Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ACUTE LYMPHOBLASTIC LEUKEMIA

Endothelial dysfunction and thromboembolism in children, adolescents, and young adults with acute lymphoblastic leukemia

Abstract

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P < 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02‒1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn >30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6–8.2 ng/mL) higher in samples with measurable asparaginase activity (P < 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Patient flow chart.
Fig. 2: Individual sample measurements of endothelial biomarkers.

References

  1. 1.

    Toft N, Birgens H, Abrahamsson J, Griškevičius L, Hallböök H, Heyman M. et al. Results of NOPHO ALL2008 treatment for patients 1-45 years with acute lymphoblastic leukemia. Leukemia. 2017;32:606–15.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Toft N, Birgens H, Abrahamsson J, Griškevičius L, Hallböök H, Heyman M, et al. Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia. Eur J Haematol. 2016;96:160–9.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Rank CU, Toft N, Tuckuviene R, Grell K, Nielsen OJ, Frandsen TL. et al. Thromboembolism in acute lymphoblastic leukemia: results of nopho all2008 protocol treatment in patients aged 1 to 45 years. Blood. 2018;131:2475–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Athale UH, Chan AKC. Thrombosis in children with acute lymphoblastic leukemia Part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res. 2003;111:125–31.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev. 2014;28:221–6.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Kuhle S, Spavor M, Massicotte P, Halton J, Cherrick I, Dix D, et al. Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost. 2008;6:589–94.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Goldenberg NA, Donadini MP, Kahn SR, Crowther M, Kenet G, Nowak-Göttl U. et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica. 2010;95:1952–9.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Musgrave KM, van Delft FW, Avery PJ, Clack RM, Chalmers EA, Qureshi A, et al. Cerebral sinovenous thrombosis in children and young adults with acute lymphoblastic leukaemia – a cohort study from the United Kingdom. Br J Haematol. 2017;179:667–9.

    PubMed  Article  Google Scholar 

  9. 9.

    Hijiya N, Van Der Sluis IM. Asparaginase-Associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2016;57:748–57.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Truelove E, Fielding AK, Hunt BJ. The coagulopathy and thrombotic risk associated with L-Asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia. 2013;27:553–9.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Ramsay NKC, Coccia PF, Krivit W, Nesbit ME, Edson JR. The effect of L‐asparaginase on plasma coagulation factors in acute lymphoblastic leukemia. Cancer. 1977;40:1398–401.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Appel IM, Hop WCJ, Van Kessel-Bakvis C, Stigter R, Pieters R. L-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia. Thromb Haemost. 2008;100:330–7.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Staddon JH, Smock KJ, Schiffman JD, Fluchel MN, Engel ME, Weyrich AS. et al. Pegasparaginase treatment alters thrombin generation by modulating the protein C and S system in acute lymphoblastic leukaemia/lymphoma. Blood Coagul Fibrinolysis. 2015;26:840–3.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    van Zaane B, Nur E, Squizzato A, Gerdes VEA, BÜLler HR, Dekkers OM, et al. Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors. J Thromb Haemost. 2010;8:2483–93.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  15. 15.

    Ozsoylu S. Effect of corticosteroids on coagulation tests. Acta Haematol. 1983;70:70.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Casillas J, Kahn KL, Doose M, Landier W, Bhatia S, Hernandez J. et al. Transitioning childhood cancer survivors to adult-centered healthcare: insights from parents, adolescent, and young adult survivors. Psychooncology. 2010;19:982–90.

    PubMed  Article  Google Scholar 

  17. 17.

    Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L’Asparaginase- induced antithrombin III deficiency. Blood. 1994;83:386–91.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Klaassen ILM, Lauw MN, Fiocco M, van der Sluis IM, Pieters R, Middeldorp S, et al. Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: risk factors and effect on prognosis. Res Pr Thromb Haemost. 2019;3:234–41.

    Article  Google Scholar 

  19. 19.

    Jarvis KB, LeBlanc M, Tulstrup M, Nielsen RL, Albertsen BK, Gupta R, et al. Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia – A NOPHO ALL2008 study. Thromb Res. 2019;184:92–8.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Jarvis KB, Nielsen RL, Gupta R, Hede FD, Huttunen P, Jónsson ÓG, et al. Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia. Thromb Res. 2020;196:15–20.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Mateos MK, Tulstrup M, Quinn MCJ, Tuckuviene R, Marshall GM, Gupta R. et al. Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children. Cancers. 2020;12:1285.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  22. 22.

    Athale UH, Mizrahi T, Laverdière C, Nayiager T, Delva YL, Foster G, et al. Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: a prospective evaluation. Pediatr Blood Cancer. 2018;65:e26938.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Mukai M, Oka T. Mechanism and management of cancer-associated thrombosis. J Cardiol. 2018;72:89–93.

    PubMed  Article  Google Scholar 

  24. 24.

    Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res. 2018;164:S94–7.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Poredos P, Jezovnik MK. Endothelial dysfunction and venous thrombosis. Angiology. 2018;69:564–7.

    PubMed  Article  Google Scholar 

  26. 26.

