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ACUTE LYMPHOBLASTIC LEUKEMIA

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

Leukemia volume 36, pages 361–369 (2022)Cite this article

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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.

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

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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.

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Authors and Affiliations

  1. Department of Pediatric and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Liv Andrés-Jensen, Kathrine Grell, Cecilie Utke Rank, Ruta Tuckuviene, Rikke Linnemann Nielsen, Thomas Leth Frandsen & Kjeld Schmiegelow

  2. Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Kathrine Grell

  3. Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Cecilie Utke Rank

  4. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

    Birgitte Klug Albertsen & Line Stensig Lynggaard

  5. Department of Clinical medicine, Aarhus University, Aarhus, Denmark

    Birgitte Klug Albertsen

  6. Department of Health technology, Technical University of Denmark, Kgs Lyngby, Denmark

    Rikke Linnemann Nielsen

  7. Department of Paediatric Haematology and Oncology, Rikshospitalet, Oslo University Hospital, Oslo, Norway

    Kirsten Brunsvig Jarvis

  8. Department of Hematology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    Petter Quist-Paulsen

  9. Clinic of Children’s diseases, Faculty of Medicine, Vilnius University, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania

    Sonata Saulyte Trakymiene

  10. Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania

    Rūta Semaškevičienė

  11. Department of Hematology and Oncology, Tallinn Children’s Hospital, Tallinn, Estonia

    Kadri Saks

  12. Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland

    Olafur Gisli Jonsson

  13. Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Pär Ingemar Johansson

  14. Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark

    Kjeld Schmiegelow

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  1. Liv Andrés-Jensen
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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.

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Correspondence to Kjeld Schmiegelow.

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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.

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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 36, 361–369 (2022). https://doi.org/10.1038/s41375-021-01383-2

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