538-7836.2009.03504.x.
    1. Gordon S.G., Cross B.A. A factor X-activating cysteine protease from malignant tissue. J. Clin. Investig. 1981;67:1665–1671. doi: 10.1172/JCI110203.
    1. Läubli H., Borsig L. Selectins promote tumor metastasis. Semin. Cancer Biol. 2010;20:169–177. doi: 10.1016/j.semcancer.2010.04.005.
    1. Goubran H.A., Kotb R.R., Stakiw J., Emara M.E., Burnouf T. Regulation of tumor growth and metastasis: The role of tumor microenvironment. Cancer Growth Metastasis. 2014;7:9–18. doi: 10.4137/CGM.S11285.
    1. Chen M., Geng J.-G. P-selectin mediates adhesion of leukocytes.; platelets.; and cancer cells in inflammation.; thrombosis.; and cancer growth and metastasis. Arch. Immunol. Ther. Exp. 2006;54:75–84. doi: 10.1007/s00005-006-0010-6.
    1. Coupland L.A., Chong B.H., Parish C.R. Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res. 2012;72:4662–4671. doi: 10.1158/0008-5472.CAN-11-4010.
    1. Kasthuri R.S., Taubman M.B., Mackman N. Role of Tissue Factor in Cancer. J. Clin. Oncol. 2009;27:4834–4838. doi: 10.1200/JCO.2009.22.6324.
    1. Gay L.J., Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer. 2011;11:123–134. doi: 10.1038/nrc3004.
    1. Di Nisio M., Ferrante N., De Tursi M., Iacobelli S., Cuccurullo F., Büller H.R., Feragalli B., Porreca E. Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Thromb. Haemost. 2010;104:1049–1054. doi: 10.1160/TH10-05-0277.
    1. Feffer S.E., Carmosino L.S., Fox R.L. Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. Cancer. 1989;63:1303–1307. doi: 10.1002/1097-0142(19890401)63:7<1303::AID-CNCR2820630713>;2-F.
    1. Sousou T., Khorana A.A. New insights into cancer-associated thrombosis. Arterioscler. Thromb. Vasc. Biol. 2009;29:316–320. doi: 10.1161/ATVBAHA.108.182196.
    1. Ferroni P., Martini F., Portarena I., Grenga I., Riondino S., La Farina F., Laudisi A., Guadagni F., Roselli M. Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients—A pilot study. Support. Care Cancer. 2012;20:2713–2720. doi: 10.1007/s00520-012-1391-1.
    1. Linkins L.A., Takach Lapner S. Review of D-dimer testing: Good, Bad, and Ugly. Int. J. Lab. Hematol. 2017;39:98–103. doi: 10.1111/ijlh.12665.
    1. Dempfle C.E., Borggrefe M. Point of care coagulation tests in critically ill patients. Semin. Thromb. Hemost. 2008;34:445–450. doi: 10.1055/s-0028-1092874.
    1. Legnani C., Fariselli S., Cini M., Oca G., Abate C., Palareti G. A new rapid bedside assay for quantitative testing of D-Dimer (Cardiac D-Dimer) in the diagnostic work-up for deep vein thrombosis. Thromb. Res. 2003;111:149–153. doi: 10.1016/j.thromres.2003.08.027.
    1. Wells P.S., Anderson D.R., Rodger M., Forgie M., Kearon C., Dreyer J., Kovacs G., Mitchell M., Lewandowski B., Kovacs M.J. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N. Engl. J. Med. 2003;349:1227–1235. doi: 10.1056/NEJMoa023153.
    1. Bucek R.A., Koca N., Reiter M., Haumer M., Zontsich T., Minar E. Algorithms for the diagnosis of deep-vein thrombosis in patients with low clinical pretest probability. Thromb. Res. 2002;105:43–47. doi: 10.1016/S0049-3848(01)00411-X.
    1. Righini M., Goehring C., Bounameaux H., Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am. J. Med. 2000;109:357–361. doi: 10.1016/S0002-9343(00)00493-9.
    1. Tardy B., Tardy-Poncet B., Viallon A., Lafond P., Page Y., Venet C., Bertrand J.C. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb. Haemost. 1998;79:38–41. doi: 10.1055/s-0037-1614215.
    1. Douma R.A., le Gal G., Söhne M., Righini M., Kamphuisen P.W., Perrier A., Kruip M.J., Bounameaux H., Büller H.R., Roy P.M. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: A retrospective analysis of 3 large cohorts. BMJ. 2010;340:c1475. doi: 10.1136/bmj.c1475.
    1. Kraaijenhagen R.A., in’t Anker P.S., Koopman M.M., Reitsma P.H., Prins M.H., van den Ende A., Buller H.R. High plasma concentration of factor VIII:C is a major risk factor for venous thromboembolism. Thromb. Haemost. 2000;83:5–9. doi: 10.1055/s-0037-1613747.
