Semin Thromb Hemost 2007; 33(4): 408-415
DOI: 10.1055/s-2007-976176
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hemorrhagic Complications in Pediatric Hematologic Malignancies

Uma H. Athale1 , Anthony K.C Chan1 , 2
  • 1Division of Pediatric Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
  • 2Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
Further Information

Publication History

Publication Date:
24 May 2007 (online)

ABSTRACT

Hematologic malignancies account for almost 40% of all cancers in children. Hemorrhage is the most common cause of early death in children with leukemia. Furthermore, major bleeding episodes lead to shorter survival and increased resource use. Potential risk factors for bleeding include hyperleukocytosis, immunophenotype of leukemia (especially acute promyelocytic leukemia), thrombocytopenia, and associated infections. Successful management of a bleeding episode is dependent on prompt identification of a child at high risk for bleeding, and should be directed at the replacement of blood products as well as to the aggressive therapy for underlying risk factors. Although in recent years there is a favorable decline in the hemorrhage-related mortality, the overall prevalence and the extent of morbidity posed by this potentially fatal complication, including disease outcome in children with hematologic malignancy, is largely unknown. In addition, there are no evidence-based guidelines for prophylactic blood or blood product transfusions. Prospective studies are required to define the epidemiology and risk factors predisposing children with hematologic malignancy to bleeding and to develop management guidelines.

