ABSTRACT
Thromboembolism (TE) is an uncommon entity in childhood. Overall 25% of children with
thrombosis and more than 40% of children with central venous line (CVL) -related TE
enrolled on the Canadian Pediatric Thrombophilia Registry had underlying diagnosis
of cancer. However, so far there are very little data describing the epidemiology
of TE in children with cancer. Most of the available information in this area originates
mainly from retrospective and some prospective observational cohort studies conducted
in children with acute lymphoblastic leukemia (ALL). Although ALL has been the most
common cancer reported in association with thrombosis in children, available data
from small studies indicate that TE is equally common in children with acute myeloid
leukemia and lymphoma. TE in association with leukemia and lymphoma seems to be a
multifactorial entity. Potential risk factors include increased thrombin generation
related to leukemia, age of the patients, use of CVL, chemotherapy including asparaginase
and corticosteroids, infections, and inherited prothrombotic state. Management of
TE in a child with cancer presents a unique challenge in terms of balancing risk versus
benefit. Conservative therapy could lead to clot extension and risks of additional
morbidity or mortality; however, chemotherapy-related thrombocytopenia and coagulopathy
increase the risk of bleeding complications. In summary, TE is a frequent and serious
complication in children with hematologic malignancies. More prospective studies are
required to define the epidemiology, pathogenesis, and management of TE in children
with hematologic malignancies.
KEYWORDS
Pediatrics - leukemia - lymphoma - thromboembolism - central venous catheter
REFERENCES
- 1
Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L.
Maturation of the hemostatic system during childhood.
Blood.
1992;
80
1998-2005
- 2
Nowak-Gottl U, Kosch A, Schlegel N.
Thromboembolism in newborns, infants and children.
Thromb Haemost.
2001;
86
464-474
- 3
Monagle P, Chan A, Massicotte P, Chalmers E, Michelson A D.
Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy.
Chest.
2004;
126
645S-687S
- 4
van Ommen C, Heijboer H, Baller H, Hirasing R, Heijmano H, Peter M.
Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands.
J Pediatr.
2001;
139
676-681
- 5
Sutor A H, Chan A K, Massicotte P.
Low-molecular-weight heparin in pediatric patients.
Semin Thromb Hemost.
2004;
30(suppl 1)
31-39
- 6
Newall F, Wallace T, Crock C et al..
Venous thromboembolic disease: a single-centre case series study.
J Paediatr Child Health.
2006;
42
803-807
- 7
Monagle P, Adams M, Mahoney M et al..
Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood
Thrombophilia Registry.
Pediatr Res.
2000;
47
763-766
- 8
Massicotte M P, Dix D, Monagle P, Adams M, Andrew M.
Central venous catheter related thrombosis in children: analysis of the Canadian Registry
of Venous Thromboembolic Complications.
J Pediatr.
1998;
133
770-776
- 9
Athale U H, Chan A K.
Thrombosis in children with acute lymphoblastic leukemia: part I. Epidemiology of
thrombosis in children with acute lymphoblastic leukemia.
Thromb Res.
2003;
111
125-131
- 10
Athale U H, Chan A K.
Thrombosis in children with acute lymphoblastic leukemia. Part II Pathogenesis of
thrombosis in children with acute lymphoblastic leukemia: effects of the disease and
therapy.
Thromb Res.
2003;
111
199-212
- 11
Athale U H, Chan A K.
Thrombosis in children with acute lymphoblastic leukemia. Part III. Pathogenesis of
thrombosis in children with acute lymphoblastic leukemia: effects of host environment.
Thromb Res.
2003;
111
321-327
- 12
Mitchell L G, Sutor A H, Andrew M.
Hemostasis in childhood acute lymphoblastic leukemia: coagulopathy induced by disease
and treatment.
Semin Thromb Hemost.
1995;
21
390-401
- 13
Ruud E, Holmstrom H, De Lange C, Hogstad E M, Wesenberg F.
Low-dose warfarin for the prevention of central line-associated thromboses in children
with malignancies-a randomized, controlled study.
Acta Paediatr.
2006;
95
1053-1059
- 14
Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L.
Central venous line-related thrombosis in children: association with central venous
line location and insertion technique.
Blood.
2003;
101
4273-4278
- 15
Unal S, Varan A, Yalcin B, Buyukpamukcu M, Gurgey A.