    1. Ay C., Vormittag R., Dunkler D., Simanek R., Chiriac A.L., Drach J., Quehenberger P., Wagner O., Zielinski C., Pabinger I. 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;27:4124–4129. doi: 10.1200/JCO.2008.21.7752.
    1. Sud R., Khorana A.A. Cancer-associated thrombosis: Risk factors, candidate biomarkers and a risk model. Thromb. Res. 2009;123:18–21. doi: 10.1016/S0049-3848(09)70137-9.
    1. Stender M.T., Frøkjaer J.B., Larsen T.B., Lundbye-Christensen S., Thorlacius-Ussing O. Preoperative plasma D-dimer is a predictor of postoperative deep venous thrombosis in colorectal cancer patients: A clinical, prospective cohort study with one-year follow-up. Dis. Colon Rectum. 2009;52:446–451. doi: 10.1007/DCR.0b013e318197e2b2.
    1. Kodama J., Seki N., Masahiro S., Kusumoto T., Nakamura K., Hongo A., Hiramatsu Y. D-dimer level as a risk factor for postoperative venous thromboembolism in Japanese women with gynecologic cancer. Ann. Oncol. 2010;21:1651–1656. doi: 10.1093/annonc/mdq012.
    1. Arpaia G., Carpenedo M., Verga M., Mastrogiacomo O., Fagnani D., Lanfredini M., Milani M., Cimminiello C. D-dimer before chemotherapy might predict venous thromboembolism. Blood Coagul. Fibrinolysis. 2009;20:170–175. doi: 10.1097/MBC.0b013e32831bc2de.
    1. Ferroni P., Martini F., Portarena I., Massimiani G., Riondino S., La Farina F., Mariotti S., Guadagni F., Roselli M. Novel high-sensitive D-dimer determination predicts chemotherapy-associated venous thromboembolism in intermediate risk lung cancer patients. Clin. Lung Cancer. 2012;13:482–487. doi: 10.1016/j.cllc.2012.03.005.
    1. Kondo S., Sasaki M., Hosoi H., Sakamoto Y., Morizane C., Ueno H., Okusaka T. Incidence and risk factors for venous thromboembolism in patients with pretreated advanced pancreatic carcinoma. Oncotarget. 2018;9:16883–16890. doi: 10.18632/oncotarget.24721.
    1. Park K., Ryoo B.Y., Ryu M.H., Park S.R., Kang M.J., Kim J.H., Han S., Kang Y.K. Incidence of venous thromboembolism and the role of D-dimer as predictive marker in patients with advanced gastric cancer receiving chemotherapy: A prospective study. World J. Gastrointest. Oncol. 2017;9:176–183. doi: 10.4251/wjgo.v9.i4.176.
    1. Roselli M., Ferroni P., Portarena I., Riondino S., La Farina F., Formica V., Vergati M., Guadagni F. Predictive value of high-sensitive D-dimer determination for chemotherapy-associated venous thromboembolism in gastrointestinal cancer patients. Thromb. Haemost. 2012;108:1243–1245. doi: 10.1160/TH12-06-0418.
    1. Wu J., Fu Z., Liu G., Xu P., Xu J., Jia X. Clinical significance of plasma D-dimer in ovarian cancer: A meta-analysis. Medicine. 2017;96:e7062. doi: 10.1097/MD.0000000000007062.
    1. Reitter E.M., Kaider A., Ay C., Quehenberger P., Marosi C., Zielinski C., Pabinger I. Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment. J. Thromb. Haemost. 2016;14:294–305. doi: 10.1111/jth.13218.
    1. Antonopoulos C.N., Sfyroeras G.S., Kakisis J.D., Moulakakis K.G., Liapis C.D. The role of soluble P selectin in the diagnosis of venous thromboembolism. Thromb. Res. 2014;133:17–24. doi: 10.1016/j.thromres.2013.08.014.
    1. Andre P., Hartwell D., Hrachovinova I., Saffaripour S., Wagner D.D. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc. Natl. Acad. Sci. USA. 2000;97:13835–13840. doi: 10.1073/pnas.250475997.
    1. Shattil S.J., Hoxie J.A., Cunningham M., Brass L.F. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J. Biol. Chem. 1985;260:11107–11114.
    1. McEver R.P., Zhu C. Rolling cell adhesion. Annu. Rev. Cell Dev. Biol. 2010;26:363–396. doi: 10.1146/annurev.cellbio.042308.113238.
    1. Fijnheer R., Frijns C.J.M., Korteweg J., Rommes H., Peters J.H., Sixma J.J., Nieuwenhuis H.K. The origin of P-selectin as a circulating plasma protein. Thromb. Haemost. 1997;77:1081–1085. doi: 10.1055/s-0038-1656116.
    1. Ferroni P., Martini F., Riondino S., La Farina F., Magnapera A., Ciatti F., Guadagni F. Soluble P-selectin as a marker of in vivo platelet activation. Clin. Chim. Acta. 2009;399:88–91. doi: 10.1016/j.cca.2008.09.018.
