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Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Study protocol

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

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Thromboembolism (TE) is a serious complication in children with acute lymphoblastic leukemia (ALL). The incidence of symptomatic thromboembolism is as high as 14% and case fatality rate of ~15%. Further, development of thromboembolism interferes with the scheduled chemotherapy with potential impact on cure rates. The exact pathogenesis of ALL-associated thromboembolism is unknown. Concomitant administration of asparaginase and steroids, two important anti-leukemic agents, is shown to increase the risk of ALL-associated TE. Dana-Farber Cancer Institute (DFCI) ALL studies reported ~10% incidence of thrombosis with significantly increased risk in older children (≥10 yrs.) and those with high-risk ALL. The majority (90%) of thromboembolic events occurred in the Consolidation phase of therapy with concomitant asparaginase and steroids when high-risk patients (including all older patients) receive higher dose steroids. Certain inherited and acquired prothrombotic defects are known to contribute to the development of TE. German investigators documented ~50% incidence of TE during therapy with concomitant asparaginase and steroids, in children with at least one prothrombotic defect. However, current evidence regarding the role of prothrombotic defects in the development of ALL-associated TE is contradictory. Although thromboprophylaxis can prevent thromboembolism, ALL and it’s therapy can increase the risk of bleeding. For judicious use of thromboprophylaxis, identifying a population at high risk for TE is important. The risk factors, including prothrombotic defects, predisposing to thrombosis in children with ALL have not been defined.

Methods

This prospective, observational cohort study aims to evaluate the prevalence of inherited prothrombotic defects in children with ALL treated on DFCI 05–01 protocol and the causal relationship of prothrombotic defects in combination with patient and disease-related factors to the development of TE. We hypothesize that the combination of prothrombotic defects and the intensive therapy with concomitant high dose steroids and asparaginase increases the risk of TE in older patients and patients with high-risk ALL.