Evaluation of thrombotic children with malignancy.
Ann Hematol.
2005;
84
395-399
- 16
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
- 17
Glaser D W, Medeiros D, Rollins N, Buchanan G R.
Catheter-related thrombosis in children with cancer.
J Pediatr.
2001;
138
255-259
- 18
Knofler R, Siegert E, Lauterbach I et al..
Clinical importance of prothrombotic risk factors in pediatric patients with malignancy-impact
of central venous lines.
Eur J Pediatr.
1999;
158(suppl 3)
147-150
- 19
Journeycake J M, Buchanan G R.
Catheter-related deep venous thrombosis and other catheter complications in children
with cancer.
J Clin Oncol.
2006;
24
4575-4580
- 20
Mitchell L, Hoogendoorn H, Giles A R, Vegh P, Andrew M.
Increased endogenous thrombin generation in children with acute lymphoblastic leukemia:
risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency.
Blood.
1994;
83
386-391
- 21
Rodeghiero F, Castaman 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
31-38
- 22
Abshire T C, Gold S H, Odom L F, Carson S D, Hathaway W E.
The coagulopathy of childhood leukemia. Thrombin activation or primary fibrinolysis?.
Cancer.
1990;
66
716-721
- 23
Oner A F, Gurgey A, Kirazli 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.
Leuk Lymphoma.
1999;
33
361-364
- 24
Giordano P, Del Vecchio G C, Santoro N et al..
Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia
immunophenotypic subgroups.
Pediatr Hematol Oncol.
2000;
17
667-672
- 25
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
108-111
- 26
Sifontes M T, Nuss R, Hunger S P, Wilimas J, Jacobson L J, Manco-Johnson M J.
The factor V Leiden mutation in children with cancer and thrombosis.
Br J Haematol.
1997;
96
484-489
- 27
Athale U H, Siciliano S A, Crowther M, Barr R D, Chan A K.
Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana-Farber
Cancer Institute protocols: effect of age and risk stratification of disease.
Br J Haematol.
2005;
129
803-810
- 28
Silverman L B, Gelber R D, Dalton V K et al..
Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber
Consortium Protocol 91-01.
Blood.
2001;
97
1211-1218
- 29
Ruud E, Holmstrom H, Hopp E, Wesenberg F.
Central line-associated venous late effects in children without prior history of thrombosis.
Acta Paediatr.
2006;
95
1060-1065
- 30
Massicotte P, Mitchell L.
Thromboprophylaxis of central venous lines in children with cancer: the first steps
taken on the long road ahead.
Acta Paediatr.
2006;
95
1049-1052
- 31
Levine M, Kakkar A K.
Catheter-associated thrombosis: thromboprophylaxis or not?.
J Clin Oncol.
2005;
23
4006-4008
- 32
Verso M, Agnelli G, Bertoglio S et al..
Enoxaparin for the prevention of venous thromboembolism associated with central vein
catheter: a double-blind, placebo-controlled, randomized study in cancer patients.
J Clin Oncol.
2005;
23
4057-4062
- 33
Caers J, Fontaine C, Vinh-Hung V et al..
Catheter tip position as a risk factor for thrombosis associated with the use of subcutaneous
infusion ports.
Support Care Cancer.
2005;
13
325-331
- 34
Lee A Y, Levine M N, Butler G et al..
Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients
with cancer.
J Clin Oncol.
2006;
24
1404-1408
- 35
Fratino G, Molinari A C, Parodi S et al..
Central venous catheter-related complications in children with oncological/hematological
diseases: an observational study of 418 devices.
Ann Oncol.
2005;
16
648-654
- 36
McLean T W, Fisher C J, Snively B M, Chauvenet A R.
Central venous lines in children with lesser risk acute lymphoblastic leukemia: optimal
type and timing of placement.
J Clin Oncol.
2005;
23
3024-3029
- 37
Male C, Julian J A, Massicotte P, Gent M, Mitchell L.
Significant association with location of central venous line placement and risk of
venous thrombosis in children.
Thromb Haemost.
2005;
94
516-521
- 38
Sutherland D E, Weitz I C, Liebman H A.
Thromboembolic complications of cancer: epidemiology, pathogenesis, diagnosis, and
treatment.