    1. Ferroni P., Riondino S., Vazzana N., Guadagni F., Davì G. Biomarkers of platelet activation in acute coronary syndromes. Thromb. Haemost. 2012;108:1109–1123. doi: 10.1160/TH12-08-0550.
    1. Ghozlan M.F., Osman A.A., Mahmoud H.M., Eissa D.G., Abuelela S. Comprehensive study on laboratory biomarkers for prediction and diagnosis of deep venous thrombosis. Blood Coagul. Fibrinolysis. 2015;26:255–260. doi: 10.1097/MBC.0000000000000164.
    1. Ay C., Simanek R., Vormittag R., Dunkler D., Alguel G., Koder S., Kornek G., Marosi C., Wagner O., Zielinski C., 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;112:2703–2708. doi: 10.1182/blood-2008-02-142422.
    1. Vormittag R., Simanek R., Ay C., Dunkler D., Quehenberger P., Marosi C., Zielinski C., Pabinger I. High factor VIII levels independently predict venous thromboembolism in cancer patients: The cancer and thrombosis study. Arterioscler. Thromb. Vasc. Biol. 2009;29:2176–2181. doi: 10.1161/ATVBAHA.109.190827.
    1. D’Souza-Schorey C., Clancy J.W. Tumor-derived microvesicles: Shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 2012;26:1287–1299. doi: 10.1101/gad.192351.112.
    1. Owens A.P., 3rd, Mackman N. Microparticles in hemostasis and thrombosis. Circ. Res. 2011;108:1284–1297. doi: 10.1161/CIRCRESAHA.110.233056.
    1. Langer F., Ruf W. Synergies of phosphatidylserine and protein disulfide isomerase in tissue factor activation. Thromb. Haemost. 2014;111:590–597. doi: 10.1160/TH13-09-0802.
    1. Aleman M.M., Gardiner C., Harrison P., Wolberg A.S. Differential contributions of monocyte- and platelet-derived microparticles towards thrombin generation and fibrin formation and stability. J. Thromb. Haemost. 2011;9:2251–2261. doi: 10.1111/j.1538-7836.2011.04488.x.
    1. Van Der Meijden P.E., Van Schilfgaarde M., Van Oerle R., Renné T., ten Cate H., Spronk H.M. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J. Thromb. Haemost. 2012;10:1355–1362. doi: 10.1111/j.1538-7836.2012.04758.x.
    1. Dachary-Prigent J., Freyssinet J.M., Pasquet J.M., Carron J.C., Nurden A.T. Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: A flow cytometry study showing a role for free sulfhydryl groups. Blood. 1993;81:2554–2565.
    1. Han X., Guo B., Li Y., Zhu B. Tissue factor in tumor microenvironment: A systematic review. J. Hematol. Oncol. 2014;1:7–54. doi: 10.1186/s13045-014-0054-8.
    1. Tilley R.E., 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;122:604–609. doi: 10.1016/j.thromres.2007.12.023.
    1. Toth B., Liebhardt S., Steinig K., Ditsch N., Rank A., Bauerfeind I., Spannagl M., Friese K., Reininger A.J. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb. Haemost. 2008;100:663–669. doi: 10.1160/TH07-10-0602.
    1. Thaler J., Ay C., Weinstabl H., Dunkler D., Simanek R., Vormittag R., Freyssinet J.M., Zielinski C., Pabinger I. Circulating procoagulant microparticles in cancer patients. Ann. Hematol. 2011;90:447–453. doi: 10.1007/s00277-010-1111-1.
    1. Laresche C., Pelletier F., Garnache-Ottou F., Lihoreau T., Biichle S., Mourey G., Saas P., Humbert P., Seilles E., Aubin F. Increased levels of circulating microparticles are associated with increased procoagulant activity in patients with cutaneous malignant melanoma. J. Investig. Dermatol. 2014;134:176–182. doi: 10.1038/jid.2013.288.
    1. Woei-A-Jin F.J., Tesselaar M.E., Garcia Rodriguez P., Romijn F.P., Bertina R.M., Osanto S. Tissue factor-bearing microparticles and CA19.9: Two players in pancreatic cancer-associated thrombosis? Br. J. Cancer. 2016;115:332–338. doi: 10.1038/bjc.2016.170.
    1. Fricke A., Ullrich P.V., Cimniak A.F.V., Becherer C., Follo M., Heinz J., Scholber J., Herget G.W., Hauschild O., Wittel U.A., et al. Levels of activated platelet-derived microvesicles in patients with soft tissue sarcoma correlate with an increased risk of venous thromboembolism. BMC Cancer. 2017;7:17–527. doi: 10.1186/s12885-017-3515-y.
    1. Campello E., Spiezia L., Radu C.M., Bulato C., Castelli M., Gavasso S., Simioni P. Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb. Res. 2011;127:473–477. doi: 10.1016/j.thromres.2011.01.002.
    1. Zwicker J.I., Liebman H.A., Neuberg D., Lacroix R., Bauer K.A., Furie B.C., Furie B. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin. Cancer Res. 2009;15:6830–6840. doi: 10.1158/1078-0432.CCR-09-0371.
