ABSTRACT
Patients in the pediatric intensive care unit (PICU) often suffer from a variety of pathophysiologic conditions that are associated with abnormal hemostasis. Bleeding is a major complication of any surgery or trauma, thus patients with inherited or acquired coagulopathies or those experiencing massive trauma or undergoing major (especially cardiac) operations present a special challenge to the ICU experts as well as to the hematologist. Awareness of thromboembolic events in the pediatric population has been increasing in the past few years mainly due to improvement in diagnostic tools, advances in new therapy and procedures, together with an increased index of suspicion. Young infants are at greater risk for either bleeding or thromboembolic events, due to lower concentration of vitamin K–dependent procoagulant clotting factors, reduced thrombin potential, and altered fibrinolytic pathway with low levels of the coagulation inhibitors. The combination of infection, hypotension, acidosis, and release of activated substances, such as tumor necrosis factor, is common after severe trauma or in seriously ill ICU patients and often leads to disseminated intravascular coagulation, which may be complicated either by bleeding or thrombosis. The conditions, risk factors, and therapeutic options available for critically ill PICU patients are discussed in this review.
KEYWORDS
Bleeding - thrombosis - pediatric - rFVIIa - DIC
REFERENCES
1
Andrew M, David M, Adams M et al..
Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE.
Blood.
1994;
83
1251-1257
2
Monagle P, Adams M, Mahoney M et al..
Outcome of pediatric thromboembolic disease: a report from the Canadian Child-hood Thrombophilia Registry.
Pediatr Res.
2000;
47
763-766
3
Van Ommen C H, Heijboer H, Büller H R, Hirasing R A, Heijmans H SA, Peters M.
Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands.
J Pediatr.
2001;
139
676-681
4
Tormene D, Gavasso S, Rossetto V, Simioni P.
Thrombosis and thrombophilia in children: a systematic review.
Semin Thromb Hemost.
2006;
32
724-728
5
Thornburg C A, Pipe S.
Neonatal thromboembolic emergencies.
Semin Fetal Neonatal Med.
2006;
11
198-206
6
Beardsley D S.
Venous thromboembolism in the neonatal period.
Semin Perinatol.
2007;
31
250-253
7
Williams M D, Chalmers E A, Gibson B E.
The investigation and management of neonatal haemostasis and thrombosis.
Br J Haematol.
2002;
119
295-309
8
Andrew M, Paes B, Milner R et al..
Development of the human coagulation system in the full-term infant.
Blood.
1987;
70
165-172
9
McEwan A.
Aspects of bleeding after cardiac surgery in children.
Paediatr Anaesth.
2007;
17
1126-1133
10
Martinowitz U, Michaelson M.
On behalf of the Israeli Multidisciplinary rFVIIa Task Force. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force.
J Thromb Haemost.
2005;
3
640-648
11
Blajchman M A, Vamvakas E C.
The continuing risk of transfusion transmitted of infections.
N Engl J Med.
2006;
355
1303-1305
12
Brohi K, Cohen M J, Devenport R A.
Acute coagulopathy of trauma: mechanism, identification and effect.
Curr Opin Crit Care.
2007;
13
680-685
13
Bulutcu F S, Ozbek U, Polat B, Yalcin Y, Karaci A R, Bayindir O.
Which may be effective to reduce blood loss after cardiac operations in cyanotic children: tranexamic acid, aprotinin or combination?.
Paediatr Anaesth.
2005;
15
41-46
14
Dietrich W, Ebell A, Busley R, Boulesteix A L.
Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery.
Ann Thorac Surg.
2007;
84
1144-1150
15
Mangano D T, Tudor I C, Dietzel C.
The risk associated with aprotinin in cardiac surgery.
N Engl J Med.
2006;
354
353-365
16
Khair K, Baker K, Mathias M, Burgess C, Leisner R.
Intranasal desmopression (Octim): a safe and efficacious treatment option for children with bleeding disorders.
Haemophilia.
2007;
13
548-551
17
Das P, Carcao M, Hitzler J.
DDAVP-induced hyponatremia in young children.
J Pediatr Hematol Oncol.
2005;
27
330-332
18
Guay J, DeMoerloose P, Lasne D.
Minimizing perioperative blood loss and transfusions in children.
Can J Anaesth.
2006;
53(6 Suppl)
S59-S67
19
Kjalke M, Johannessen M, Hedner U.
Effect of recombinant factor VIIa (NovoSeven) on thrombocytopenia-like conditions in vitro
.
Semin Hematol.
2001;
38
15-20
20
Galan A M, Tonda R, Pino M et al..
Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in platelet disorder.
Transfusion.
2003;
43
885-892
21
Lisman T, Mosnier L O, Lambert T et al..
Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A.
Blood.
2002;
99
175-179
22
Antovic J P, Antovic A.
Does recombinant factor VIIa, apart from overall hemostasis, regulate TAFI dependent fibrinolysis? In vitro analysis using overall hemostasis potential (OHP) assay.
