Pathology & Oncology Research

, Volume 24, Issue 2, pp 345–352 | Cite as

Expression of Coagulation Factor XIII Subunit A Correlates with Outcome in Childhood Acute Lymphoblastic Leukemia

  • Bettina Kárai
  • Zsuzsanna Hevessy
  • Eszter Szánthó
  • László Csáthy
  • Anikó Ujfalusi
  • Katalin Gyurina
  • István Szegedi
  • János Kappelmayer
  • Csongor KissEmail author
Original Article


Previously we identified B-cell lineage leukemic lymphoblasts as a new expression site for subunit A of blood coagulation factor XIII (FXIII-A). On the basis of FXIII-A expression, various subgroups of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be identified. Fifty-five children with BCP-ALL were included in the study. Bone marrow samples were obtained by aspiration and the presence of FXIII-A was detected by flow cytometry. G-banding and fluorescent in situ hybridization was performed according to standard procedures. The 10-year event-free survival (EFS) and overall survival (OS) rate of FXIII-A-positive and FXIII-A-negative patients showed significant differences (EFS: 84% vs. 61%, respectively; p = 0.031; OS: 89% vs. 61%; p = 0.008). Of all the parameters examined, there was correlation only between FXIII-A expression and ‘B-other’ genetic subgroup. Further multivariate Cox regression analysis of FXIII-subtype and genetic group or ‘B-other’ subgroup identified the FXIII-A negative characteristic as an independent factor associated with poor outcome in BCP-ALL. We found an excellent correlation between long-term survival and the FXIII-A-positive phenotype of BCP lymphoblasts at presentation. The results presented seem to be convincing enough to suggest a possible role for FXIII-A expression in the prognostic grouping of childhood BCP-ALL patients.


Precursor B-cell acute lymphoblastic leukemia Immunophenotype Factor XIII-A ‘B-other’ ALL 



The authors thank Dr. Erzsébet Balogh for performing the cytogenetic analyses and Csaba Antal for his administrative help. They are also grateful to all the physicians and assistants participating in the clinical care of patients and in the execution of flow cytometry investigations at the departments of the University of Debrecen. The authors express their gratitude to Dr. Kálmán Nagy and their coworkers at the Borsod-Abaúj-Zemplén County Hospital and University Hospital for providing bone marrow samples for flow cytometric analysis. Finally, they thank Attila Kárai for proofing and editing the manuscript. This study was supported by an OTKA K-108885 grant (CsK).

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare no conflict of interest.

Supplementary material

12253_2017_236_MOESM1_ESM.pdf (94 kb)
Online Resource 1 The prognostic value of ‘B-other’ characteristics in children with B-cell precursor ALL. When analyzed by Kaplan-Meier plots, significant difference was found in overall survival (p = 0.021), and a tendency in event-free survival between children with ‘B-other’ characteristics and those with recurrent genetic alterations. (PDF 94.4 kb)
12253_2017_236_MOESM2_ESM.pdf (81 kb)
Online Resource 2 Investigation of the prognostic impact of ‘B-other’ characteristics and that of FXIII-A manifestation by multivariate Cox regression analyses. In the Cox model, including either parameter and adjusting initial prognostic parameters (age and WBC) FXIII-A character had the most potent, significant effect on overall survival (HR: 4.8; 95% CI: 1.2–19.2; p = 0.025) (PDF 81.3 kb)
12253_2017_236_MOESM3_ESM.pdf (19 kb)
Online Resource 3 The prognostic value of MRD in bone marrow on day 15 in children with B-cell precursor ALL. Kaplan-Meier plots of event-free (a) and overall survival (b) of the various prognostic groups based on MRD classification by flow cytometric analysis. Significant difference was found between flow-medium-risk (FMR) and flow-high-risk (FHR) group both in terms of event-free and overall survival (p = 0.01 and p = 0.004). (PDF 18.7 kb)