Discussion

The results of the proposed study will help design studies of prophylactic anticoagulant therapy. Thromboprophylaxis given to a targeted population will likely reduce the incidence of TE in children with ALL and ultimately improve their quality of life and prospects for cure.
Literature
1.
Steering Committee of the National Institute of Canada and the Canadian Cancer Society. Canadian Cancer Statistics 2006. Toronto; 2006. p. 69–71. www.​cancer.​ca.
2.
SEER Cancer statistics review, 1973–1992. US Department of Health and Human Services, NIH publication No. 96–2789. p. 463.
3.
Marina N. Long term survivors of childhood cancer: The medical consequences of cure. Pediatr Clin N Am. 1997;44:1021–42.CrossRef
4.
Mitchell LG, Sutor AN, Andrew M. Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease and treatment. Seminars in Thrombosis & Hemostasis. 1995;21:390–401.CrossRef
5.
Athale UH, Chan AKC. Thrombosis in children with acute lymphoblastic leukemia Part I: Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res. 2003;111:125–31.CrossRefPubMed
6.
Mongale P, Michelson AD, Bovil E, Andrew M. Antithrombotic therapy in children. Chest. 2001;119:344–370S.CrossRef
7.
van Ommen CH, Heijboer H, Baller HR, Hirasing RA, Heijmano HSA, Peter M. Venous thromboembolism in childhood: A prospective two-year registry in The Netherlands. J Pediatr. 2001;139:676–81.CrossRefPubMed
8.
Sutor AH, Chan AKC, Massicotte P. Low molecular weight heparin in pediatric patients. Seminars in Thrombosis Hemostasis. 2004;30:31–9.PubMed
9.
Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L. PARKAA investigators. Central venous line related-thrombosis: association with central venous line location and insertion technique. Blood. 2003;101:4273–8.CrossRefPubMed
10.
Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Arkin S, Declerck L, Cohen HJ, Sallan SE. Improved outcome of children with acute lymphoblastic leukemia: results of Dana-Farber consortium protocol 91-01. Blood. 2001;97:1211–7.CrossRefPubMed
11.
Margolin JF, Steuber CP. Poplack DG. Acute lymphoblastic leukemia. In: Oizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology. Fourth ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 489–544.
12.
Athale UH, Chan AKC. Thrombosis in children with acute lymphoblastic leukemia Part II: Pathogenesis of tthrombosis in children with acute lymphoblastic leukemia: Effects of the disease and therapy. Thromb Res. 2003;111:199–212.CrossRefPubMed
13.
Athale UH, Chan AKC. Thrombosis in children with acute lymphoblastic leukemia Part III: Pathogenesis of tthrombosis in children with acute lymphoblastic leukemia: Effects of host environment. Thromb Res. 2003;111:321–7.CrossRefPubMed
14.
Mitchell L, Hoogendoorn H, Giles PV, Andrew M. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L’Asparginase-induced antithrombin III deficiency. Blood. 1994;83:386–91.PubMed
15.
Rodeghiero F, Castman G, Dini E. Fibrinopeptide A changes during remission induction treatment with L-asparaginase in acute lymphoblastic leukemia: evidence for activation of blood coagulation. Thromb Res. 1990;57:31–8.CrossRefPubMed
16.
Abshire TC, Gold SH, Odom LF, Carson SD, Hathaway WE. The coagulopathy of childhood leukemia. Thrombin activation or primary fibrinolysis. Cancer. 1990;66:716–21.CrossRefPubMed
17.
Oner AF, Gurgey A, Kirazi S, Okur H, Tunc B. Changes of hemostatic factors in children with acute lymphoblastic leukemia receiving combined chemotherapy including high dose methylprednisolone and L-asparaginase. Leukemia & Lymphoma. 1999;33:361–4.CrossRef
18.
Giordano P, Del Vecchio GC, Santoro NAG, Coppola B, Altomare M, Schettini F, Iolascon A, De Mattia D. Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotype subgroup. Ped hematology & Oncology. 2000;17:667–72.CrossRef
19.
Uszynski M, Osinska M, Zekanowska E, Ziolkowska 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;6:108–11.PubMed
20.
Semeraro N, Montemurro P, Giordano P, Schettini F, Santoro N, De Mattia D, Giordano D, Conese M, Colucci M. Unbalanced coagulation-fibrinolysis potential during L-asparaginase therapy in children with acute lymphoblastic leukemia. Thrombosis Haemostasis. 1990;64:38–40.PubMed
21.
Andrew M, Brooker L, Mitchell L. Acquired antithrombin III deficiency secondary to asparaginase therapy in childhood acute lymphoblastic leukemia. Blood Coagul Fibrinolysis. 1994;5(1):S24–36.CrossRefPubMed
22.
Muller HJ, Boos J. Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol. 1998;28:97–113.CrossRefPubMed
23.
Isacson S. The effect of prednisolone on the coagulation and fibrinolytic system. Scan J Haemetol. 1970;7:21–216.
24.
Ozsoylu S, Strauss HS, Diamond LK. Effect of corticosteroids on coagulation of blood. Nature. 1962;195:1214–5.CrossRefPubMed
25.
Zanon PDB, Fornasiero L, Boscaro M, Cappellato G, Fabris F. Girolami A. Increased factor VII associated activities in Cushing’s Syndrome: A probable hypercoagulable state. Thromb Heamosta, 1982; 47: 116-117.
26.
Jorgenson KA, Sorenson P, Freund L. Effect of glucocorticoids on some coagulation tests. Acta Haematol. 1982:68–39. 4
27.
Halton J, Mitchell LG, Vegh PA, MA A. The levels of coagulation system proteins cycle in children with acute lymphoblastic leukemia (ALL) independent of L-Asparginase administration. (Abst.) Pediatr Res. 1992;4:141A.
28.
Ozturk G, Ozsoylu S, Gursel T. Effects of methylprednisolone on F VIII:C and v WF levels. Eur J Haematology. 1994;53:119–20.CrossRef
29.
Sartori TM, Maurizio PG, Sara P, Ugolino L, Annalisa A, Panagiotis T, Massimo F, Antonio G. Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi. J Heart Lung Transplant. 1999;18:693–700.CrossRefPubMed
30.
Patrassi GM, Sartori MT, Riggotti P, Di Lansdro D, Theodoridis P, Fioretti M, Capalbo M, Saggiorato G, Boeri G, Girolami A. Reduced fibrinolytic potential one year after kidney transplantation: relationship to long term steroid therapy. Transplantation. 1995;59:1416–20.CrossRefPubMed
31.
Patrassi GM, Dal Bo ZR, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state of patients with Cushing’s syndrome. Thromb Haemost. 1992;54:518–20.
32.
