Hemostasis and Thrombosis in Critically Ill Children

 

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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.

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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 4 Tormene D, Gavasso S, Rossetto V, Simioni P. Thrombosis and thrombophilia in children: a systematic review.  Semin Thromb Hemost. 2006;  32 724-728
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Thornburg C A, Pipe S. Neonatal thromboembolic emergencies.  Semin Fetal Neonatal Med. 2006;  11 198-206
  CrossrefPubMedGoogle Scholar
• 6 Beardsley D S. Venous thromboembolism in the neonatal period.  Semin Perinatol. 2007;  31 250-253
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 9 McEwan A. Aspects of bleeding after cardiac surgery in children.  Paediatr Anaesth. 2007;  17 1126-1133
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 11 Blajchman M A, Vamvakas E C. The continuing risk of transfusion transmitted of infections.  N Engl J Med. 2006;  355 1303-1305
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 17 Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children.  J Pediatr Hematol Oncol. 2005;  27 330-332
  CrossrefPubMedGoogle Scholar
• 18 Guay J, DeMoerloose P, Lasne D. Minimizing perioperative blood loss and transfusions in children.  Can J Anaesth. 2006;  53(6 Suppl) S59-S67
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 23 Mathew P, Young G. Recombinant factor VIIa in paediatric bleeding disorders—a 2006 review.  Haemophilia. 2006;  12 457-472
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 29 Pettersson M, Fischler B, Petrini P et al.. Recombinant FVIIa in children with liver disease.  Thromb Res. 2005;  116 185-197
  CrossrefPubMedGoogle Scholar
• 30 Greisen G, Andreasen R B. Recombinant factor VIIa in preterm neonates with prolonged prothrombin time.  Blood Coagul Fibrinolysis. 2003;  14 117-120
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 39 Hoffman M, Monroe D M. A cell-based model of hemostasis.  Thromb Haemost. 2001;  85 958-965
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 42 Mannucci P M, Levi M. Prevention and treatment of major blood loss.  N Engl J Med. 2007;  356 2301-2311
  CrossrefPubMedGoogle Scholar
• 43 Levi M, Ten Cate H. Dissemination intravascular coagulation.  N Engl J Med. 1999;  341 586-592
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 45 Levi M, De jonge E, Van der Poll T. Sepsis and disseminated intravascular coagulation.  J Thromb Thrombolysis. 2003;  16 43-47
  CrossrefPubMedGoogle Scholar
• 46 Levi M. Disseminated intravascular coagulation—What's new?.  Crit Care Clin. 2005;  21 449-467
  CrossrefPubMedGoogle Scholar
• 47 Marti-Carvajal A, Salanti G, Cardona A F. Human recombinant activated protein for severe sepsis.  Cochrane Database Syst Rev. 2007;  (3) CD004388
  PubMedGoogle Scholar
• 48 Kylat R I, Ohlsson A. A recombinant human activated protein C for severe sepsis in neonates.  Cochrane Database Syst Rev. 2006;  (19) CD005385
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 50 Glaser D W, Medeiros D, Rollins N et al.. Catheter-related thrombosis in children with cancer.  J Pediatr. 2001;  138 255-259
  CrossrefPubMedGoogle Scholar
• 51 Journeycake J M, Buchanan G R. Thrombotic complications of central venous catheters in children.  Curr Opin Hematol. 2003;  10 369-374
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 55 Hermansen M C, Hermansen M G. Intravascular catheter complications in the neonatal intensive care unit.  Clin Perinatol. 2005;  32 141-156
  CrossrefPubMedGoogle Scholar
• 56 Albisetti M, Schmugge M, Haas R et al.. Arterial thromboembolic complications in critically ill children.  J Crit Care. 2005;  20 296-300
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 59 Goldenberg N A. Long-term outcomes of venous thrombosis in children.  Curr Opin Hematol. 2005;  12 370-376
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 62 Young G. Diagnosis and treatment of thrombosis in children: general principles.  Pediatr Blood Cancer. 2006;  46 540-546
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 65 Athale U H, Chan A K. Thromboembolic complications in pediatric hematologic malignancies.  Semin Thromb Hemost. 2007;  33 416-426
  Article in Thieme ConnectPubMedGoogle Scholar
• 66 Kajimoto H, Nakazawa M, Murasaki K et al.. Increased thrombogenesity in patients with cyanotic congenital heart disease.  Circ J. 2007;  71 948-953
  CrossrefPubMedGoogle Scholar
• 67 Berkun Y, Padeh S, Barash J et al.. Antiphospholipid syndrome and recurrent thrombosis in children.  Arthritis Rheum. 2006;  55 850-885
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 69 Nowak-Gottl U, Kosch A, Schlegel N et al.. Thromboembolism in children.  Curr Opin Hematol. 2002;  9 448-453
  CrossrefPubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 71 Zimbelman J, Lefkowitz J, Schaeffer C et al.. Unusual complications of warfarin therapy: skin necrosis and priapism.  J Pediatr. 2000;  137 266-268
  CrossrefPubMedGoogle Scholar
• 72 Pescatore S L. Clinical management of protein C deficiency.  Expert Opin Pharmacother. 2001;  2 431-439
  CrossrefPubMedGoogle Scholar
• 73 Monagle P, Michelson A D, Bovill E, Andrew M. Antithrombotic therapy in children.  Chest. 2001;  119 344S-370S
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 79 Belvis R. Thrombolysis for acute stroke in pediatrics.  Stroke. 2007;  38 1722-1723
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Gili KenetM.D. 

Director, Thrombosis Unit, National Hemophilia Center

Sheba Medical Center, Tel-Hashomer, Israel 52621

Email: gili.kenet@sheba.health.gov