Thromboembolic Complications in Pediatric Hematologic Malignancies

Uma H. Athale; Anthony K. C. Chan

doi:10.1055/s-2007-976177

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2007; 33(4): 416-426
DOI: 10.1055/s-2007-976177

Thromboembolic 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

Abstract

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

Full Text

References

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

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