Am J Hematol.
2003;
72
43-52
- 39
Lee A Y, Levine M N.
The thrombophilic state induced by therapeutic agents in the cancer patient.
Semin Thromb Hemost.
1999;
25
137-145
- 40
Haddad T C, Greeno E W.
Chemotherapy-induced thrombosis.
Thromb Res.
2006;
118
555-568
- 41
Mills P J, Parker B, Jones V et al..
The effects of standard anthracycline-based chemotherapy on soluble ICAM-1 and vascular
endothelial growth factor levels in breast cancer.
Clin Cancer Res.
2004;
10
4998-5003
- 42
Togna G I, Togna A R, Franconi M, Caprino L.
Cisplatin triggers platelet activation.
Thromb Res.
2000;
99
503-509
- 43
Walsh J, Wheeler H R, Geczy C L.
Modulation of tissue factor on human monocytes by cisplatin and adriamycin.
Br J Haematol.
1992;
81
480-488
- 44
Wang J, Weiss I, Svoboda K, Kwaan H C.
Thrombogenic role of cells undergoing apoptosis.
Br J Haematol.
2001;
115
382-391
- 45
Morel O, Toti F, Hugel B et al..
Procoagulant microparticles: disrupting the vascular homeostasis equation?.
Arterioscler Thromb Vasc Biol.
2006;
26
2594-2604
- 46
Nowak-Gottl U, Wermes C, Junker R et al..
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
1595-1599
- 47
Mauz-Korholz C, Junker R, Gobel U, Nowak-Gottl U.
Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with
delayed E. coli asparaginase (COALL-92 and 97 protocols).
Thromb Haemost.
2000;
83
840-843
- 48
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
165-172
- 49
Muller H J, Boos J.
Use of L-asparaginase in childhood ALL.
Crit Rev Oncol Hematol.
1998;
28
97-113
- 50
Ozturk G, Ozsoylu S, Gursel T.
Effects of methylprednisolone on FVIII:C and vWF levels.
Eur J Haematol.
1994;
53
119-120
- 51
Sartori T M, Maurizio P G, Sara P et al..
Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis
and myocardial microthrombi generation.
J Heart Lung Transplant.
1999;
18
693-700
- 52
Patrassi G M, Sartori M T, Rigotti P et al..
Reduced fibrinolytic potential one year after kidney transplantation. Relationship
to long-term steroid treatment.
Transplantation.
1995;
59
1416-1420
- 53
Patrassi G M, Dal Bo Zanon R, Boscaro M, Martinelli S, Girolami A.
Further studies on the hypercoagulable state of patients with Cushing's syndrome.
Thromb Haemost.
1985;
54
518-520
- 54
Patrassi G M, Sartori M T, Viero M L, 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
789-793
- 55
Sartori M T, Patrassi G M, Rigotti P et al..
Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal
transplant recipients.
Transplantation.
2000;
69
2116-2121
- 56
Sartori M T, Rigotti P, Marchini F et al..
Plasma fibrinolytic capacity in renal transplant recipients: effect of steroid-free
immunosuppression therapy.
Transplantation.
2003;
75
994-998
- 57
Patrassi G M, Sartori M T, Livi U et al..
Impairment of fibrinolytic potential in long-term steroid treatment after heart transplantation.
Transplantation.
1997;
64
1610-1614
- 58
van Giezen J J, Jansen J W.
Inhibition of fibrinolytic activity in-vivo by dexamethasone is counterbalanced by
an inhibition of platelet aggregation.
Thromb Haemost.
1992;
68
69-73
- 59
van Giezen J J, Brakkee J G, Dreteler G H, Bouma B N, Jansen J W.
Dexamethasone affects platelet aggregation and fibrinolytic activity in rats at different
doses which is reflected by their effect on arterial thrombosis.
Blood Coagul Fibrinolysis.
1994;
5
249-255
- 60
Nowak-Gottl U, Ahlke E, Fleischhack G et al..
Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols):
prednisone versus dexamethasone administration.
Blood.
2003;
101
2529-2533
- 61
Caruso V, Iacoviello L, Di Castelnuovo A et al..
Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis
of 17 prospective studies comprising 1752 pediatric patients.
Blood.
2006;
108
2216-2222
- 62
Raad I I, Luna M, Khalil S A, Costerton J W, Lam C, Bodey G P.