    Bochenek ML, Schäfer K. Role of endothelial cells in acute and chronic thrombosis. Hamostaseologie. 2019;39:128–39.

    PubMed  Article  Google Scholar 

  27. 27.

    Shogo T, Shigeru K, Shinichi O, Nobuo A. Plasma thrombomodulin in health and diseases. Blood. 1990;76:2024–9.

    Article  Google Scholar 

  28. 28.

    Bertrand J, Bollmann M. Soluble syndecans: biomarkers for diseases and therapeutic options. Br J Pharmacol. 2019;176:67–81.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Wu FTH, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med. 2010;14:528–52.

    CAS  PubMed  Google Scholar 

  30. 30.

    Frandsen TL, Heyman M, Abrahamsson J, Vettenranta K, Åsberg A, Vaitkeviciene G. et al. Complying with the European Clinical Trials directive while surviving the administrative pressure - an alternative approach to toxicity registration in a cancer trial. Eur J Cancer. 2014;50:251–9.

    PubMed  Article  Google Scholar 

  31. 31.

    Tulstrup M, Moriyama T, Jiang C, Grosjean M, Nersting J, Abrahamsson J. et al. Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia. Blood. 2020;136:1161–8.

    PubMed  Article  Google Scholar 

  32. 32.

    Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, et al. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: A NOPHO ALL2008 randomized study. J Clin Oncol. 2019;37:1638–46.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Højfeldt SG, Wolthers BO, Tulstrup M, Abrahamsson J, Gupta R, Harila-Saari A, et al. Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. Br J Haematol. 2019;184:405–17.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Chang CC, Chow CC, Tellier LCAM, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Pearson JD. Endothelial cell function and thrombosis. Bailliere’s Best Pr Res Clin Haematol. 1994;7:441–52.

    CAS  Article  Google Scholar 

  36. 36.

    Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyamal I, Zushi M, et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 1987;6:1891–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Luan ZG, Zhang H, Yang PT, Ma XC, Zhang C, Guo RX. HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF-α in human umbilical vein endothelial cells. Immunobiology. 2010;215:956–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Leung LLK, Myles T, Nishimura T, Song JJ, Robinson WH. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI). Mol Immunol. 2008;45:4080–3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001;276:11199–203.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Gando S, Nakanishi Y, Kameue T, Nanzaki S. Soluble thrombomodulin increases in patients with disseminated intravascular coagulation and in those with multiple organ dysfunction syndrome after trauma: role of neutrophil elastase. J Trauma - Inj Infect Crit Care. 1995;39:660–4.

    CAS  Article  Google Scholar 

  41. 41.

    Ikegami K, Suzuki Y, Yukioka T, Matsuda H, Shimazaki S. Endothelial cell injury, as quantified by the soluble thrombomodulin level, predicts sepsis/multiple organ dysfunction syndrome after blunt trauma. J Trauma - Inj Infect Crit Care. 1998;44:789–95.

    CAS  Article  Google Scholar 

  42. 42.

    Lin SM, Wang YM, Lin HC, Lee KY, Huang CDA, Liu CY, et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med. 2008;36:683–9.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl J Med. 2001;345:408–16.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Diebel LN, Diebel ME, Martin JV, Liberati DM. Acute hyperglycemia exacerbates trauma-induced endothelial and glycocalyx injury: an in vitro model. J Trauma Acute Care Surg. 2018;85:960–7.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Boehme MWJ, Deng Y, Raeth U, Bierhaus A, Ziegler R, Stremmel W. et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-α and neutrophils: In vivo and in vitro studies. Immunology. 1996;87:134–13440.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hatzipantelis ES, Athanassiou-Metaxa M, Gombakis N, Tzimouli V, Taparkou A, Sidi-Fragandrea V, et al. Thrombomodulin and von Willebrand factor: relation to endothelial dysfunction and disease outcome in children with acute lymphoblastic leukemia. Acta Haematol. 2011;125:130–5.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Hagag AAE, Abdel-Lateef AE, Aly R. Prognostic value of plasma levels of thrombomodulin and von Willebrand factor in Egyptian children with acute lymphoblastic leukemia. J Oncol Pharm Pr. 2014;20:356–61.

    Article  CAS  Google Scholar 

  48. 48.

    Öner AF, Gürgey A, Kirazli Ş, Okur H, Tunç B. Changes of hemostatic factors in children with acute lymphoblastic leukemia receiving combined chemotherapy including high dose methylprednisolone and L-asparaginase. Leuk Lymphoma. 1999;33:361–4.

    PubMed  Article  Google Scholar 

  49. 49.

    Yue L, Deng X, Yang M, Li X. Elevated B-type natriuretic peptide (BNP) and soluble thrombomodulin (sTM) indicates severity and poor prognosis of sepsis. Ann Palliat Med. 2021;10:5561–7.

    PubMed  Article  Google Scholar 

  50. 50.

