Ayça Koca YOZGAT, İbrahim EKER, Orhan GÜRSEL, Muhammed Fevzi KILINÇKAYA, Abdurrahman KARA, Neşe YARALI, Namık Yaşar ÖZBEK

Thrombin generation in children with febrile neutropenia

Background. Febrile neutropenia (FN) is a common and serious complication in patients with leukemia. Hemostasis and inflammation are two interrelated systems in response to infection. We aimed to investigate the course of thrombin formation in febrile neutropenia attack of children with acute lymphoblastic leukemia (ALL). Methods. Thrombin generation was monitored in children treated for ALL at diagnosis of febrile neutropenia (FN) (t 0 ), at 48th hour of FN (t 1 ) and after recovery from neutropenia (t 2). Results. Twenty-nine patients and 50 healthy children as control were enrolled into the study. Mean endogenous thrombin potential (ETP) and mean peak value of thrombin results at t 1 were significantly higher than at t 0, t 2 and control groups, respectively. A positive but statistically nonsignificant correlation between ETP values at t 1 and duration of neutropenia was observed. Conclusion. Although thrombin generation is enhanced both due to chemotherapy or malignancy itself, our results revealed that thrombin formation also increased in neutropenic infection of children with leukemia.

PDF

___

1. Levi M, ten Cate H, Bauer KA, et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-120.

2. Franco RF, de Jonge E, Dekkers PE, et al. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 2000; 96: 554-559.

3. Coughlin SR. Thrombin signalling and protease- activated receptors. Nature 2000; 407: 258-264.

4. Colotta F, Sciacca FL, Sironi M, Luini W, Rabiet MJ, Mantovani A. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-985.

5. Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413: 74-78.

6. Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 1999; 94: 3413-3420.

7. Yang X, Cheng X, Tang Y, et al. The role of type 1 interferons in coagulation induced by gram-negative bacteria. Blood 2020; 135: 1087-1100.

8. Febril Nötropeni Çalışma Grubu. Febril Nötropenik Hastalarda Tanı ve Tedavi Kılavuzu. Flora 2004; 9: 5-28.

9. ALL IC-BFM 2009. A Randomized Trial of the I-BFM- SG for the Management of Childhood non-B Acute Lymphoblastic Leukemia. Final Version of Therapy Protocol from August 14, 2009. Available at: https:// www.bialaczka.org/wp-content/uploads/2016/10/ ALLIC_BFM_2009.pdf (Accessed on April 16, 2021)

10. Henze G. ALL-REZ BFM 2002: Multi-Center Study for Children with Relapsed Acute Lymphoblastic Leukemia. Bethesda: National Library of Medicine, Identifier: NCT00114348. Available at: https:// clinicaltrials.gov/ct2/show/NCT00114348 (Accessed on April 16, 2021)

11. Macfarlane RG, Biggs R. A thrombin generation test. The application in haemophilia and thrombocytopenia. J Clin Pathol 1953; 6: 3-8.

12. Dargaud Y, Wolberg AS, Luddington R, et al. Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: an international multicentre study. Thromb Res 2012; 130: 929-934.

13. van Veen JJ, Gatt A, Makris M. Thrombin generation testing in routine clinical practice: are we there yet? Br J Haematol 2008; 142: 889-903.

14. Chantarangkul V, Clerici M, Bressi A, Giesen PL, Tripodi A. Thrombin generation assessed as endogenous thrombin potential (ETP) in patients with hypo- or hypo-coagulability. Haematologica 2003; 88: 547-554.

15. Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone Jr MA. Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 1984; 160: 618-623.

16. Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost 2006; 32(Suppl 1): 3-15.

17. Schuliga M. The inflammatory actions of coagulant and fibrinolytic proteases in disease. Mediators Inflamm 2015; 2015: 437695.

18. Bos MM, Smeets LS, Dumay I, de Jonge E. Bloodstream infections in patients with or without cancer in a large community hospital. Infection 2013; 41: 949-958.

19. Mihajlovic D, Brkic S, Lendak D, Novakov Mikic A, Draskovic B, Mitic G. Endogenous thrombin potential as marker of procoagulant response that can be useful in early stage of sepsis. Blood Coagul Fibrinolysis 2017; 28: 460-467.

20. Carlier L, Hunault G, Lerolle N, Macchi L. Ex vivo thrombin generation patterns in septic patients with and without disseminated intravascular coagulation. Thromb Res 2015; 135: 192-197.

21. Collins PW, Macchiavello LI, Lewis SJ, et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol 2006; 135: 220-227.

22. Petros S, Kliem P, Siegemund T, Siegemund R. Thrombin generation in severe sepsis. Thromb Res 2012; 129: 797-800.

23. Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 1996; 88: 881-886.

24. Picoli-Quaino SK, Alves BE, Faiotto VB, et al. Impairment of thrombin generation in the early phases of the host response of sepsis. J Crit Care 2014; 29: 31-36.

25. Yenigürbüz FD, Kizmazoglu D, Ates H, et al. Analysis of apoptotic, platelet-derived, endothelial- derived, and tissue factor-positive microparticles of children with acute lymphoblastic leukemia during induction therapy. Blood Coagul Fibrinolysis 2019; 30: 149-155