Thromb Haemost.
2003;
90
620-627
23
Mathew P, Young G.
Recombinant factor VIIa in paediatric bleeding disorders—a 2006 review.
Haemophilia.
2006;
12
457-472
24
Levi M, Peters M, Buller H R.
Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review.
Crit Care Med.
2005;
33
883-890
25
Kolban M, Balachowska-Kosciolek I, Chmielnicki M.
Recombinant coagulation factor VIIa—a novel haemostatic agent in scoliosis surgery?.
Eur Spine J.
2006;
15
944-952
26
Heisel M, Nagib M, Madsen L et al..
Use of recombinant factor VIIa (rFVIIa) to control intraoperative bleeding in pediatric brain tumor patients.
Pediatr Blood Cancer.
2004;
43
703-705
27
Almeida A M, Khair K, Hann I, Liesner R.
The use of recombinant factor VIIa in children with inherited platelet function disorders.
Br J Haematol.
2003;
121
477-481
28
Chuansumrit A, Tangnararatchakit K, Lektakul Y et al..
The use of recombinant activated factor VII for controlling life-threatening bleeding in dengue shock syndrome.
Blood Coagul Fibrinolysis.
2004;
15
335-342
29
Pettersson M, Fischler B, Petrini P et al..
Recombinant FVIIa in children with liver disease.
Thromb Res.
2005;
116
185-197
30
Greisen G, Andreasen R B.
Recombinant factor VIIa in preterm neonates with prolonged prothrombin time.
Blood Coagul Fibrinolysis.
2003;
14
117-120
31
Brown J B, Emerick K M, Brown D L et al..
Recombinant factor VIIa improves coagulopathy caused by liver failure.
J Pediatr Gastroenterol Nutr.
2003;
37
268-272
32
Tobias J D, Groeper K, Berkenbosch J W.
Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients.
South Med J.
2003;
96
12-16
33
Markiewicz M, Kalicinski P, Kaminski A et al..
Acute coagulopathy after reperfusion of the liver graft in children: correction with recombinant activated factor VII.
Transplant Proc.
2003;
35
2318-2319
34
Tobias J D, Simsic J M, Weinstein S et al..
Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients.
J Intensive Care Med.
2004;
19
270-273
35
Pychynska-Pokorska M, Moll J J, Krajewski , Jarosik P.
The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass.
Pediatr Crit Care Med.
2004;
5
246-250
36
Agarwal H S, Bennett J E, Churchwell K B et al..
Recombinant factor VII for postoperative bleeding in neonatal and pediatric cardiac surgery.
Ann Thorac Surg.
2007;
84
161-168
37
Veldman A, Neuhacuser C, Akintuerk H, Thul J, Schranz D, Michel-Behnke I.
Recombinant factor VIIa in the treatment of persistant hemorrhage in pediatric patients on ECMO following surgery for congenital heart disease.
Paediatr Anaesth.
2007;
17
1176-1181
38
Monroe D M, Roberts H R.
Mechanism of action of high-dose factor VIIa: points of agreement and disagreement.
Arterioscler Thromb Vasc Biol.
2003;
23
8-9
39
Hoffman M, Monroe D M.
A cell-based model of hemostasis.
Thromb Haemost.
2001;
85
958-965
40
Abshire T C.
Dose optimization of recombinant factor VIIa for control of mild to moderate bleeds in inhibitor patients: improved efficacy with higher dosing.
Semin Hematol.
2004;
41
3-7
41
O'Connell K A, Wood J J, Wise R P et al..
Thromboembolic adverse events after use of recombinant human coagulation factor IIa.
JAMA.
2006;
295
293-298
42
Mannucci P M, Levi M.
Prevention and treatment of major blood loss.
N Engl J Med.
2007;
356
2301-2311
43
Levi M, Ten Cate H.
Dissemination intravascular coagulation.
N Engl J Med.
1999;
341
586-592
44
Faust S N, Levin M, Harrison O B et al..
Dysfunction of endothelial protein C activation in severe meningococcal sepsis.
N Engl J Med.
2001;
345
408-416
45
Levi M, De jonge E, Van der Poll T.
Sepsis and disseminated intravascular coagulation.
J Thromb Thrombolysis.
2003;
16
43-47
46
Levi M.
Disseminated intravascular coagulation—What's new?.
Crit Care Clin.
2005;
21
449-467
47
Marti-Carvajal A, Salanti G, Cardona A F.
Human recombinant activated protein for severe sepsis.
Cochrane Database Syst Rev.
2007;
(3)
CD004388
48
Kylat R I, Ohlsson A.
A recombinant human activated protein C for severe sepsis in neonates.
Cochrane Database Syst Rev.
2006;
(19)
CD005385
49
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
50
Glaser D W, Medeiros D, Rollins N et al..
Catheter-related thrombosis in children with cancer.
J Pediatr.
2001;
138
255-259
51
Journeycake J M, Buchanan G R.
Thrombotic complications of central venous catheters in children.