    Sertoglu E, Omma A, Yucel C, Colak S, Sandıkcı SC, Ozgurtas T. The relationship of serum VEGF and sVEGFR-1 levels with vascular involvement in patients with Behçet’s disease. Scand J Clin Lab Invest. 2018;78:443–9.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Shibuya M. Vascular endothelial growth factor and its receptor system: Physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153:13–9.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Ostrowski SR, Sørensen AM, Windeløv NA, Perner A, Welling KL, Wanscher M, et al. High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study. Scand J Trauma Resusc Emerg Med. 2012;20:1–8.

    Article  Google Scholar 

  53. 53.

    Greco M, Palumbo C, Sicuro F, Lobreglio G. Soluble Fms-Like Tyrosine Kinase-1 is a marker of endothelial dysfunction during sepsis. J Clin Med Res. 2018;10:700–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Wu FTH, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS. A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med. 2010;14:528–52.

    CAS  PubMed  Google Scholar 

  55. 55.

    Hu Q, Dey AL, Yang Y, Shen Y, Jilani IB, Estey EH. et al. Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes. Cancer. 2004;100:1884–91.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Tang T, Lai H, Huang X, Gu L, Shi H. Application of serum markers in diagnosis and staging of ovarian endometriosis. J Obstet Gynaecol Res. 2021;47:1441–50.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Uchimido R, Schmidt EP, Shapiro NI. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care. 2019;23:16.

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Reitsma S, Slaaf DW, Vink H, Van Zandvoort MAMJ, Oude Egbrink MGA. The endothelial glycocalyx: composition, functions, and visualization. Pflug Arch Eur J Physiol. 2007;454:345–59.

    CAS  Article  Google Scholar 

  59. 59.

    Nieuwdorp M, Van Haeften TW, Gouverneur MCLG, Mooij HL, Van Lieshout MHP, Levi M. et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes. 2006;55:480–6.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Sharma M, Tyagi S, Tripathi P, Seth T. Syndecan-1 (sCD138) levels in chronic lymphocytic leukemia: clinical and hematological correlations. Blood Res. 2018;53:205–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Seidel C, Sundan A, Hjorth M, Turesson I, Dahl IMS, Abildgaard N. et al. Serum syndecan-1: a new independent prognostic marker in multiple myeloma. Blood. 2000;95:388–92.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Alghandour R, Ebrahim MA, Ghazy H, Shamaa S, Emarah Z, Al-Gayyar MM. Evaluation of the diagnostic and prognostic value of syndecan-1 in acute leukemia patients. Cureus. 2020;12:1–10.

    Google Scholar 

  63. 63.

    Kastritis E, Laina A, Georgiopoulos G, Gavriatopoulou M, Evangelos EP, Fotiou ED. et al. Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study. Leukemia. 2021;e-pub ahead of print. Available from: https://doi.org/10.1038/s41375-021-01141-4.

  64. 64.

    Guy A, Poisson J, James C, James C. Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms. Leukemia. 2021;35:935–55.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Kiseleva RY, Glassman PM, Greineder CF, Hood ED, Shuvaev VV, Muzykantov VR. Targeting therapeutics to endothelium: are we there yet? Drug Deliv Transl Res. 2018;8:883–902.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Rank CU, Lynggaard LS, Als-Nielsen B, Stock W, Toft N, Nielsen OJ, et al. Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2020;10:1465–858.

    Google Scholar 

Download references

Acknowledgements

The authors thank all patients involved in this study as well as all colleagues contributing to collection of data and conduction of laboratory analyses. We thank Laboratory assistant Jane H. Knudsen, A-research Lab, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital.

Funding

This study was supported by research grants from the Danish Childhood Cancer Foundation. RLN was supported by an Interreg grant for the Interregional Childhood Oncology Precision Medicine Exploration (iCOPE) project.

Author information

Affiliations

Authors

Contributions

Contributions: LAJ designed the study, collected, analyzed and interpreted data, and wrote and edited the paper: K. Schmiegelow served as principal investigator for the NOPHO ALL2008 protocol, interpreted data, and critically reviewed the paper; PIJ designed the study, interpreted data, and critically reviewed the paper; TLF served as a childhood investigator, collected data, supervised toxicity reporting, and critically reviewed the paper; KG interpreted data, and critically reviewed statistical analyses and the paper; CUR served as an adult investigator, contributed to TE data collection, and critically reviewed the paper; BKA and LS collected ASP data and edited the paper; RT served as principal investigator for the NOPHO ALL2008 TE working group, collected data and edited the paper; RLN performed genetic analyses and edited the paper; KBK, SST, K.Saks, and OGJ served as childhood investigators, collected data, and edited the paper; PQ-P and RS served as adult investigators, collected data, and edited the paper.

Corresponding author

Correspondence to Kjeld Schmiegelow.

Ethics declarations

Competing interests

K.Schmiegelow has received speaker fee and/or Advisory Board Honoraria from Jazz Pharmaceuticals (2020) and Servier (2020); speaker fee from Amgen (2020) and Medscape (2020); and Educational grant from Servier (2020). All other authors declare no competing financial interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Andrés-Jensen, L., Grell, K., Rank, C.U. et al. Endothelial dysfunction and thromboembolism in children, adolescents, and young adults with acute lymphoblastic leukemia. Leukemia (2021). https://doi.org/10.1038/s41375-021-01383-2

Download citation

Search

Quick links