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Semin Thromb Hemost 2022; 48(03): 323-337
DOI: 10.1055/s-0041-1733961
Review Article

New Insights in Coagulation and Fibrinolysis in Patients with Primary Brain Cancer: A Systematic Review

Anne Winther-Larsen
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Birgitte Sandfeld-Paulsen
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
› Author Affiliations Funding None.
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Abstract

Patients with primary brain tumors have a high incidence of thrombosis and hemorrhage. The underlying mechanism is believed to be derangement of their hemostatic system. To get nearer a clarification of this, we aimed to systematically review the existing literature regarding primary and secondary hemostasis as well as fibrinolysis in patients with primary brain tumor. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, and Web of Science were searched on December 15, 2020, without time restrictions. Studies were included if they evaluated at least one blood coagulation and/or fibrinolysis parameter in patients with primary brain cancer. In total, 26 articles including 3,288 patients were included. Overall, increased activity of secondary hemostasis was observed as increased prothrombin fragment 1 + 2 and endogenous thrombin generation levels were found in glioma patients compared with controls. Furthermore, data showed a state of hypofibrinolysis with increased plasminogen activator inhibitor 1 and prolonged clot lysis time in glioma patients. In contrast, no consistent increase in the primary hemostasis was identified; however, data suggested that increased sP-selectin could be a biomarker of increased venous thromboembolism risk and that increased platelet count may be prognostic for survival. Lastly, data indicated that fibrinogen and D-dimer could hold prognostic value. In conclusion, this review indicates that an increased activity of secondary hemostasis and impaired fibrinolysis could be important players in the pathogeneses behind the high risk of thromboembolisms observed in brain cancer patients. Thus, long-term thromboprophylaxis may be beneficial and additional studies addressing this issue are wanted.