  1. 1.
    Conter V, Arico M, Basso G, Biondi A, Barisone E, Messina C, Parasole R, De Rossi G, Locatelli F, Pession A, Santoro N, Micalizzi C, Citterio M, Rizzari C, Silvestri D, Rondelli R, Lo Nigro L, Ziino O, Testi AM, Masera G, Valsecchi MG, Associazione Italiana di Ematologia ed Oncologia P (2010) Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia. Leukemia 24(2):255–264CrossRefPubMedGoogle Scholar
  2. 2.
    Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M (2010) Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 24(2):265–284CrossRefPubMedGoogle Scholar
  3. 3.
    Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M (2014) Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 32(3):174–184CrossRefPubMedGoogle Scholar
  4. 4.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114(5):937–951CrossRefPubMedGoogle Scholar
  5. 5.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405CrossRefPubMedGoogle Scholar
  6. 6.
    Moorman AV (2016) New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica 101(4):407–416CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446(7137):758–764CrossRefPubMedGoogle Scholar
  8. 8.
    Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, Bakkus M, Thielemans K, Grandchamp B, Vilmer E (1998) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--childhood leukemia cooperative group. N Engl J Med 339(9):591–598CrossRefPubMedGoogle Scholar
  9. 9.
    Coustan-Smith E, Sancho J, Hancock ML, Boyett JM, Behm FG, Raimondi SC, Sandlund JT, Rivera GK, Rubnitz JE, Ribeiro RC, Pui CH, Campana D (2000) Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96(8):2691–2696PubMedGoogle Scholar
  10. 10.
    Dworzak MN, Froschl G, Printz D, Mann G, Potschger U, Muhlegger N, Fritsch G, Gadner H, Austrian Berlin-Frankfurt-Munster Study G (2002) Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 99(6):1952–1958CrossRefPubMedGoogle Scholar
  11. 11.
    Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvestri D, Benetello A, Buldini B, Maglia O, Masera G, Conter V, Arico M, Biondi A, Gaipa G (2009) Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27(31):5168–5174CrossRefPubMedGoogle Scholar
  12. 12.
    Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM, Children's Oncology G (2008) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology group study. Blood 111(12):5477–5485CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mejstrikova E, Fronkova E, Kalina T, Omelka M, Batinic D, Dubravcic K, Pospisilova K, Vaskova M, Luria D, Cheng SH, Ng M, Leung Y, Kappelmayer J, Kiss F, Izraeli S, Stark B, Schrappe M, Trka J, Stary J, Hrusak O (2010) Detection of residual B precursor lymphoblastic leukemia by uniform gating flow cytometry. Pediatr Blood Cancer 54(1):62–70CrossRefPubMedGoogle Scholar
  14. 14.
    Dworzak MN, Gaipa G, Ratei R, Veltroni M, Schumich A, Maglia O, Karawajew L, Benetello A, Potschger U, Husak Z, Gadner H, Biondi A, Ludwig WD, Basso G (2008) Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible. Cytometry B Clin Cytom 74(6):331–340CrossRefPubMedGoogle Scholar
  15. 15.
    van Dongen JJ, van der Velden VH, Bruggemann M, Orfao A (2015) Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 125(26):3996–4009CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Boldt DH, Kopecky KJ, Head D, Gehly G, Radich JP, Appelbaum FR (1994) Expression of myeloid antigens by blast cells in acute lymphoblastic leukemia of adults. The southwest Oncology group experience. Leukemia 8(12):2118–2126PubMedGoogle Scholar
  17. 17.
    Invernizzi R, De Fazio P, Iannone AM, Zambelli LM, Rastaldi MP, Ippoliti G, Ascari E (1992) Immunocytochemical detection of factor XIII A--subunit in acute leukemia. Leuk Res 16(8):829–836CrossRefPubMedGoogle Scholar
  18. 18.
    Kappelmayer J, Simon A, Katona E, Szanto A, Nagy L, Kiss A, Kiss C, Muszbek L (2005) Coagulation factor XIII-A. A flow cytometric intracellular marker in the classification of acute myeloid leukemias. Thromb Haemost 94(2):454–459PubMedGoogle Scholar
  19. 19.
    Kiss F, Simon A, Csathy L, Hevessy Z, Katona E, Kiss C, Kappelmayer J (2008) A coagulation factor becomes useful in the study of acute leukemias: studies with blood coagulation factor XIII. Cytometry A 73(3):194–201CrossRefPubMedGoogle Scholar
  20. 20.
