Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciences0869-60472414-3545"Paediatrician" Publishers LLC145910.15690/vramn1459Review ArticleRisk Factors in Cancer PatientsSlukhanchukEkaterina V.<p>MD, PhD</p>beloborodova@rambler.ruhttps://orcid.org/0000-0001-7441-2778BitsadzeVictoria O.<p>MD, PhD, Professor</p>vikabits@mail.ruhttps://orcid.org/0000-0001-8404-1042TyanAnatoly G.<p>MD, PhD</p>tag-75@mail.ruhttps://orcid.org/0000-0003-1659-4256KhizroevaJamilya Kh.<p>MD, PhD, Professor</p>jamatotu@gmail.comhttps://orcid.org/0000-0002-0725-9686TretyakovaMaria V.<p>MD, PhD</p>tretyakova777@yandex.ruhttps://orcid.org/0000-0002-3628-0804SolopovaAntonina G.<p>MD, PhD, Professor</p>antoninasolopova@yandex.ruhttps://orcid.org/0000-0002-7456-2386MuyangMeng<p>PhD Student</p>mmy88888@163.comhttps://orcid.org/0000-0002-8326-556XElalamyIsmail<p>MD, PhD, Professor</p>ismail.elalamy@aphp.frhttps://orcid.org/0000-0002-9576-1368GrisJean-Christophe<p>MD, PhD, Professor</p>jean.christophe.gris@chu-nimes.frhttps://orcid.org/0000-0002-9899-9910AyCihan<p>Department of Medicine, Clinical Division of Hematology and Hemostaseology, MD, Professor</p>cihan.ay@hotmail.comhttps://orcid.org/0000-0003-2607-9717MakatsariaAleksander D.<p>MD, PhD, Professor, Academician of the RAS</p>gemostasis@mail.ruhttps://orcid.org/0000-0001-7415-4633Petrovsky National Research Centre of SurgeryI.M. Sechenov First Moscow State Medical University (Sechenov University)“Medical Center” LLCMedicine Sorbonne University, Thrombosis Center, Tenon University HospitalUniversity MontpellierMedical University of Vienna301120217654654750610202006102021Copyright © 2021, "Paediatrician" Publishers LLC2021<p>Numerous studies in recent years have proven that the oncological process is an independent risk factor for thrombosis. For a long period of time and at the moment, research is continuing on the pathogenesis of a prothrombotic state in cancer patients. It was shown that the degree of risk is influenced by such indicators as the histological type of tumor, the stage of development of the disease, surgery, duration and type of anesthesia, chemotherapy, hormonal therapy, age, the presence of central venous catheters, immobilization, thrombophilia, history of thrombosis, infections. Thrombosis in cancer patients is triggered by thrombogenic factors associated with the tumor, patient-associated factors and environmental factors. The tumor cell affects the balance of hemostasis by releasing procoagulant substances, profibrinolytic, proproteolytic and proaggregant activity, expression of adhesion molecules, secretion of proinflammatory and proangiogenic cytokines; new participants in the process have also been identified. Studies have confirmed the fact that inflammation and thrombosis are inextricably linked with each other and play an important role in the progression of the disease and metastasis. All this opens up new horizons for the development of modern innovative strategies for treating cancer patients and increasing survival.</p>thrombosisrisk factorsoncological processmetastasispathogenesis of thrombosisтромбозфакторы рискаонкологический процессметастазированиепатогенез тромбоза[Wun T, White RH. Venous thromboembolism (VTE) in patients with cancer: epidemiology and risk factors. Cancer Invest. 2009;27 (Suppl 1):63–74. doi: https://doi.org/10.1080/07357900802656681][O’Connell C, Razavi P, Ghalichi M, et al. Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi‐row detector computed tomography scanning. J Thromb Haemost. 2011;9(2):305–311. doi: https://doi.org/10.1111/j.1538-7836.2010.04114.x][Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies. J Clin Oncol. 2009;27:4848–4857 doi: https://doi.org/10.1097/CCO.0b013e3283592331][Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer. 2010;102:S2–S9. doi: https://doi.org/10.1038/sj.bjc.6605599][Chen N, Ren M, Li R, et al. Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma. Mol Cancer. 2015;14:140. doi: https://doi.org/10.1186/s12943-015-0418-x][Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single‐institution study. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2009;115:3919–3923. doi: https://doi.org/10.1002/cncr.24480][Blix K, Jensvoll H, Brækkan SK, 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: https://doi.org/10.1371/journal.pone.0073447][Kim J-E, Lee N, Gu J-Y, et al. Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation. Thromb Res. 2015;135:1064–1069. doi: https://doi.org/10.1016/j.thromres.2015.03.014][Geddings JE, Hisada Y, Boulaftali Y, et al. Tissue factor–positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost. 2016;14:153–166. doi: https://doi.org/10.1111/jth.13181][Gardiner C, Harrison P, Belting M, et al. Extracellular vesicles, tissue factor, cancer and thrombosis–discussion themes of the ISEV 2014 Educational Day. J Extracell Vesicles. 