Keywords

brain cancer - coagulation - fibrinolysis - hemostasis - thrombosis

Supplementary Material



Publication History

Article published online:
08 October 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Falanga A, Russo L, Verzeroli C. Mechanisms of thrombosis in cancer. Thromb Res 2013; 131 (Suppl. 01) S59-S62
    CrossrefPubMedGoogle Scholar
  • 2 Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 2012; 9 (07) e1001275
    CrossrefPubMedGoogle Scholar
  • 3 Qian C, Yan H, Hu X, Zhang W, Liu H. Increased risk of venous thromboembolism in patients with brain tumors: a systematic review and meta-analysis. Thromb Res 2016; 137: 58-63
    CrossrefPubMedGoogle Scholar
  • 4 Diaz M, Jo J, Smolkin M, Ratcliffe SJ, Schiff D. Risk of venous thromboembolism in grade II-IV gliomas as a function of molecular subtype. Neurology 2021; 96 (07) e1063-e1069
    CrossrefPubMedGoogle Scholar
  • 5 Semrad TJ, O'Donnell R, Wun T. et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007; 106 (04) 601-608
    CrossrefPubMedGoogle Scholar
  • 6 Riedl J, Ay C. Venous thromboembolism in brain tumors: risk factors, molecular mechanisms, and clinical challenges. Semin Thromb Hemost 2019; 45 (04) 334-341
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 2009; 27 (29) 4865-4873
    CrossrefPubMedGoogle Scholar
  • 8 Loynes JT, Zacharski LR. The coagulation system as a target for experimental therapy of human gliomas. Expert Opin Ther Targets 2003; 7 (03) 399-404
    CrossrefPubMedGoogle Scholar
  • 9 Jo JT, Schiff D, Perry JR. Thrombosis in brain tumors. Semin Thromb Hemost 2014; 40 (03) 325-331
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Suzuki-Inoue K, Kato Y, Inoue O. et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 2007; 282 (36) 25993-26001
    CrossrefPubMedGoogle Scholar
  • 11 Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood 2013; 122 (12) 2011-2018
    CrossrefPubMedGoogle Scholar
  • 12 Navi BB, Reichman JS, Berlin D. et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology 2010; 74 (06) 494-501
    CrossrefPubMedGoogle Scholar
  • 13 Lieu AS, Hwang SL, Howng SL, Chai CY. Brain tumors with hemorrhage. J Formos Med Assoc 1999; 98 (05) 365-367
    PubMedGoogle Scholar
  • 14 Mantia C, Zwicker JI. Anticoagulation in the setting of primary and metastatic brain tumors. Cancer Treat Res 2019; 179: 179-189
    CrossrefPubMedGoogle Scholar
  • 15 Velander AJ, DeAngelis LM, Navi BB. Intracranial hemorrhage in patients with cancer. Curr Atheroscler Rep 2012; 14 (04) 373-381
    CrossrefPubMedGoogle Scholar
  • 16 Howie C, Erker C, Crooks B, Moorehead P, Kulkarni K. Incidence and risk factors of venous thrombotic events in pediatric patients with CNS tumors compared with non-CNS cancer: A population-based cohort study. Thromb Res 2021; 200: 51-55
    CrossrefPubMedGoogle Scholar
  • 17 Boulouis G, Blauwblomme T, Hak JF. et al. Nontraumatic pediatric intracerebral hemorrhage. Stroke 2019; 50 (12) 3654-3661
    CrossrefPubMedGoogle Scholar
  • 18 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6 (07) e1000100
    CrossrefPubMedGoogle Scholar
  • 19 Quality Assessment tool for Controlled Intervention Studies and the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, National Institute of Health, USA. Quality Assessment Tool for Observational Cohort and Cross-Sectional Studi. Accessed March 4, 2021 at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
    PubMedGoogle Scholar
  • 20 Vukovich TC, Gabriel A, Schaeffer B, Veitl M, Matula C, Spiss CK. Hemostasis activation in patients undergoing brain tumor surgery. J Neurosurg 1997; 87 (04) 508-511
    CrossrefPubMedGoogle Scholar
  • 21 Wang PF, Meng Z, Song HW. et al. Preoperative changes in hematological markers and predictors of glioma grade and survival. Front Pharmacol 2018; 9 (AUG): 886
    CrossrefPubMedGoogle Scholar
  • 22 Ilich A, Kumar V, Henderson M. et al. Biomarkers in cancer patients at risk for venous thromboembolism: data from the AVERT study. Thromb Res 2020; 191 (Suppl. 01) S31-S36
    CrossrefPubMedGoogle Scholar
  • 23 Nolte I, Przibylla H, Bostel T, Groden C, Brockmann MA. Tumor-platelet interactions: glioblastoma growth is accompanied by increasing platelet counts. Clin Neurol Neurosurg 2008; 110 (04) 339-342
    CrossrefPubMedGoogle Scholar
  • 24 Subeikshanan V, Dutt A, Basu D, Tejus MN, Maurya VP, Madhugiri VS. A prospective comparative clinical study of peripheral blood counts and indices in patients with primary brain tumors. J Postgrad Med 2016; 62 (02) 86-90
    CrossrefPubMedGoogle Scholar
  • 25 Girolami A. A coagulation study in patients with neuroblastoma. Tumori 1967; 53 (05) 495-502
    CrossrefPubMedGoogle Scholar
  • 26 Scott JP, Morgan E. Coagulopathy of disseminated neuroblastoma. J Pediatr 1983; 103 (02) 219-222
    CrossrefPubMedGoogle Scholar
  • 27 El Kady N, Khedr H, Yosry M, El Mekawi S. Perioperative assessment of coagulation in paediatric neurosurgical patients using thromboelastography. Eur J Anaesthesiol 2009; 26 (04) 293-297
    CrossrefPubMedGoogle Scholar
  • 28 Dagistan Y, Dagistan E, Citisli V. Evaluation of simple blood counts as inflammation markers for brain tumor patients. Neurol Neurochir Pol 2016; 50 (04) 231-235
    CrossrefPubMedGoogle Scholar
  • 29 Iwadate Y, Hayama M, Adachi A. et al. High serum level of plasminogen activator inhibitor-1 predicts histological grade of intracerebral gliomas. Anticancer Res 2008; 28 (1B): 415-418
    PubMedGoogle Scholar
  • 30 Reynés G, Vila V, Martín M. et al. Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma. J Neurooncol 2011; 102 (01) 35-41
    CrossrefPubMedGoogle Scholar