The relationship between the thrombotic and infectious complications of central venous
catheters.
JAMA.
1994;
271
1014-1016
- 63
van Rooden C J, Schippers E F, Barge R M et al..
Infectious complications of central venous catheters increase the risk of catheter-related
thrombosis in hematology patients: a prospective study.
J Clin Oncol.
2005;
23
2655-2660
- 64
Bick R L.
Cancer-associated thrombosis.
N Engl J Med.
2003;
349
109-111
- 65
Hack C E.
Tissue factor pathway of coagulation in sepsis.
Crit Care Med.
2000;
28
S25-S30
- 66
Esmon C.
The protein C pathway.
Crit Care Med.
2000;
28
S44-S48
- 67
Elhasid R, Lanir N, Sharon R et al..
Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with
acute lymphoblastic leukemia.
Blood Coagul Fibrinolysis.
2001;
12
367-370
- 68
Kishi S, Griener J, Cheng C et al..
Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia.
J Clin Oncol.
2003;
21
3084-3091
- 69
Mitchell L G, Andrew M, Hanna K et al..
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 Lymphoblastic
Leukemia Treated with Asparaginase (PARKAA) Study.
Cancer.
2003;
97
508-516
- 70
Ruud E, Holmstrom H, Brosstad F, Wesenberg F.
Children with acute lymphoblastic leukaemia have high plasma levels of total homocysteine
at time of diagnosis.
Scand J Clin Lab Invest.
2006;
66
67-78
- 71
Stiakaki E, Germanakis I, Sfyridaki C, Katzilakis N, Danilatou V, Kalmanti M.
Prevalence of factor V Leiden and other thrombophilic traits among Cretan children
with malignancy.
Pediatr Blood Cancer.
2005;
44
386-389
- 72
Randolph A G, Cook D J, Gonzales C A, Andrew M.
Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis
of randomized controlled trials.
Chest.
1998;
113
165-171
- 73
Couban S, Goodyear M, Burnell M et al..
Randomized placebo-controlled study of low-dose warfarin for the prevention of central
venous catheter-associated thrombosis in patients with cancer.
J Clin Oncol.
2005;
23
4063-4069
- 74
Agnelli G, Verso M.
Is antithrombotic prophylaxis required in cancer patients with central venous catheters?
No.
J Thromb Haemost.
2006;
4
14-15
- 75
Massicotte P, Julian J A, Gent M et al..
An open-label randomized controlled trial of low molecular weight heparin for the
prevention of central venous line-related thrombotic complications in children: the
PROTEKT trial.
Thromb Res.
2003;
109
101-108
- 76
Murphy M S, John P R, Mayer A D, Buckels J A, Kelly D A.
Heparin therapy and bone fractures.
Lancet.
1992;
340
1098
- 77
Avioli L V.
Heparin-induced osteopenia: an appraisal.
Adv Exp Med Biol.
1975;
52
375-387
- 78
Sackler J P, Liu L.
Heparin-induced osteoporosis.
Br J Radiol.
1973;
46
548-550
- 79
Roebuck D J.
Skeletal complications in pediatric oncology patients.
Radiographics.
1999;
19
873-885
- 80
Halton J M, Atkinson S A, Fraher L et al..
Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic
leukemia.
J Bone Miner Res.
1996;
11
1774-1783
- 81
Arikoski P, Komulainen J, Riikonen P et al..
Impaired development of bone mineral density during chemotherapy: a prospective analysis
of 46 children newly diagnosed with cancer.
J Bone Miner Res.
1999;
14
2002-2009
- 82
Dolovich L R, Ginsberg J S, Douketis J D, Holbrook A M, Cheah G.
A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin
in the treatment of venous thromboembolism: examining some unanswered questions regarding
location of treatment, product type, and dosing frequency.
Arch Intern Med.
2000;
160
181-188
- 83
van Den Belt A G, Prins M H, Lensing A W et al..
Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated
heparin for venous thromboembolism.
Cochrane Database Syst Rev.
2000;
CD001100
- 84
Gould M K, Dembitzer A D, Doyle R L, Hastie T J, Garber A M.
Low-molecular-weight heparins compared with unfractionated heparin for treatment of
acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
Ann Intern Med.