Patrassi GM, Sartori MT, Viero ML, Scarano L, Boscaro M, Girolami A. The fibrinolytic potential in patients with Cushing’s disease: a clue to their hypercoagulable state. Blood Coagul Fibrinolysis. 1992;3:789–93.CrossRefPubMed
33.
Sartori MT, Patrassi GM, Rigotti P, Marchini F, Massimo F, Spiezia L, Girolami A. Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients. Transplantation. 2002;69:2116–21.CrossRef
34.
Sartori MT, Rigotti P, Marchini F, Spiezia L, Baldan N, Furian L, Varvarikis C, Girolami A. Plasma fibrinolytic capacity in renal transplant recipients: effect of steroid-free immunosuppression therapy. Transplantation. 2003;75:994–8.CrossRefPubMed
35.
Patrassi GM, Sartori MT, Livi U, Casonato A, Danesin C, Vettore S, Girolami A. Impairment of fibrinolytic potential in long term steroid treatment after renal transplantation. Transplantation. 1997;64:1610–4.CrossRefPubMed
36.
van Giezen JJW. Inhibition of fibrinolytic activity in-vivo by Dex is counterbalanced by an inhibition of platelet aggregation. Thromb Haemost. 1992;68:69–73.PubMed
37.
van Giezen JJ, Brakkee JG, Dreteler GH, Bouma BN, Jansen JW. Dex affects platelet aggregation and fibrinolytic activity in rats at different doses which is reflected by their effects on arterial thrombi. Blood Coagul Fibrinolysis. 1994;5:249–55.CrossRefPubMed
38.
Nowak-Gottl U, Wermes C, Junker R, Koch HG, Schobess R, Fleischhack G, Schwabe D, Ehrenforth S. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood. 1999;93:1595–9.PubMed
39.
Mauz- Korholz C, Junker R, Gobel U, Nowalk-Gottl U. Prothrombotic risk factors in children with acute lymphoblatic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost. 2000;83:840–3.PubMed
40.
Nowak-Gottl U, Heinecke A, von Kries R, Nurnberger W, Munchow N, Junker R. Thrombotic events revisited in children with acute lymphoblastic leukemia. Impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res. 2001;103:165–72.CrossRefPubMed
41.
Lane DA, et al. Inherited thrombophilia: Part I. Thrombosis Hemostasis. 1996;76:651–62.
42.
Lane DA, et al. Inherited thrombophilia: Part II. Thrombosis Hemostasis. 1996;76:824–34.
43.
Crowther MA, Kelton JG. Congenital thrombophiliac states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138:128–34.CrossRefPubMed
44.
Ridker PM, et al. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999;99:999–1004.CrossRefPubMed
45.
Fross P, Bloom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtman LAJ, den HeuvelLP v, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995:10–111.
46.
Nowak-Gottl U, Junker R, Hartmeier M, Koch HG, Munchow N, Assman G, von Eckardstein A. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood. Circulation. 1999;100:743.CrossRefPubMed
47.
Nowak-Gottl U, Schobess R, Kumik K, Schwabe D, Fleischhack G, Junker R. Elevated lipoprotein (a) concentration is an independent risk factor of venous thromboembolism. Blood. 2002;99:3476–7.CrossRefPubMed
48.
Mitchell LG, Andrew M, Hanna K, Abshire T, Anderson R, Cherrick I, Desai S, Mahoney D, McCuster P, Wu J, Dahl G, Chait P, de Veber G, Lee KG, Mikulis D, Ginsberg J, Way C. 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 Lymphoblastc Leukemia Treated with Asparaginase (PARKAA) study. Cancer. 2003;97:508–16.CrossRefPubMed
49.
Elhasid R, Lanir N, Sharon R, Arush M, Weyl B, Levin C, Potovsky S, Barak AB, Brenner B. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis. 2001;12:367–70.CrossRefPubMed
50.
Stiakaki E, Germanakis I, Sfyridaki C, Katzilakis N, Danilatou V, Kalmanti M. Prevalence of Factor V Leiden and other thrombophiliac traits among Cretan children with malignancy. Pediatric Blood Cancer. 2005;44:386–9.CrossRefPubMed
51.
Athale UH, Siciliano SA, Crowther M, Barr RD, Chan AKC. Thromboembolism (TE) in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute (DFCI) protocols: effect of age and risk stratification of ALL. British Journal of Haemetology. 2005;129:803–10.CrossRef
52.
Silverman LB, deClerck L, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Lipton JM, Cohen HJ, Sallan SE. Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia. 2000;14:2247–56.CrossRefPubMed
53.
Athale U, Siciliano SA, Barr RD, Chan AK. Thromboembolism (TE) in children with acute lymphoblastic leukemia (ALL) treated on Dana Farber Cancer Institute (DFCI) protocols. Exp Clin Cardiol. 2005;10:17.
54.
Nowak-Gottl U, Ahlke E, Fleischhack G, Schwabe D, Schobess R, Schumann C, Junker R. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood. 2003;101:2529–33.CrossRefPubMed
55.
Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt AK, O’Brien JE, Supko JG, Asselin BA, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc J-M, Michon B, Schorin MA, Welch JJG, Lipshultz SE, Kutock JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia (DFCI 05–001): a randomized, open-label phase 3 trial. The Lancet Oncology 2015, 16:1677–1690 (online) http://​dx.​doi.​org/​10.​1016/​S1470-2045(15)000363-0
56.
Monagle P, Chan A, Massicote P, Chalmers E, Michelson AD. Antithrombotic therapy in children: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:645S–87S.CrossRefPubMed
57.
Male C, Kuhle S, Mitchell L. Diagnosis of venous thromboembolism in children. Semin Thromb Haemost. 2002;87:593–8.
58.
Andrew M, Vegh P, Johnston M, et al. Maturation of hemostatic system in childhood. Blood. 1992;80:1988–2005.
59.
Horton J. Venous thrombotic events in cancer; the bottom line. Cancer Control. 2005;12:31–7.PubMed
60.
Liebman HA. Current perspectives on primary prophylaxis and patient risk factors for venous thromboembolism in the cancer patients. Cancer Control. 2005;12:11–6.PubMed
61.
deVebre G. In pursuit of evidence-based treatments for pediatric stroke. Lancet Neurol. 2005;4:432–6.CrossRef
62.
Santoro N, Giordano P, Vecchio GCD, Guido G, Rizzari C, Varotto S, Masera G, Mattia DD. Ischemic stroke in children treated for acute lymphoblastic leukemia. A retrospective study. J Pediatr Hematol Oncol. 2005;27:153–7.CrossRefPubMed
Metadata
Title
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
Publication date
01-12-2017
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3306-5

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