  • 31 Can O, Erdemgil Y, Yildirim ZZ. et al. Quantification of fibrin degradation products in glioma and meningioma patients. Cancer Biomark 2014; 14 (04) 253-258
    CrossrefPubMedGoogle Scholar
  • 32 Navone SE, Guarnaccia L, Locatelli M. et al. Significance and prognostic value of the coagulation profile in patients with glioblastoma: implications for personalized therapy. World Neurosurg 2019; 121: e621-e629
    CrossrefPubMedGoogle Scholar
  • 33 Sawaya R, Ramo OJ, Glas-Greenwalt P, Wu SZ. Plasma fibrinolytic profile in patients with brain tumors. Thromb Haemost 1991; 65 (01) 15-19
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Sawaya R, Glas-Greenwalt P. Postoperative venous thromboembolism and brain tumors: Part II. Hemostatic profile. J Neurooncol 1992; 14 (02) 127-134
    PubMedGoogle Scholar
  • 35 Wang PF, Zhang J, Cai HQ. et al. Sanbo scoring system, based on age and pre-treatment hematological markers, is a non-invasive and independent prognostic predictor for patients with primary glioblastomas: a retrospective multicenter study. J Cancer 2019; 10 (23) 5654-5660
    CrossrefPubMedGoogle Scholar
  • 36 Pace A, Mandoj C, Antenucci A. et al. A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma. J Neurooncol 2018; 138 (03) 527-535
    CrossrefPubMedGoogle Scholar
  • 37 Hoke M, Dieckmann K, Koppensteiner R, Schillinger M, Marosi C, Mlekusch W. Prognostic value of plasma D-dimer levels in patients with glioblastoma multiforme - Results from a pilot study. Wien Klin Wochenschr 2011; 123 (7-8): 199-203
    CrossrefPubMedGoogle Scholar
  • 38 Hao Y, Li X, Chen H. et al. A cumulative score based on preoperative neutrophil-lymphocyte ratio and fibrinogen in predicting overall survival of patients with glioblastoma multiforme. World Neurosurg 2019; 128: e427-e433
    CrossrefPubMedGoogle Scholar
  • 39 Zhang Q, Wu H, Zhang J, Qi Q, Zhang W, Xia R. Preoperative immune response is associated with perioperative transfusion requirements in glioma surgery. J Cancer 2019; 10 (15) 3526-3532
    CrossrefPubMedGoogle Scholar
  • 40 Thaler J, Ay C, Kaider A. et al. Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas. Neuro-oncol 2014; 16 (12) 1645-1651
    CrossrefPubMedGoogle Scholar
  • 41 Streiff MB, Ye X, Kickler TS. et al. A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors. J Neurooncol 2015; 124 (02) 299-305
    CrossrefPubMedGoogle Scholar
  • 42 Maas SLN, Draaisma K, Snijders TJ. et al. Routine blood tests do not predict survival in patients with glioblastoma-multivariable analysis of 497 patients. World Neurosurg 2019; 126: e1081-e1091
    CrossrefPubMedGoogle Scholar
  • 43 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
    CrossrefPubMedGoogle Scholar
  • 44 Ay C, Dunkler D, Pirker R. et al. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97 (08) 1158-1164
    CrossrefPubMedGoogle Scholar
  • 45 Brockmann MA, Giese A, Mueller K. et al. Preoperative thrombocytosis predicts poor survival in patients with glioblastoma. Neuro-oncol 2007; 9 (03) 335-342
    CrossrefPubMedGoogle Scholar
  • 46 Simanek R, Vormittag R, Ay C. et al. High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2010; 8 (01) 114-120
    CrossrefPubMedGoogle Scholar
  • 47 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 (07) 2703-2708
    CrossrefPubMedGoogle Scholar
  • 48 Castellón Rubio VE, Segura PP, Muñoz A, Farré AL, Ruiz LC, Lorente JA. High plasma levels of soluble P-selectin and factor VIII predict venous thromboembolism in non-small cell lung cancer patients: the Thrombo-Nsclc risk score. Thromb Res 2020; 196: 349-354
    CrossrefPubMedGoogle Scholar
  • 49 Lundbech M, Krag AE, Christensen TD, Hvas AM. Thrombin generation, thrombin-antithrombin complex, and prothrombin fragment F1+2 as biomarkers for hypercoagulability in cancer patients. Thromb Res 2020; 186: 80-85
    CrossrefPubMedGoogle Scholar
  • 50 Perisanidis C, Psyrri A, Cohen EE. et al. Prognostic role of pretreatment plasma fibrinogen in patients with solid tumors: a systematic review and meta-analysis. Cancer Treat Rev 2015; 41 (10) 960-970
    CrossrefPubMedGoogle Scholar
  • 51 Huang G, Jiang H, Lin Y. et al. Prognostic value of plasma fibrinogen in hepatocellular carcinoma: a meta-analysis. Cancer Manag Res 2018; 10: 5027-5041
    CrossrefPubMedGoogle Scholar
  • 52 Tian Y, Hong M, Jing S. et al. Clinical and prognostic effect of plasma fibrinogen in renal cell carcinoma: a meta-analysis. BioMed Res Int 2017; 2017: 9591506
    CrossrefPubMedGoogle Scholar
  • 53 Hisada Y, Garratt KB, Maqsood A. et al. Plasminogen activator inhibitor 1 and venous thrombosis in pancreatic cancer. Blood Adv 2021; 5 (02) 487-495
    CrossrefPubMedGoogle Scholar
  • 54 Li W, Tang Y, Song Y. et al. Prognostic role of pretreatment plasma D-dimer in patients with solid tumors: a systematic review and meta-analysis. Cell Physiol Biochem 2018; 45 (04) 1663-1676
    CrossrefPubMedGoogle Scholar
  • 55 Li J, Wang Y, Li J, Che G. Prognostic value of pretreatment D-dimer level in small-cell lung cancer: a meta-analysis. Technol Cancer Res Treat 2021; 20: 1533033821989822
    PubMedGoogle Scholar
  • 56 Perry JR, Julian JA, Laperriere NJ. et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8 (09) 1959-1965
    CrossrefPubMedGoogle Scholar
  • 57 Perry SL, Bohlin C, Reardon DA. et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. J Neurooncol 2009; 95 (01) 129-134
    CrossrefPubMedGoogle Scholar
  • 58 Robins HI, O'Neill A, Gilbert M. et al. Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial. Cancer Chemother Pharmacol 2008; 62 (02) 227-233
    CrossrefPubMedGoogle Scholar
  • 59 Bukhari SS, Shamim MS. Utility of tranexamic acid to minimize blood loss in brain tumour surgery. J Pak Med Assoc 2020; 70 (04) 764-766
    PubMedGoogle Scholar