Display options
Share it on

Pediatr Blood Cancer. 2021 Dec 28;e29522. doi: 10.1002/pbc.29522. Epub 2021 Dec 28.

Markers of hypercoagulability in children with newly diagnosed acute lymphoblastic leukemia.

Pediatric blood & cancer

Roxana Carmona, Hande Kizilocak, Elizabeth Marquez-Casas, Siobhan Vasquez, Lingyun Ji, Richard H Ko, Guy Young, Julie Jaffray

Affiliations

  1. Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, Los Angeles, California, USA.
  2. Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.
  3. Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

PMID: 34963026 DOI: 10.1002/pbc.29522

Abstract

BACKGROUND: Venous thromboembolism (VTE) is a known complication for children with acute lymphoblastic leukemia (ALL). The aim of this study was to identify laboratory biomarkers that predict which children with ALL are at risk for VTE during induction chemotherapy.

MATERIALS AND METHODS: Newly diagnosed ALL patients admitted to Children's Hospital Los Angeles with a central venous catheter (CVC) were eligible to participate. Participants' blood samples (complete blood count [CBC], quantitative D-dimer, prothrombin fragment 1.2 [PTF 1.2], and thrombin-antithrombin complexes [TAT]) were collected at day 0 (baseline/prior to induction), day 7 (±2 days), day 14 (±2 days), day 21 (±2 days), and day 28 (±2 days) of induction chemotherapy or until participants presented with a symptomatic VTE.

RESULTS: Seventy-five participants aged 1-21 years were enrolled and included in the final analysis. Twenty-six (35%) of the 75 participants were diagnosed with a CVC-associated VTE (22 asymptomatic and four symptomatic). There was a statistically significant difference between VTE and non-VTE participants for D-dimer (odds ratio [OR] 1.61, 95% confidence interval [CI]: 1.59-1.64), TAT (OR 1.34, 95% CI: 1.32-1.38), and PTF 1.2 (OR 1.31, 95% CI: 1.25-1.37) at all time points. Participants >10 years had a significantly higher risk of developing a VTE compared to participants <4 years (p = .007).

CONCLUSION: Older children with ALL as well as those with an elevated TAT, PTF 1.2, or D-dimer showed an increased risk of VTE, which may hold potential for predicting VTE in future studies.

© 2021 Wiley Periodicals LLC.

Keywords: acute lymphoblastic leukemia; hypercoagulability; pediatrics; venous thromboembolism