Curr Opin Hematol.
2003;
10
369-374
52
Dubois J, Rypens F, Garel L, David M, Lacroix J, Gauvin F.
Incidence of deep vein thrombosis related to peripherally inserted central catheters in children and adolescents.
CMAJ.
2007;
177
1185-1190
53
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
54
Ruud E, Holmstrøm H, Hopp E, Wesenberg F.
Central line-associated venous late effects in children without prior history of thrombosis.
Acta Paediatr.
2006;
95
1060-1065
55
Hermansen M C, Hermansen M G.
Intravascular catheter complications in the neonatal intensive care unit.
Clin Perinatol.
2005;
32
141-156
56
Albisetti M, Schmugge M, Haas R et al..
Arterial thromboembolic complications in critically ill children.
J Crit Care.
2005;
20
296-300
57
Monagle P, Newall F, Barnes C et al..
Arterial thromboembolic disease: a single-centre case series study.
J Paediatr Child Health.
2008;
44
28-32
58
Kirkham F, Sebire G, Steinlin M et al..
Arterial ischaemic stroke in children. Review of the literature and strategies for future stroke studies.
Thromb Haemost.
2004;
92
697-706
59
Goldenberg N A.
Long-term outcomes of venous thrombosis in children.
Curr Opin Hematol.
2005;
12
370-376
60
Nowak-Göttl U, Junker R, Kreuz W et al..
Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.
Blood.
2001;
97
858-862
61
Goldenberg N A, Knapp-Clevenger R, Manco-Johnson M J. Mountain States Regional Thrombophilia Group .
Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children.
N Engl J Med.
2004;
351
1081-1088
62
Young G.
Diagnosis and treatment of thrombosis in children: general principles.
Pediatr Blood Cancer.
2006;
46
540-546
63
Kotsakis A, Cook D, Griffith L et al..
Clinically important venous thromboembolism in pediatric critical care: a Canadian survery.
J Crit Care.
2005;
20
373-380
64
Grandas O H, Klar M, Goldman M H, Filston H C.
Deep venous thrombosis in the pediatric trauma population: an unusual event: report of three cases.
Am Surg.
2000;
66
273-276
65
Athale U H, Chan A K.
Thromboembolic complications in pediatric hematologic malignancies.
Semin Thromb Hemost.
2007;
33
416-426
66
Kajimoto H, Nakazawa M, Murasaki K et al..
Increased thrombogenesity in patients with cyanotic congenital heart disease.
Circ J.
2007;
71
948-953
67
Berkun Y, Padeh S, Barash J et al..
Antiphospholipid syndrome and recurrent thrombosis in children.
Arthritis Rheum.
2006;
55
850-885
68
Dentali F, Gianni M, Agnelli G, Ageno W.
Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: a meta-analysis.
J Thromb Haemost.
2008;
6
70-75
69
Nowak-Gottl U, Kosch A, Schlegel N et al..
Thromboembolism in children.
Curr Opin Hematol.
2002;
9
448-453
70
Marlar R A, Neumann A.
Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies.
Semin Thromb Hemost.
1990;
16
299-309
71
Zimbelman J, Lefkowitz J, Schaeffer C et al..
Unusual complications of warfarin therapy: skin necrosis and priapism.
J Pediatr.
2000;
137
266-268
72
Pescatore S L.
Clinical management of protein C deficiency.
Expert Opin Pharmacother.
2001;
2
431-439
73
Monagle P, Michelson A D, Bovill E, Andrew M.
Antithrombotic therapy in children.
Chest.
2001;
119
344S-370S
74
Shah P S, Shah N.
Heparin-bonded catheters for prolonging the patency of central venous catheters in children.
Cochrane Database Syst Rev.
2007;
(4)
CD005983
75
Nowak-Göttl U, Bidingmayer C, Krümpel A et al..
Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children.
Br J Pharmacol.
2008;
153
1120-1127
76
Robinson A, Fellows K E, Bridges N D, Rome J J.
Effectiveness of pharmacomechanical thrombolysis in infants and children.
Am J Cardiol.
2001;
87
496-499
77
Manco-Johnson M J, Grabowski E F, Hellgreen M et al..
Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and standardization Committee of the International Society of Thrombosis and Haemostasis.
Thromb Haemost.
2002;
88
157-158
78
Goldenberg N A, Durham J D, Knapp-Clevenger R, Manco-Johnson M J.
A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children.
Blood.
2007;
110
45-53
79
Belvis R.
Thrombolysis for acute stroke in pediatrics.
Stroke.
2007;
38
1722-1723
80
Young G, Tarantino M D, Whorley J.
Pilot dose-finding and safety study of bivalirudin in infants < 6 months of age with thrombosis.
J Thromb Haemost.
2007;
5
1654-1659
Gili KenetM.D.
Director, Thrombosis Unit, National Hemophilia Center
Sheba Medical Center, Tel-Hashomer, Israel 52621
Email: gili.kenet@sheba.health.gov