    1. van Doormaal F., Kleinjan A., Berckmans R.J., Mackman N., Manly D., Kamphuisen P.W., Richel D.J., Büller H.R., Sturk A., Nieuwland R. Coagulation activation and microparticle-associated coagulant activity in cancer patients. An exploratory prospective study. Thromb. Haemost. 2012;108:160–165. doi: 10.1160/TH12-02-0099.
    1. Tesselaar M.E., Romijn F.P., van der Linden I.K., Prins F.A., Bertina R.M., Osanto S. Microparticles-associated tissue factor activity: A link between cancer and thrombosis? J. Thromb. Haemost. 2007;5:520–527. doi: 10.1111/j.1538-7836.2007.02369.x.
    1. Lee R.D., Barcel D.A., Williams J.C., Wang J.G., Boles J.C., Manly D.A., Key N.S., Mackman N. Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity. Thromb. Res. 2012;129:80–85. doi: 10.1016/j.thromres.2011.06.004.
    1. Yuana Y., Bertina R.M., Osanto S. Pre-analytical and analytical issues in the analysis of blood microparticles. Thromb. Haemost. 2011;105:396–408. doi: 10.1160/TH10-09-0595.
    1. Mooberry M.J., Key N.S. Microparticle analysis in disorders of hemostasis and thrombosis. Cytom. A. 2016;89:111–122. doi: 10.1002/cyto.a.22647.
    1. Guthrie G.J., Roxburgh C.S., Horgan P.G., McMillan D.C. Does interleukin-6 link explain the link between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer? Cancer Treat. Rev. 2013;39:89–96. doi: 10.1016/j.ctrv.2012.07.003.
    1. Kaminska J., Kowalska M.M., Nowacki M.P., Chwalinski M.G., Rysinska A., Fuksiewicz M. CRP, TNF-alpha, IL-1ra, IL-6, IL-8 and IL-10 in blood serum of colorectal cancer patients. Pathol. Oncol. Res. 2000;6:38–41. doi: 10.1007/BF03032656.
    1. Reitter E.M., Ay C., Kaider A., Pirker R., Zielinski C., Zlabinger G., Pabinger I. Interleukin levels and their potential association with venous thromboembolism and survival in cancer patients. Clin. Exp. Immunol. 2014;177:253–260. doi: 10.1111/cei.12308.
    1. Nilsson M.B., Langley R.R., Fidler I.J. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65:10794–10800. doi: 10.1158/0008-5472.CAN-05-0623.
    1. Stone R.L., Nick A.M., McNeish I.A., Balkwill F., Han H.D., Bottsford-Miller J., Rupairmoole R., Armaiz-Pena G.N., Pecot C.V., Coward J., et al. Paraneoplastic thrombocytosis in ovarian cancer. N. Engl. J. Med. 2012;366:610–618. doi: 10.1056/NEJMoa1110352.
    1. Matsuo K., Hasegawa K., Yoshino K., Murakami R., Hisamatsu T., Stone R.L., Previs R.A., Hansen J.M., Ikeda Y., Miyara A., et al. Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. Eur. J. Cancer. 2015;51:1978–1988. doi: 10.1016/j.ejca.2015.07.012.
    1. Sarig G., Miacheli Y., Lanir N., Brenner B., Haim N. Mechanisms for acquired activated protein C resistance in cancer patients. J. Thromb. Haemost. 2005;3:589–590. doi: 10.1111/j.1538-7836.2005.01168.x.
    1. Haim N., Lanir N., Hoffman R., Haim A., Tsalik M., Brenner B. Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism. Am. J. Med. 2001;110:91–96. doi: 10.1016/S0002-9343(00)00691-4.
    1. Green D., Maliekel K., Sushko E., Akhtar R., Soff G.A. Activated-protein-C resistance in cancer patients. Haemostasis. 1997;27:112–118. doi: 10.1159/000217442.
    1. Erman M., Abali H., Oran B., Haznedaroglu I.C., Canpinar H., Kirazli S., Celik I. Tamoxifen-induced tissue factor pathway inhibitor reduction: A clue for an acquired thrombophilic state? Ann. Oncol. 2004;15:1622–1626. doi: 10.1093/annonc/mdh437.
    1. Elice F., Fink L., Tricot G., Barlogie B., Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Br. J. Haematol. 2006;134:399–405. doi: 10.1111/j.1365-2141.2006.06208.x.
    1. Ferroni P., Martini F., Portarena I., Grenga I., Riondino S., La Farina F., Laudisi A., Roselli M., Guadagni F. An activated protein C-dependent thrombin generation assay predicts chemotherapy-associated venous thromboembolism in cancer patients. Thromb. Haemost. 2011;105:931–932. doi: 10.1160/TH10-11-0757.
    1. Negaard H.F.S., Iversen P.O., Østenstad B., Mowinckel M.C., Sandset P.M. Increased acquired activated protein C resistance in unselected patients with hematological malignancies. J. Thromb. Haemost. 2008;6:1482–1487. doi: 10.1111/j.1538-7836.2008.03060.x.
