Blood coagulation in venous thrombosis, complicating treatment of children, adolescents and young adults with lymphomas

Objective of the study was to compare blood clotting parameters in lymphoma patients with or without venous thrombosis (VT), as well as to analyze the duration and outcome of anticoagulant therapy in children, adolescents and young adults with lymphoma, whose program treatment was complicated by VT.

Materials and methods . The analysis included 28 patients with lymphoma (Hodgkin lymphoma – 5, non-Hodgkin lymphoma – 23), aged from 2 to 25 years (median – 16.0 years), whose program treatment in 2005–2017 was complicated by VT. The case-control study was carried out to compare the parameters of blood coagulation. The control group consisted of 22 patients, aged from 2 to 20 years (median – 15.5 years) with the same diagnosis, age, therapy protocol and phase of treatment who had no thrombotic complications. The comparison group consisted of 35 healthy children aged from 3 to 18 years (median – 14.0 years).

Results . There was no difference in majority of blood clotting parameters in lymphoma patients with or without VT. Hyperfibrinogenemia and an increased D-dimers level distinguished patients with lymphoma, regardless of the presence or absence of thrombosis, from healthy children of the same age (р <0.05). Anticoagulant therapy up to 3 months received 10 patients, for 4–6 months – 4, for 7–12 months – 12, up to 18 months – 2. One adult patient with a homozygous mutation 20210G>A gene of the factor II takes warfarin continuously for a long time after relapse of VT. Complete recanalization of the thrombosed vessel occurred within the first 3 months in 9 patients, within 4–6 months – in 1, within 7–12 months ‒ in 4. Partial recanalization within 3–12 months was confirmed in 8 patients. Vein obliteration, mainly the internal jugular vein, as the outcome of VT occurred in 6 patients within 4–12 months.

Conclusion . Detection of routine blood clotting parameters does not allow identifying patients with thrombosis among children, adolescents and young adults with lymphoma. Fibrinogen and D-dimers levels were significantly higher in lymphoma patients, than in healthy children. Anticoagulant therapy for 3–12 months led to the complete or partial recanalization of VT in 79 % of patients. To detect blood clotting parameters by thrombosis development, as well as to reveal and monitor transient and permanent risk factors are necessary to specify the cause of VT and to determine the appropriate anticoagulant therapy.

1. Khorana A.A. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125(6):490–3. DOI: 10.1016/j.thromres.2009.12.023. PMID: 20097409.

2. Timp J.F., Braekkan S.K., Versteeg H.H., Cannegieter S.C. Epidemiology of cancerassociated venous thrombosis. Blood 2013;122(10):1712–23. DOI: 10.1182/blood-2013-04-460121. PMID: 23908465.

3. Athale U., Siciliano S., Thabane L. et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer 2008;51(6):792–7. DOI: 10.1002/pbc.21734. PMID: 18798556.

4. Walker A., Grainge M., Card T. et al. Venous thromboembolism in children with cancer – a population-based cohort study. Thromb Res 2014;133(3):340–4. DOI: 10.1016/j.thromres.2013.12.021. PMID: 24388573.

5. Kenet G., Lütkhoff L.K., Albisetti M. et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and metaanalysis of observational studies. Circulation 2010;121(16):1838–47. DOI: 10.1161/CIRCULATIONAHA.109.913673. PMID: 20385928.

6. Holmes M.V., Newcombe P., Hubacek J.A. et al. Effect modification by population dietary folateon the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomized trials. Lancet 2011;378(9791):584–94. DOI: 10.1016/S0140-6736(11)60872-6. PMID: 21803414.

7. Lyman G.H., Khorana A.A., Kuderer N.M. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013;31(17):2189–204. DOI: 10.1200/JCO.2013.49.1118. PMID: 23669224.

8. Kearon С., Akl E., Ornelas J. et al. Antithrombotic therapy for VTE disease. CHEST guideline and expert panel report. Chest 2016;149(2):315–52. DOI: 10.1016/j.chest.2015.11.026. PMID: 26867832.

9. Monagle P., Chan A.K., Goldenberg N.A. et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 2012;141(2 Suppl):e737S–801S. DOI: 10.1378/chest.11–2308. PMID: 22315277.

10. Carrier M., Khorana A., Zwicker J. et al. Management of challenging cases of patients with cancerassociated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013;11(9):1760–5. DOI: 10.1111/jth.12338. PMID: 23809334.

11. Cazals-Hatem D., Lepage E., Brice P. et al. Primary mediastinal large B-cell lymphoma: a clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA (“Groupe d’Etude des Lymphomas de l’Adulte”) study. Am J Surg Pathol 1996;20(7):877–88. PMID: 8669537.

12. Kerlin B., Stephens J., Hogan M. et al. Development of a pediatric-specific clinical probability tool for diagnosis of venous thromboembolism: a feasibility study. Pediatr Res 2015;77(3):463–71. DOI: 10.1038/pr.2014.198. PMID: 25518012.

13. Andrew M., Vegh P., Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992;80(8):1998–2005. PMID: 1391957.

14. Toulon P., Berruyer M., BrionneFranqois M. et al. Age dependency for coagulation parameters in paediatric populations. Thromb Haemost 2016;116(1):9–17. DOI: 10.1160/TH15-12-0964. PMID: 26988943.

15. Poort S.R., Rosendaal F.R., Reitsma P.H., Bertina R.M. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88(10):3698–703. PMID: 8916933.

16. Nasiruddin, Zahur-ur-Rehman, Anwar M. et al. Frequency of factor V Leiden mutation. J Coll Physicians Surg Pak 2005;15(1):15–7. DOI: 01.2005/JCPSP.1517. PMID: 15670517.

17. Khorana A.A., Kuderer N.M., Culakova E. et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111(10):4902–7. DOI: 10.1182/blood-2007-10-116327. PMID: 18216292.

18. Bahl V., Hu H., Henke H.R. et al. A Validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg 2010;251(2):344–50. DOI: 10.1097/SLA.0b013e3181b7fca6. PMID: 19779324.

19. Ay C., Dunkler D., Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010;116(24): 5377–82. DOI: 10.1182/blood-2010-02-270116. PMID: 20829374.

20. Pusterla S., Previtali S., Marziali S. et al. Antiphospholipid antibodies in lymphoma: prevalence and clinical significance. Hematol J 2004;5(4):341–6. DOI: 10.1038/sj.thj.6200377. PMID: 15297851.

21. Bairey O., Blickstein D., Monselise Y. et al. Antiphospholipid antibodies may be a new prognostic parameter in aggressive non-Hodgkin’s lymphoma. Eur J Haematol 2006;76(5):384–91. DOI: 10.1111/j.1600-0609.2005.00620.x. PMID: 16466368.

22. Genvresse I., Leftner D., Shelth-Schwalbe E., Buttgereit F. Prevalence and clinical significance of anticardiolipin and anti-β glycoprotein I antibodies in patients with non-Hodgkin’s lymphoma. Eur J Haematol 2002;68(2):84–90. PMID: 12038453.