1999;
130
800-809
- 85
Massicotte P, Adams M, Marzinotto V, Brooker L A, Andrew M.
Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose
finding study.
J Pediatr.
1996;
128
313-318
- 86
Albisetti M, Andrew M.
Low molecular weight heparin in children.
Eur J Pediatr.
2002;
161
71-77
- 87
Dix D, Andrew M, Marzinotto V et al..
The use of low molecular weight heparin in pediatric patients: a prospective cohort
study.
J Pediatr.
2000;
136
439-445
- 88
Nohe N, Flemmer A, Rumler R, Praun M, Auberger K.
The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis
in childhood: a report on 48 cases.
Eur J Pediatr.
1999;
158(suppl 3)
S134-S139
- 89
Lee A Y, Levine M N, Baker R I et al..
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous
thromboembolism in patients with cancer.
N Engl J Med.
2003;
349
146-153
- 90
Massicotte P, Julian J A, Gent M et al..
An open-label randomized controlled trial of low molecular weight heparin compared
to heparin and coumadin for the treatment of venous thromboembolic events in children:
the REVIVE trial.
Thromb Res.
2003;
109
85-92
- 91
Linkins L A, Weitz J I.
New anticoagulants.
Semin Thromb Hemost.
2003;
29
619-631
- 92
Deitcher S R, Topoulos A P, Bartholomew J R, Kichuk-Chrisant M R.
Lepirudin anticoagulation for heparin-induced thrombocytopenia.
J Pediatr.
2002;
140
264-266
- 93
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
- 94
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
- 95
Gugliotta L, D'Angelo A, Mattioli Belmonte M et al..
Hypercoagulability during L-asparaginase treatment: the effect of antithrombin III
supplementation in vivo.
Br J Haematol.
1990;
74
465-470
- 96
Zaunschirm A, Muntean W.
Correction of hemostatic imbalances induced by L-asparaginase therapy in children
with acute lymphoblastic leukemia.
Pediatr Hematol Oncol.
1986;
3
19-25
- 97
Nowak-Gottl U, Kuhn N, Wolff J E et al..
Inhibition of hypercoagulation by antithrombin substitution in E. coli L-asparaginase-treated children.
Eur J Haematol.
1996;
56
35-38
- 98
Wiernikowski J T, Crowther M, Clase C M, Ingram A, Andrew M, Chan A K.
Stability and sterility of recombinant tissue plasminogen activator at -30 degrees
C.
Lancet.
2000;
355
2221-2222
- 99
Choi M, Massicotte M P, Marzinotto V, Chan A K, Holmes J L, Andrew M.
The use of alteplase to restore patency of central venous lines in pediatric patients:
a cohort study.
J Pediatr.
2001;
139
152-156
- 100
Wiernikowski J T, Athale U H.
Thromboembolic complications in children with cancer.
Thromb Res.
2006;
118
137-152
- 101
Levine M, Gent M, Hirsh J et al..
A comparison of low-molecular-weight heparin administered primarily at home with unfractionated
heparin administered in the hospital for proximal deep-vein thrombosis.
N Engl J Med.
1996;
334
677-681
- 102
Koopman M M, Prandoni P, Piovella F et al..
Treatment of venous thrombosis with intravenous unfractionated heparin administered
in the hospital as compared with subcutaneous low-molecular-weight heparin administered
at home. The Tasman Study Group.
N Engl J Med.
1996;
334
682-687
- 103
Revel-Vilk S, Chan A K.
Anticoagulation therapy in children.
Semin Thromb Hemost.
2003;
29
425-432
- 104
Streif W, Andrew M, Marzinotto V et al..
Analysis of warfarin therapy in pediatric patients: A prospective cohort study of
319 patients.
Blood.
1999;
94
3007-3014
- 105 Managle T, Chan A KC, de Veder G, Massicotte M P. Vitamin K antagonist warfarin
and acenocoumarol therapy. In: Andrew's Pediatric Thromboembolism and Stroke. 3rd
ed. Hamilton, Canada; BC Decker 2006: 104-115
- 106
Buck M L.
Anticoagulation with warfarin in infants and children.
Ann Pharmacother.
1996;
30
1316-1322
Anthony K.C Chan
3N27D, McMaster University
1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
eMail: akchan@mcmaster.ca