    1. Ferroni P., Riondino S., Portarena I., Formica V., La Farina F., Martini F., Massimiani G., Palmirotta R., Guadagni F., Roselli M. Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer. Int. J. Colorectal Dis. 2012;27:1561–1567. doi: 10.1007/s00384-012-1493-8.
    1. Reitsma P.H., Rosendaal F.R. Activation of innate immunity in patients with venous thrombosis: The Leiden Thrombophilia Study. J. Thromb. Haemost. 2004;2:619–622. doi: 10.1111/j.1538-7836.2004.00689.x.
    1. Federici A.B. The von Willebrand factor from basic mechanisms to clinical practice. Blood Transfus. 2011;9:s1–s2. doi: 10.2450/2011.001S.
    1. Koster T., Blann A.D., Briet E., Vandenbroucke J.P., Rosendaal F.R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345:152–155. doi: 10.1016/S0140-6736(95)90166-3.
    1. Tsai A.W., Cushman M., Rosamond W.D., Heckbert S.R., Tracy R.P., Aleksic N., Folsom A.R. Coagulation factors, inflammation markers, and venous thromboembolism: The longitudinal investigation of thromboembolism etiology (LITE) Am. J. Med. 2002;113:636–642. doi: 10.1016/S0002-9343(02)01345-1.
    1. Payne A.B., Miller C.H., Hooper W.C., Lally C., Austin H.D. High factor VIII, von Willebrand factor, and fibrinogen levels and risk of venous thromboembolism in blacks and whites. Ethn. Dis. 2014;24:169–174.
    1. Jenkins P.V., Rawley O., Smith O.P., O’Donnell J.S. Elevated factor VIII levels and risk of venous thrombosis. Br. J. Haematol. 2012;157:653–663. doi: 10.1111/j.1365-2141.2012.09134.x.
    1. Kyrle P.A., Minar E., Hirschl M., Bialonczyk C., Stain M., Schneider B., Weltermann A., Speiser W., Lechner K., Eichinger S. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N. Eng. J. Med. 2000;343:457–462. doi: 10.1056/NEJM200008173430702.
    1. Legnani C., Cosmi B., Cini M., Frascaro M., Guazzaloca G., Palareti G. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br. J. Haematol. 2004;124:504–510. doi: 10.1046/j.1365-2141.2003.04795.x.
    1. Rickles F.R., Levine M.N., Dvorak H.F. Abnormalities of hemostasis in malignancy. In: Colman R.W., Hirsh J., Marder V.J., Clowes A.W., George J.N., editors. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2001. pp. 1131–1152.
    1. Ferroni P., Santilli F., Guadagni F., Basili S., Davì G. Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis. Curr. Med. Chem. 2007;14:2170–2180. doi: 10.2174/092986707781389664.
    1. Thomas M.R., Storey R.F. The role of platelets in inflammation. Thromb. Haemost. 2015;114:449–458. doi: 10.1160/TH14-12-1067.
    1. Nilsson R.J.A., Balaj L., Hulleman E., van Rijn S., Pegtel D.M., Walraven M., Widmark A., Gerritsen W.R., Verheul H.M., Vandertop W.P., et al. Blood platelets contain tumor-derived RNA biomarkers. Blood. 2011;118:3680–3683. doi: 10.1182/blood-2011-03-344408.
    1. Plantureux L., Crescence L., Dignat-George F., Panicot-Dubois L., Dubois C. Effects of platelets on cancer progression. Thromb. Res. 2018;164(Suppl. 1):S40–S47. doi: 10.1016/j.thromres.2018.01.035.
    1. Khorana A.A., Francis C.W., Culakova E., Lyman G.H. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104:2822–2829. doi: 10.1002/cncr.21496.
    1. Mandalà M., Barni S., Prins M., Labianca R., Tondini C., Russo L., Milesi A., Cremonesi M., Zaccanelli M., Regonesi C., et al. Acquired and inherited risk factors for developing venous thromboembolism in cancer patients receiving adjuvant chemotherapy: A prospective trial. Ann. Oncol. 2010;21:871–876. doi: 10.1093/annonc/mdp354.
    1. Vemulapalli S., Chintala L., Tsimberidou A.M., Dhillon N., Lei X., Hong D., Kurzrock R. Clinical outcomes and factors predicting development of venous thromboembolic complications in patients with advanced refractory cancer in a Phase I Clinic: The M. D. Anderson Cancer Center experience. Am. J. Hematol. 2009;84:408–413. doi: 10.1002/ajh.21423.
    1. Simanek R., Vormittag R., Ay C., Alguel G., Dunkler D., Schwarzinger I., Steger G., Jaeger U., Zielinski C., Pabinger I. High platelet count associated with venous thromboembolism in cancer patients: Results from the Vienna Cancer and Thrombosis Study (CATS) J. Thromb. Haemost. 2010;8:114–120. doi: 10.1111/j.1538-7836.2009.03680.x.