References

  1. Kizilocak H, Okcu F. Late effects of therapy in childhood acute lymphoblastic leukemia survivors. Turk J Haematol. 2019;36:1-11. https://doi.org/10.4274/tjh.galenos.2018.2018.0150 - PubMed
  2. Jaffray J, Goldenberg N. Current approaches in the treatment of catheter-related deep venous thrombosis in children. Expert Rev Hematol. 2020;13:607-617. - PubMed
  3. Levy-Mendelovich S, Barg AA, Kenet G. Thrombosis in pediatric patients with leukemia. Thromb Res. 2018;164:94-97. - PubMed
  4. Athale UH, Chan AK. Thrombosis in children with acute lymphoblastic leukemia: part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res. 2003;111:125-131. - PubMed
  5. Mitchell LG, Andrew M, Hanna K, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer. 2003;97:508-516. - PubMed
  6. Ay C, Dunkler D, Simanek R, et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol. 2011;29:2099-2103. - PubMed
  7. Ay C, Pabinger I. Predictive potential of haemostatic biomarkers for venous thromboembolism in cancer patients. Thromb Res. 2012;129:6-9. - PubMed
  8. Fidan E, Kavgaci H, Orem A, et al. Thrombin activatable fibrinolysis inhibitor and thrombin-antithrombin-III-complex levels in patients with gastric cancer. Tumour Biol. 2012;33:1519-1525. - PubMed
  9. Ota S, Wada H, Abe Y, et al. Elevated levels of prothrombin fragment 1 + 2 indicate high risk of thrombosis. Clin Appl Thromb Hemost. 2008;14:279-285. - PubMed
  10. 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;27:4124-4129. - PubMed
  11. Grilz E, Marosi C, Königsbrügge O, et al. Association of complete blood count parameters, d-dimer, and soluble P-selectin with risk of arterial thromboembolism in patients with cancer. J Thromb Haemost. 2019;17:1335-1344. - PubMed
  12. Jaffray J, Mahajerin A, Young G, et al. A multi-institutional registry of pediatric hospital-acquired thrombosis cases: the Children's Hospital-Acquired Thrombosis (CHAT) project. Thromb Res. 2018;161:67-72. - PubMed
  13. van Es N, Ventresca M, Di Nisio M, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: an individual patient data meta-analysis. J Thromb Haemost. 2020;18:1940-1951. - PubMed
  14. Mitchell LG, Halton JM, Vegh PA, et al. Effect of disease and chemotherapy on hemostasis in children with acute lymphoid leukemia. Am J Pediatr Hematol Oncol. 1994;16:120-126. - PubMed
  15. Athale UH, Laverdiere C, Nayiager T, et al. Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer. 2017;17:313. - PubMed
  16. Nowak-Göttl U, Heinecke A, von Kries R, Nürnberger W, Münchow N, Junker R. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res. 2001;103:165-172. - PubMed
  17. Male C, Chait P, Andrew M, et al. Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood. 2003;101:4273-4278. - PubMed
  18. Lippi G, Cervellin G, Franchini M, Favaloro EJ. Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future. J Thromb Thrombolysis. 2010;30:459-471. - PubMed
  19. Hanzal E, Tatra G. Prothrombin fragment F 1 + 2 plasma concentrations in patients with gynecologic malignancies. Gynecol Oncol. 1993;49:373-376. - PubMed
  20. Lippi G, Franchini M, Targher G, Favaloro EJ. Help me, doctor! My D-dimer is raised. Ann Med. 2008;40:594-605. - PubMed
  21. Seitz R, Rappe N, Kraus M, et al. Activation of coagulation and fibrinolysis in patients with lung cancer: relation to tumour stage and prognosis. Blood Coagul Fibrinolysis. 1993;4:249-254. - PubMed
  22. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377-381. - PubMed
  23. Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. - PubMed
  24. StataCorp. Stata Statistical Software: Release 11. StataCorp LP; 2009. - PubMed
  25. Iversen LH, Thorlacius-Ussing O. Relationship of coagulation test abnormalities to tumour burden and postoperative DVT in resected colorectal cancer. Thromb Haemost. 2002;87:402-408. - PubMed
  26. 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. - PubMed
  27. Appel IM, Hop WC, 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;100:330-337. - PubMed
  28. Giordano P, Molinari AC, Del Vecchio GC, et al. Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol. 2010;85:325-330. - PubMed
  29. Klaassen ILM, Lauw MN, Fiocco M, et al. Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: risk factors and effect on prognosis. Res Pract Thromb Haemost. 2019;3:234-241. - PubMed
  30. Uszyński M, Osińska M, Zekanowska E, Ziółkowska E. Children with acute lymphoblastic leukemia: is there any subgroup of children without elevated thrombin generation? A preliminary study utilizing measurements of thrombin-antithrombin III complexes. Med Sci Monit. 2000;6:108-111. - PubMed
  31. Tuckuviene R, Ranta S, Albertsen BK, et al. Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study. J Thromb Haemost. 2016;14:485-494. - PubMed
  32. Kwaan HC, Vicuna B. Incidence and pathogenesis of thrombosis in hematologic malignancies. Semin Thromb Hemost. 2007;33:303-312. - PubMed
  33. Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost. 1999;25:199-208. - PubMed
  34. Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104:2822-2829. - PubMed
  35. Faustino EV, Spinella PC, Li S, et al. Incidence and acute complications of asymptomatic central venous catheter-related deep venous thrombosis in critically ill children. J Pediatr. 2013;162:387-391. - PubMed
  36. Jones S, Butt W, Monagle P, Cain T, Newall F. The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children. Blood. 2019;133:857-866. - PubMed

Publication Types