    Simon A, Bagoly Z, Hevessy Z, Csathy L, Katona E, Vereb G, Ujfalusi A, Szerafin L, Muszbek L, Kappelmayer J (2012) Expression of coagulation factor XIII subunit a in acute promyelocytic leukemia. Cytometry B Clin Cytom 82(4):209–216CrossRefPubMedGoogle Scholar
  21. 21.
    Kiss F, Hevessy Z, Veszpremi A, Katona E, Kiss C, Vereb G, Muszbek L, Kappelmayer JN (2006) Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit a. Thromb Haemost 96(2):176–182PubMedGoogle Scholar
  22. 22.
    Katona EE, Ajzner E, Toth K, Karpati L, Muszbek L (2001) Enzyme-linked immunosorbent assay for the determination of blood coagulation factor XIII A-subunit in plasma and in cell lysates. J Immunol Methods 258(1–2):127–135CrossRefGoogle Scholar
  23. 23.
    Simons A, Shaffer LG, Hastings RJ (2013) Cytogenetic nomenclature: changes in the ISCN 2013 compared to the 2009 edition. Cytogenet Genome Res 141(1):1–6CrossRefPubMedGoogle Scholar
  24. 24.
    Muszbek L, Yee VC, Hevessy Z (1999) Blood coagulation factor XIII: structure and function. Thromb Res 94(5):271–305CrossRefPubMedGoogle Scholar
  25. 25.
    Muszbek L, Adany R, Mikkola H (1996) Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci 33(5):357–421CrossRefPubMedGoogle Scholar
  26. 26.
    Inbal A, Lubetsky A, Krapp T, Castel D, Shaish A, Dickneitte G, Modis L, Muszbek L, Inbal A (2005) Impaired wound healing in factor XIII deficient mice. Thromb Haemost 94(2):432–437PubMedGoogle Scholar
  27. 27.
    Richardson VR, Cordell P, Standeven KF, Carter AM (2013) Substrates of factor XIII-A: roles in thrombosis and wound healing. Clin Sci (Lond) 124(3):123–137CrossRefGoogle Scholar
  28. 28.
    Bagoly Z, Katona E, Muszbek L (2012) Factor XIII and inflammatory cells. Thromb Res 129:S77–S81CrossRefPubMedGoogle Scholar
  29. 29.
    Serrano K, Devine DV (2002) Intracellular factor XIII crosslinks platelet cytoskeletal elements upon platelet activation. Thromb Haemost 88(2):315–320PubMedGoogle Scholar
  30. 30.
    Jayo A, Conde I, Lastres P, Jimenez-Yuste V, Gonzalez-Manchon C (2009) New insights into the expression and role of platelet factor XIII-A. J Thromb Haemost 7(7):1184–1191CrossRefPubMedGoogle Scholar
  31. 31.
    Kulkarni S, Jackson SP (2004) Platelet factor XIII and calpain negatively regulate integrin alpha(IIb)beta(3) adhesive function and thrombus growth. J Biol Chem 279(29):30697–30706CrossRefPubMedGoogle Scholar
  32. 32.
    Malara A, Gruppi C, Rebuzzini P, Visai L, Perotti C, Moratti R, Balduini C, Tira ME, Balduini A (2011) Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A. Blood 117(8):2476–2483CrossRefPubMedGoogle Scholar
  33. 33.
    Guerrouahen BS, Al-Hijji I, Tabrizi AR (2011) Osteoblastic and vascular endothelial niches, their control on normal hematopoietic stem cells, and their consequences on the development of leukemia. Stem Cells Int. doi: 10.4061/2011/375857 PubMedPubMedCentralGoogle Scholar
  34. 34.
    Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, Van Zutven LJ, Beverloo HB, Van der Spek PJ, Escherich G, Horstmann MA, Janka-Schaub GE, Kamps WA, Evans WE, Pieters R (2009) A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 10(2):125–134CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ, Chen IM, Atlas SR, Kang H, Ar K, Wilson CS, Wharton W, Murphy M, Devidas M, Carroll AJ, Borowitz MJ, Bowman WP, Downing JR, Relling M, Yang J, Bhojwani D, Carroll WL, Camitta B, Reaman GH, Smith M, Hunger SP, Willman CL (2010) Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 116(23):4874–4884CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, Caye A, Vivent J, Costa V, Ferster A, Lutz P, Mazingue F, Millot F, Plantaz D, Plat G, Plouvier E, Poiree M, Sirvent N, Uyttebroeck A, Yakouben K, Girard S, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cave H, European Organisation for R, Treatment of Cancer CsLG (2015) IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's leukemia group study 58951. Leukemia 29(11):2154–2161CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Bettina Kárai
    • 1
  • Zsuzsanna Hevessy
    • 1
  • Eszter Szánthó
    • 1
  • László Csáthy
    • 1
  • Anikó Ujfalusi
    • 1
  • Katalin Gyurina
    • 2
  • István Szegedi
    • 2
  • János Kappelmayer
    • 1
  • Csongor Kiss
    • 2
    Email author
  1. 1.Department of Laboratory Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  2. 2.Department of Pediatric Hematology and Oncology, Institute of Pediatrics, Faculty of MedicineUniversity of DebrecenDebrecenHungary

Personalised recommendations