    1. Poruk K.E., Firpo M.A., Huerter L.M., Scaife C.L., Emerson L.L., Boucher K.M., Jones K.A., Mulvihill S.J. Serum platelet factor 4 is an independent predictor of survival and venous thromboembolism in patients with pancreatic adenocarcinoma. Cancer Epidemiol. Biomark. Prev. 2010;19:2605–2610. doi: 10.1158/1055-9965.EPI-10-0178.
    1. Jensvoll H., Blix K., Brækkan S.K., Hansen J.B. Platelet count measured prior to cancer development is a risk factor for future symptomatic venous thromboembolism: The Tromsø Study. PLoS ONE. 2014;9:e92011. doi: 10.1371/journal.pone.0092011.
    1. Ferroni P., Guadagni F., Riondino S., Portarena I., Mariotti S., La Farina F., Davi G., Roselli M. Evaluation of mean platelet volume as a predictive marker for cancer-associated venous thromboembolism during chemotherapy. Haematologica. 2014;99:1638–1644. doi: 10.3324/haematol.2014.109470.
    1. Riedl J., Kaider A., Reitter E.M., Marosi C., Jäger U., Schwarzinger I., Zielinski C., Pabinger I., Ay C. Association of mean platelet volume with risk of venous thromboembolism and mortality in patients with cancer. Results from the Vienna Cancer and Thrombosis Study (CATS) Thromb. Haemost. 2014;111:670–678. doi: 10.1160/TH13-07-0603.
    1. Rupa-Matysek J., Gil L., Barańska M., Dytfeld D., Komarnicki M. Mean platelet volume as a predictive marker for venous thromboembolism in patients treated for Hodgkin lymphoma. Oncotarget. 2018;9:21190–21200. doi: 10.18632/oncotarget.25002.
    1. Rupa-Matysek J., Gil L., Kroll-Balcerzak R., Barańska M., Komarnicki M. Mean platelet volume as a predictive marker for venous thromboembolism and mortality in patients treated for diffuse large B-cell lymphoma. Hematol. Oncol. 2017;35:456–464. doi: 10.1002/hon.2321.
    1. Ferroni P., Riondino S., Formica V., Cereda V., Tosetto L., La Farina F., Valente M.G., Vergati M., Guadagni F., Roselli M. Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio. Int. J. Cancer. 2015;136:1234–1240. doi: 10.1002/ijc.29076.
    1. Trujillo-Santos J., Di Micco P., Iannuzzo M., Lecumberri R., Guijarro R., Madridano O., Monreal M., RIETE Investigators Elevated white blood cell count and outcome in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb. Haemost. 2008;100:905–911. doi: 10.1160/TH08-05-0339.
    1. Blix K., Jensvoll H., Brækkan S.K., Hansen J.B. White blood cell count measured prior to cancer development is associated with future risk of venous thromboembolism—The Tromsø study. PLoS ONE. 2013;8:e73447. doi: 10.1371/journal.pone.0073447.
    1. Connolly G.C., Khorana A.A., Kuderer N.M., Culakova E., Francis C.W., Lyman G.H. Leukocytosis, thrombosis and early mortality in cancer patients initiating chemotherapy. Thromb. Res. 2010;126:113–118. doi: 10.1016/j.thromres.2010.05.012.
    1. Rojnuckarin P., Uaprasert N., Sriuranpong V. Monocyte count associated with subsequent symptomatic venous thromboembolism (VTE) in hospitalized patients with solid tumors. Thromb. Res. 2012;130:e279–e282. doi: 10.1016/j.thromres.2012.09.015.
    1. Pabinger I., Posch F. Flamethrowers: Blood cells and cancer thrombosis risk. Hematology Am. Soc. Hematol. Educ. Program. 2014;2014:410–417. doi: 10.1182/asheducation-2014.1.410.
    1. Budzianowski J., Pieszko K., Burchardt P., Rzeźniczak J., Hiczkiewicz J. The role of hematological indices in patients with acute coronary syndrome. Dis. Mark. 2017;2017:3041565. doi: 10.1155/2017/3041565.
    1. Yang W., Liu Y. Platelet-lymphocyte ratio is a predictor of venous thromboembolism in cancer patients. Thromb. Res. 2015;136:212–215. doi: 10.1016/j.thromres.2014.11.025.
    1. Tham T., Rahman L., Persaud C., Olson C., Costantino P. Venous thromboembolism risk in head and neck cancer: Significance of the preoperative platelet-to-lymphocyte ratio. Otolaryngol. Head Neck. Surg. 2018;159:85–91. doi: 10.1177/0194599818756851.
    1. Grilz E., Posch F., Königsbrügge O., Schwarzinger I., Lang I.M., Marosi C., Pabinger I., Ay C. Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with the risk of thromboembolism and mortality in patients with cancer. Thromb. Haemost. 2018;118:1875–1884. doi: 10.1055/s-0038-1673401.