2015;4:26901. doi: https://doi.org/10.3402/jev.v4.26901][Stark K, Schubert I, Joshi U, et al. Distinct pathogenesis of pancreatic cancer microvesicle-associated venous thrombosis identifies new antithrombotic targets in vivo. Arterioscler Thromb Vasc Biol. 2018;38:772–786. doi: https://doi.org/10.1161/ATVBAHA.117.310262][Geddings JE, Mackman N. Tumor-derived tissue factor–positive microparticles and venous thrombosis in cancer patients. Blood. 2013;122:1873–1880. doi: https://doi.org/10.1182/blood-2013-04-460139][Shindo K, Aishima S, Ohuchida K, et al. Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer. 2013;12:168. doi: https://doi.org/10.1186/1476-4598-12-168][Gagliano N, Celesti G, Tacchini L, et al. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma: Characterization in a 3D-cell culture model. World J Gastroenterol. 2016;22(18):4466–4483. doi: https://doi.org/10.3748/wjg.v22.i18.4466][Payne H, Ponomaryov T, Watson SP, et al. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood. 2017;129:2013–2020. doi: https://doi.org/10.1182/blood-2016-09-742999][Abdol Razak NB, Jones G, Bhandari M, et al. Cancer-associated thrombosis: An overview of mechanisms, risk factors, and treatment. Cancers. 2018;10:380. doi: https://doi.org/10.3390/cancers10100380][Chrysanthopoulou A, Kambas K, Stakos D, et al. Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation. The Journal of Pathology. 2017;243:111–122. doi: https://doi.org/10.1002/path.4935][Abdol Razak N, Elaskalani O, Metharom P. Pancreatic cancer-induced neutrophil extracellular traps: A potential contributor to cancer-associated thrombosis. Int J Mol Sci. 2017;18(3):487 doi: https://doi.org/10.3390/ijms18030487][Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535. doi: https://doi.org/10.1126/science.1092385][Von Brühl M-L, Stark K, Steinhart A, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4):819–835. doi: https://doi.org/10.1084/jem.20112322][Brill A, Fuchs T, Savchenko A, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10:136–144. doi: https://doi.org/10.1111/j.1538-7836.2011.04544.x][Leal AC, Mizurini DM, Gomes T, et al. Tumor-derived exosomes induce the formation of neutrophil extracellular traps: Implications for the establishment of cancer-associated thrombosis. Sci Rep. 2017;7:1–12. doi: https://doi.org/10.1038/s41598-017-06893-7][Brinkmann V. Neutrophil extracellular traps in the second decade. J Innate Immun. 2018;10:414–421. doi: https://doi.org/10.1159/000489829][Lam FW, Cruz MA, Parikh K, et al. Histones stimulate von Willebrand factor release in vitro and in vivo. Haematologica. 2016;101:e277. doi: https://doi.org/10.3324/haematol.2015.140632][McDonald B, Davis RP, Kim S-J, et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood. 2017;129:1357–1367. doi: https://doi.org/10.1182/blood-2016-09-741298][Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012;32:1777–1783. doi: https://doi.org/10.1161/ATVBAHA.111.242859][Mauracher LM, Posch F, Martinod K, et al. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost. 2018;16:508–518. doi: https://doi.org/10.1111/jth.13951][Wolach O, Sellar RS, Martinod K, et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med. 2018;10(436):eaan8292. doi: https://doi.org/10.1126/scitranslmed.aan8292][Schedel F, Mayer‐Hain S, Pappelbaum KI, et al. Evidence and impact of neutrophil extracellular traps in malignant melanoma. Pigment Cell Melanoma Res. 2020;33:63–73. doi: https://doi.org/10.1111/pcmr.12818][Teijeira Á, Garasa S, Gato M, et al. Cxcr1 and cxcr2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity. 2020. doi: https://doi.org/10.1016/j.immuni.2020.03.001][Khizroeva J, Makatsariya A, Bitsadze V, et al. Laboratory monitoring of COVID-19 patients and importance of coagulopathy markers. Obstetrics, Gynecology and Reproduction. 2020;14:132–147. doi: https://doi.org/10.17749/2313-7347.141][Yang L-Y, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. Journal of Hematology & Oncology. 2020;13:1–15. doi: https://doi.org/10.1186/s13045-019-0836-0][Makatsariya A, Slukhanchuk E, Bitsadze V, et al. COVID-19, neutrophil extracellular traps and vascular complications in obstetric practice. J Perinat Med. 2020;48(9):985-994. doi: https://doi.org/10.1515/jpm-2020-0280][White C, Noble SI, Watson M, et al. Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): A prospective longitudinal observational study. Lancet Haematol. 2019;6:e79–e88. doi: https://doi.org/10.1016/S2352-3026(18)30215-1][Grilz E, Mauracher LM, Posch F, et al. Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer. Br J Haematol. 2019;186:311–320. doi: https://doi.org/10.1111/bjh.15906][Meier TR, Myers Jr DD, Wrobleski SK, et al. Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation. Thromb Haemostas. 2008;99:343–351. doi: https://doi.org/10.1160/TH07-10-0608][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;112:2703–2708. doi: https://doi.org/10.1182/blood-2008-02-142422][Kaur S, Kumar S, Momi N, et al. Mucins in pancreatic cancer and its microenvironment. Nat Rev Gastroenterol Hepatol. 2013;10:607–620. doi: https://doi.org/10.1038/nrgastro.2013.120][Shao B, Wahrenbrock MG, Yao L, et al. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood. 2011;118:4015–4023. doi: https://doi.org/10.1182/blood-2011-07-368514][Muz B, de la Puente P, Azab F, et al. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83. doi: https://doi.org/10.2147/HP.S93413][Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2017;36:293–303. doi: https://doi.org/10.1038/onc.2016.206][Hernandez C, Huebener P, Schwabe RF. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene. 2016;35:5931–5941. doi: https://doi.org/10.1038/onc.2016.104][Yang X, Wang H, Zhang M, et al. HMGB1: a novel protein that induced platelets active and aggregation via Toll-like receptor-4, NF-κB and cGMP dependent mechanisms. Diagn Pathol. 2015;10:134. doi: https://doi.org/10.1186/s13000-018-0747-3][Tadie J-M, Bae H-B, Jiang S, et al. HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am J Physiol Lung Cell Mol Physiol. 2013;304(5):L342–L349. doi: https://doi.org/10.1152/ajplung.00151.2012][Khorana AA. The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: Strategies for improving VTE prophylaxis in hospitalized cancer patients. Oncologist. 2007;12(11):1361–1370. doi: https://doi.org/10.1634/theoncologist.12-11-1361][Lechner D, Kollars M, Gleiss A, et al. Chemotherapy‐induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity. J Thromb Haemost. 2007;5:2445–2452. doi: https://doi.org/10.1111/j.1538-7836.2007.02788.x][Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: A review. Oncologist. 2011;16:432. doi: https://doi.org/10.1634/theoncologist.2010-0271][Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clin Oncol. 2005;23:5474–5483. doi: https://doi.org/10.1200/JCO.2005.04.192][Choueiri TK, Schutz F, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28(13):2280–2285. doi: https://doi.org/10.1200/JCO.2009.27.2757][Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: Results of a comprehensive meta-analysis. J Natl Cancer Inst. 2005;97(7):489–498. doi: https://doi.org/10.1093/jnci/dji087][Shivakumar SP, Anderson DR, Couban S. Catheter-associated thrombosis in patients with malignancy. J Clin Oncol. 2009;27:4858–4864. doi: https://doi.org/10.1200/JCO.2009.22.6126][Verso M, Agnelli G, Kamphuisen PW, et al. Risk factors for upper limb deep vein thrombosis associated with the use of central vein catheter in cancer patients. Intern Emerg Med. 2008;3(2):117–122. doi: https://doi.org/10.1007/s11739-008-0125-3][Khorana AA, Dalal M, Lin J, et al. 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: https://doi.org/10.1002/cncr.27772][Khorana AA. Cancer and coagulation. Am J Hematol. 2012;87 (Suppl 1):S82–S87. doi: https://doi.org/10.1002/ajh.23143][Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902–4907. doi: https://doi.org/10.1182/blood.V104.11.2586.2586][Khorana AA. Risk assessment and prophylaxis for VTE in cancer patients. J Natl Compr Canc Netw. 2011;9(7):789–797. doi: https://doi.org/10.1182/blood.V104.11.2586.2586][Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116:5377–5382. doi: https://doi.org/10.1182/blood-2010-02-270116][Khorana AA, Francis CW. Risk prediction of cancer-associated thrombosis: appraising the first decade and developing the future. Thromb Res. 2018;164:S70–S76. doi: https://doi.org/10.1016/j.thromres.2018.01.036][Verso M, Agnelli G, Barni S, et al. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: The Protecht score. Intern Emerg Med. 2012;7:291. doi: https://doi.org/10.1007/s11739-012-0784-y][Sohne M, Kruip M, Nijkeuter M, et al. Accuracy of clinical decision rule, D‐dimer and spiral computed tomography in patients with malignancy, previous venous thromboembolism, COPD or heart failure and in older patients with suspected pulmonary embolism. J Thromb Haemost. 2006;4:1042–1046. doi: https://doi.org/10.1007/s11739-012-0784-y][Posch F, Riedl J, Reitter E-M, et al. Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D-Dimer analysis: A prospective study. J Thromb Haemost. 2020;18(6):1348–1356. doi: https://doi.org/10.1111/jth.14774]