REFERENCES

  • 1 Canada NCI .Canadian Cancer Statistics. Toronto; NCI 69-71
  • 2 Smith M. Childhood cancer: Incidence, survival, and mortality. In: Pizzo P Principles and Practice of Pediatric Oncology. Philadelphia, PA; Lippincott Williams & Wilkins 2002: 1-12
  • 3 Sandlund J T, Downing J R, Crist W M. Non-Hodgkin's lymphoma in childhood.  N Engl J Med. 1996;  334 1238-1248
  • 4 Slats A M, Egeler R M, van der Does-van den Berg A et al.. Causes of death-other than progressive leukemia-in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience.  Leukemia. 2005;  19 537-544
  • 5 Brenner B, Hoffman R, Balashov D, Shutluko E, Culic S D, Nizamoutdinova E. Control of bleeding caused by thrombocytopenia associated with hematologic malignancy: an audit of the clinical use of recombinant activated factor VII.  Clin Appl Thromb Hemost. 2005;  11 401-410
  • 6 Rubnitz J E, Lensing S, Zhou Y et al.. Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience.  Cancer. 2004;  101 1677-1684
  • 7 Wheeler K, Chessells J M, Bailey C C, Richards S M. Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X.  Arch Dis Child. 1996;  74 101-107
  • 8 Liang D C, Hung I J, Yang C P et al.. Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: a report from the Taiwan Pediatric Oncology Group.  Leukemia. 1999;  13 155-160
  • 9 Riley L C, Hann I M, Wheatley K, Stevens R F. Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council acute myeloid leukaemia trial (MRC AML10). The MCR Childhood Leukaemia Working Party.  Br J Haematol. 1999;  106 436-444
  • 10 Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T. Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98.  J Clin Oncol. 2004;  22 4384-4393
  • 11 Creutzig U, Zimmermann M, Ritter J et al.. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials.  Leukemia. 2005;  19 2030-2042
  • 12 O'Brien T A, Russell S J, Vowels M R et al.. Results of consecutive trials for children newly diagnosed with acute myeloid leukemia from the Australian and New Zealand Children's Cancer Study Group.  Blood. 2002;  100 2708-2716
  • 13 Clavell L A, Gelber R D, Cohen H J et al.. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia.  N Engl J Med. 1986;  315 657-663
  • 14 Ribeiro R C, Pui C H. The clinical and biological correlates of coagulopathy in children with acute leukemia.  J Clin Oncol. 1986;  4 1212-1218
  • 15 Wermes C, von Depka Prondzinski M, Lichtinghagen R, Barthels M, Welte K, Sykora K W. Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters.  Eur J Pediatr. 1999;  158(suppl 3) S143-S146
  • 16 Woods W G, Kobrinsky N, Buckley J D et al.. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group.  Blood. 1996;  87 4979-4989
  • 17 Kim H, Lee J H, Choi S J, Kim W K, Lee J S, Lee K H. Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.  Haematologica. 2004;  89 622-624
  • 18 Goad K E, Gralnick H R. Coagulation disorders in cancer.  Hematol Oncol Clin North Am. 1996;  10 457-484
  • 19 Wilde J T, Davies J M. Haemostatic problems in acute leukaemia.  Blood Rev. 1990;  4 245-251
  • 20 Quinones-Hinojosa A, Gulati M, Singh V, Lawton M T. Spontaneous intracerebral hemorrhage due to coagulation disorders.  Neurosurg Focus. 2003;  15 1-15
  • 21 Kyrnetskiy E E, Kun L E, Boop F A, Sanford R A, Khan R B. Types, causes, and outcome of intracranial hemorrhage in children with cancer.  J Neurosurg. 2005;  102 31-35
  • 22 Ott N, Ramsay N K, Priest J R et al.. Sequelae of thrombotic or hemorrhagic complications following L-asparaginase therapy for childhood lymphoblastic leukemia.  Am J Pediatr Hematol Oncol. 1988;  10 191-195
  • 23 Soylu A R, Buyukasik Y, Cetiner D et al.. Overt gastrointestinal bleeding in haematologic neoplasms.  Dig Liver Dis. 2005;  37 917-922
  • 24 Schwartz J M, Wolford J L, Thornquist M D et al.. Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome.  Am J Gastroenterol. 2001;  96 385-393
  • 25 Jackson N, Reddy S C, Hishamuddin M, Low H C. Retinal findings in adult leukaemia: correlation with leukocytosis.  Clin Lab Haematol. 1996;  18 105-109
  • 26 Reddy S C, Quah S H, Low H C, Jackson N. Prognostic significance of retinopathy at presentation in adult acute leukemia.  Ann Hematol. 1998;  76 15-18
  • 27 Reddy S C, Menon B S. A prospective study of ocular manifestations in childhood acute leukaemia.  Acta Ophthalmol Scand. 1998;  76 700-703
  • 28 Reddy S C, Jackson N. Retinopathy in acute leukaemia at initial diagnosis: correlation of fundus lesions and haematological parameters.  Acta Ophthalmol Scand. 2004;  82 81-85
  • 29 Rogers Z. Hematologic supportive care. In: Pizzo P Principles and Practice of Pediatric Oncology. Philadelphia; Lippincott Williams & Wilkins 2002: 1205-1238
  • 30 Wehmeier A, Sudhoff T, Meierkord F. Relation of platelet abnormalities to thrombosis and hemorrhage in chronic myeloproliferative disorders.  Semin Thromb Hemost. 1997;  23 391-402
  • 31 Behm F. Manifestations of the bone marrow. In: Parham D Pediatric Neoplasia: Morphology and Biology. Philadelphia; Lippincott-Raven 1996: 449-504
  • 32 Falanga A, Barbui T. Coagulopathy of acute promyelocytic leukemia.  Acta Haematol. 2001;  106 43-51
  • 33 Tallman M S, Andersen J W, Schiffer C A et al.. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol.  Blood. 2002;  100 4298-4302
  • 34 Ucar C, Caliskan U. Successful treatment of acute lymphoblastic leukemia with L-asparaginase-induced intracranial hemorrhage to activated recombinant factor VIIa in a child.  Pediatr Hematol Oncol. 2006;  23 339-345
  • 35 Sanz M A. Treatment of acute promyelocytic leukemia.  Hematology (Am Soc Hematol Educ Program). 2006;  147-155
  • 36 Gmur J, Burger J, Schanz U, Fehr J, Schaffner A. Safety of stringent prophylactic platelet transfusion policy for patients with acute leukaemia.  Lancet. 1991;  338 1223-1226
  • 37 Callow C R, Swindell R, Randall W, Chopra R. The frequency of bleeding complications in patients with haematological malignancy following the introduction of a stringent prophylactic platelet transfusion policy.  Br J Haematol. 2002;  118 677-682
  • 38 Gil-Fernandez J J, Alegre A, Fernandez-Villalta M J et al.. Clinical results of a stringent policy on prophylactic platelet transfusion: non-randomized comparative analysis in 190 bone marrow transplant patients from a single institution.  Bone Marrow Transplant. 1996;  18 931-935
  • 39 Heckman K D, Weiner G J, Davis C S, Strauss R G, Jones M P, Burns C P. Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10,000/microL versus 20,000/microL.  J Clin Oncol. 1997;  15 1143-1149
  • 40 Howard S C, Gajjar A J, Cheng C et al.. Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia.  JAMA. 2002;  288 2001-2007
  • 41 Vavricka S R, Walter R B, Irani S, Halter J, Schanz U. Safety of lumbar puncture for adults with acute leukemia and restrictive prophylactic platelet transfusion.  Ann Hematol. 2003;  82 570-573
  • 42 Howard S C, Gajjar A, Ribeiro R C et al.. Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia.  JAMA. 2000;  284 2222-2224
  • 43 Priest J R, Ramsay N K, Bennett A J, Krivit W, Edson J R. The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia.  J Pediatr. 1982;  100 990-995
  • 44 Legnani C, Palareti G, Pession A et al.. Intravascular coagulation phenomena associated with prevalent fall in fibrinogen and plasminogen during L-asparaginase treatment in leukemic children.  Haemostasis. 1988;  18 179-186
  • 45 Ramsay N K, Coccia P F, Krivit W, Nesbit M E, Edson J R. The effect of L-asparaginase of plasma coagulation factors in acute lymphoblastic leukemia.  Cancer. 1977;  40 1398-1401
  • 46 Homans A C, Rybak M E, Baglini R L, Tiarks C, Steiner M E, Forman E N. Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia.  J Clin Oncol. 1987;  5 811-817
  • 47 Halton J M, Mitchell L G, Vegh P, Eves M, Andrew M E. Fresh frozen plasma has no beneficial effect on the hemostatic system in children receiving L-asparaginase.  Am J Hematol. 1994;  47 157-161
  • 48 Nowak-Gottl U, Rath B, Binder M et al.. Inefficacy of fresh frozen plasma in the treatment of L-asparaginase-induced coagulation factor deficiencies during ALL induction therapy.  Haematologica. 1995;  80 451-453
  • 49 Das P, Carcao M, Hitzler J. Use of recombinant factor VIIa prior to lumbar puncture in pediatric patients with acute leukemia.  Pediatr Blood Cancer. 2006;  47 206-209

Anthony K.C Chan

3N27D, McMaster University

1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5

Email: akchan@mcmaster.ca

    >