    1. Königsbrügge O., Posch F., Riedl J., Reitter E.-M., Zielinski C., Pabinger I., Ay C. Association between decreased serum albumin with risk of venous thromboembolism and mortality in cancer patients. Oncologist. 2016;21:252–257. doi: 10.1634/theoncologist.2015-0284.
    1. Shah M.A., Capanu M., Soff G., Asmis T., Kelsen D.P. Risk factors for developing a new venous thromboembolism in ambulatory patients with non-hematologic malignancies and impact on survival for gastroesophageal malignancies. J. Thromb. Haemost. 2010;8:1702–1709. doi: 10.1111/j.1538-7836.2010.03948.x.
    1. Ferroni P., Roselli M., Riondino S., Cavaliere F., Guadagni F. Insulin resistance as a predictor of venous thromboembolism in breast cancer. Endocr. Relat. Cancer. 2016;23:L25–L28. doi: 10.1530/ERC-16-0187.
    1. Guadagni F., Riondino S., Formica V., Del Monte G., Morelli A.M., Lucchetti J., Spila A., D’Alessandro R., Della-Morte D., Ferroni P., et al. Clinical significance of glycemic parameters on venous thromboembolism risk prediction in gastrointestinal cancer. World J. Gastroenterol. 2017;23:5187–5195. doi: 10.3748/wjg.v23.i28.5187.
    1. Stegenga M.E., van der Crabben S.N., Blumer R.M., Levi M., Meijers J.C., Serlie M.J., Tanck M.W., Sauerwein H.P., van der Poll T. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood. 2008;112:82–89. doi: 10.1182/blood-2007-11-121723.
    1. Ferroni P., Roselli M., Riondino S., Guadagni F. Predictive value of HDL cholesterol for cancer-associated venous thromboembolism during chemotherapy. J. Thromb. Haemost. 2014;12:2049–2053. doi: 10.1111/jth.12737.
    1. Lötsch F., Königsbrügge O., Posch F., Zielinski C., Pabinger I., Ay C. Statins are associated with low risk of venous thromboembolism in patients with cancer: A prospective and observational cohort study. Thromb. Res. 2014;134:1008–1013. doi: 10.1016/j.thromres.2014.09.001.
    1. Khemasuwan D., Divietro M.L., Tangdhanakanond K., Pomerantz S.C., Eiger G. Statins decrease the occurrence of venous thromboembolism in patients with cancer. Am. J. Med. 2010;123:60–65. doi: 10.1016/j.amjmed.2009.05.025.
    1. De Moreuil C., Le Mao R., Tromeur C., Couturaud F., Lacut K., Delluc A. Association between statin exposure and venous thromboembolism risk in cancer patients. Data from the EDITH case-control study. Eur. J. Intern. Med. 2017;46:e42–e44. doi: 10.1016/j.ejim.2017.10.008.
    1. El-Refai S.M., Black E.P., Adams V.R., Talbert J.C., Brown J.D. Statin use and venous thromboembolism in cancer: A large, active comparator, propensity score matched cohort study. Thromb. Res. 2017;158:49–58. doi: 10.1016/j.thromres.2017.08.001.
    1. Peippo M.H., Kurki S., Lassila R., Carpén O.M. Real-world features associated with cancer-related venous thromboembolic events. ESMO Open. 2018;3:e000363. doi: 10.1136/esmoopen-2018-000363.
    1. Ferroni P., Guadagni F., Laudisi A., Vergati M., Riondino S., Russo A., Davì G., Roselli M. Estimated glomerular filtration rate is an easy predictor of venous thromboembolism in cancer patients undergoing platinum-based chemotherapy. Oncologist. 2014;19:562–567. doi: 10.1634/theoncologist.2013-0339.
    1. Khorana A.A., Otten H.M., Zwicker J.I., Connolly G.C., Bancel D.F., Pabinger I. Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism in cancer outpatients: Guidance from the SSC of the ISTH. J. Thromb. Haemost. 2014;12:1928–1931. doi: 10.1111/jth.12725.
    1. Lee Y.G., Lee E., Kim I., Lee K.W., Kim T.M., Lee S.H., Kim D.W., Heo D.S. Cisplatin-based chemotherapy is a strong risk factor for thromboembolic events in small-cell lung cancer. Cancer Res. Treat. 2015;47:670–675. doi: 10.4143/crt.2014.045.
    1. Alexander M., Burbury K. A systematic review of biomarkers for the prediction of thromboembolism in lung cancer—Results, practical issues and proposed strategies for future risk prediction models. Thromb. Res. 2016;148:63–69. doi: 10.1016/j.thromres.2016.10.020.
    1. van Es N., Franke V.F., Middeldorp S., Wilmink J.W., Büller H.R. The Khorana score for the prediction of venous thromboembolism in patients with pancreatic cancer. Thromb. Res. 2017;150:30–32. doi: 10.1016/j.thromres.2016.12.013.
    1. Khorana A.A., Soff G.A., Kakkar A.K., Vadhan-Raj S., Riess H., Wun T., Streiff M.B., Garcia D.A., Liebman H.A., Belani C., et al. Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI); Proceedings of the 60th American Society of Hematology (ASH) Annual Meeting and Exposition; San Diego, CA, USA. 1–4 December 2018.
    1. Carrier M., Abou-Nassar K., Mallick R., Tagalakis V., Shivakumar S., Schattner A., Kuruvilla P., Hill D., Spadafora S., Marquis K., et al. AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N. Engl. J. Med. 2018 doi: 10.1056/NEJMoa1814468.
    1. Mulder F.I., Candeloro M., Kamphuisen P.W., Di Nisio M., Bossuyt P.M., Guman N., Smit K., Büller H.R., van Es N., CAT Prediction Collaborators The Khorana score for prediction of venous thromboembolism in cancer patients: A systematic review and meta-analysis. Haematologica. 2019 doi: 10.3324/haematol.2018.209114.
    1. Scotté F., Elalamy I., Mayeur D., Meyer G. Physicians’ decision about long-term thromboprophylaxis in cancer outpatients: CAT AXIS, a case vignette study on clinical practice in France. Support. Care Cancer. 2018;26:2049–2056. doi: 10.1007/s00520-017-4034-8.
    1. Van Es N., Di Nisio M., Cesarman G., Kleinjan A., Otten H.M., Mahé I., Wilts I.T., Twint D.C., Porreca E., Arrieta O., et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: A prospective cohort study. Haematologica. 2017;102:1494–1501. doi: 10.3324/haematol.2017.169060.
    1. Gerotziafas G.T., Taher A., Abdel-Razeq H., AboElnazar E., Spyropoulos A.C., El Shemmari S., Larsen A.K., Elalamy I. COMPASS–CAT Working Group. A predictive score for thrombosis associated with breast, colorectal, lung, or ovarian cancer: The Prospective COMPASS-Cancer-Associated Thrombosis Study. Oncologist. 2017;22:1222–1231. doi: 10.1634/theoncologist.2016-0414.
    1. Cella C.A., Di Minno G., Carlomagno C., Arcopinto M., Cerbone A.M., Matano E., Tufano A., Lordick F., De Simone B., Arturo C., et al. Preventing venous thromboembolism in ambulatory cancer patients: The ONKOTEV Study. Oncologist. 2017;22:601–608. doi: 10.1634/theoncologist.2016-0246.
    1. Muñoz Martín A.J., Ortega I., Font C., Pachón V., Castellón V., Martínez-Marín V., Salgado M., Martínez E., Calzas J., Rupérez A., et al. Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer. Br. J. Cancer. 2018;118:1056–1061. doi: 10.1038/s41416-018-0027-8.
    1. Pabinger I., van Es N., Heinze G., Posch F., Riedl J., Reitter E.M., Di Nisio M., Cesarman-Maus G., Kraaijpoel N., Zielinski C.C., et al. A clinical prediction model for cancer-associated venous thromboembolism: A development and validation study in two independent prospective cohorts. Lancet Haematol. 2018;5:e289–e298. doi: 10.1016/S2352-3026(18)30063-2.
    1. Ferroni P., Roselli M., Zanzotto F.M., Guadagni F. Artificial intelligence for cancer-associated thrombosis risk assessment. Lancet Haematol. 2018;5:e391. doi: 10.1016/S2352-3026(18)30111-X.
    1. Cancer Moonshot℠. [(accessed on 7 December 2018)]; Available online: .
    1. Fayyad U., Shapiro G., Smyth P. From data mining to knowledge discovery in database. AI Mag. 1996;17:37–54.
    1. Ferroni P., Zanzotto F.M., Scarpato N., Riondino S., Nanni U., Roselli M., Guadagni F. Risk Assessment for venous thromboembolism in chemotherapy-treated ambulatory cancer patients: A machine learning approach. Med. Decis. Mak. 2017;37:234–242. doi: 10.1177/0272989X16662654.
    1. Ferroni P., Zanzotto F.M., Scarpato N., Riondino S., Guadagni F., Roselli M. Validation of a machine learning approach for venous thromboembolism risk prediction in oncology. Dis. Mark. 2017;2017:8781379. doi: 10.1155/2017/8781379.
    1. Lustig D.B., Rodriguez R., Wells P.S. Implementation and validation of a risk stratification method at The Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis. Thromb. Res. 2015;136:1099–1102. doi: 10.1016/j.thromres.2015.08.002.
    1. Wu P.Y., Cheng C.W., Kaddi C., Venugopalan J., Hoffman R., Wang M.D. Omic and electronic health record Big Data analytics for precision medicine. IEEE Trans. Biomed. Eng. 2017;64:263–273. doi: 10.1109/TBME.2016.2573285.
    1. Alonso S.G., de la Torre Díez I., Rodrigues J.J.P.C., Hamrioui S., López-Coronado M. A systematic review of techniques and sources of Big Data in the healthcare sector. J. Med. Syst. 2017;41:183. doi: 10.1007/s10916-017-0832-2.

Source: PubMed

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