1080 SECTION IX Pediatric Critical Care Hematology and Oncology TABLE 90 4 Assays Used in the Monitoring of UFH Therapy Assay Common Uses Advantages Disadvantages in Children aPTT F Clot Coagulation s[.]
1080 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology TABLE 90.4 Assays Used in the Monitoring of UFH Therapy Assay Common Uses Advantages Disadvantages in Children aPTT F-Clot Coagulation screening assay Therapeutic UFH monitoring Low cost Easy to perform Widely available Baseline aPTT often prolonged in children Wide variability in reagent sensitivity to age-related differences Nonphysiologic measure of UFH effect No validation of therapeutic ranges in children TCT F-Clot Coagulation screening assay Therapeutic UFH monitoring (rarely) Easy to perform Patients previously exposed to topical thrombin may have antibodies causing prolongation of the clotting time Optimal concentration of thrombin used for the assay is unknown No validated reference range for UFH in children ACT F-Clot CPB, extracorporeal circuits Easy bedside whole blood test Extensive experience in most PICUs Does not correlate with any specific measures of heparin activity Analyzer dependent Anti-Xa F-Ch Calibration of aPTT reference ranges Therapeutic UFH monitoring Direct measure of UFH inhibition of Xa Easy to perform Not as widely available as aPTT and costs significantly more Does not measure other mechanisms of UFH effect (e.g., anti-IIa) and assumes constant ration of effect, which is not true in children Some kits have exogenous AT, others have dextran sulphate, both of which will introduce in vitro error in small children for different reasons Protamine titration Q Not used clinically Used by reference laboratories Only assay that directly measures UFH concentration Low cost Not widely available Automated methods have not been validated for management of therapeutic UFH and manual methods labor intensive aPTT, Activated partial thromboplastin time; AT, antithrombin; CPB, cardiopulmonary bypass; F-Ch, functional, chromogenic assay; F-Clot, functional, clot-based assay; PICUs, pediatric intensive care units; Q, quantitative assay; TCT, thrombin clotting time; UFH, unfractionated heparin It is not hard to see how such errors occur in busy units that operate 24 hours per day Units should actively manage the choices of UFH preparations available to their staff to minimize the risk of confusion Staff should be educated in the dangers of UFH and encouraged to be vigilant at all times when administering a drug that consistently ranks in hospital lists of the drugs most commonly involved in medication errors Another adverse event from UFH only recently reported has been anaphylaxis, which in 2007 to 2008 accounted for over 80 deaths due to an unintended contaminant introduced in the manufacturing process.118 Again, while there is almost nothing in the medical literature describing these events, the FDA released a number of warning statements; one impact of this has been changes to the labeling of UFH The potential for contamination of drug products made from biological sources will always be real An important mechanism to minimize this risk is to ensure that children receive UFH only when the risks are clearly outweighed by the benefits UFH has been described as being ubiquitous in PICUs; thus, clinicians should actively minimize unnecessary exposure to it In summary, anticoagulation in children in the PICU is common, and UFH is currently the most common anticoagulant While there remain many concerns about the potential adverse effects of UFH, there are currently no real alternative anticoagulant agents available for intravenous use in sick children Many adverse events are related to dosing errors, and it is likely that PICUs can significantly improve the safety of UFH by developing systems to prevent medication errors In addition, there is emerging evidence that our understanding of the pharmacokinetics of UFH in children and of the assays used to monitor UFH in children is far from ideal Urgent research is required to improve the safety and utility of UFH in critically ill children Thromboprophylaxis in the Pediatric Intensive Care Unit In critically ill adults, pharmacologic thromboprophylaxis is highly recommended owing to its proven efficacy and safety in the prevention of DVT The patient populations that require pharmacologic prophylaxis in pediatrics are less well defined.119 One of the many issues with studying this area is the difference in nomenclature regarding “prophylaxis.” VTE prophylaxis with UFH or LMWH is often confused with “line prophylaxis” or “line patency prophylaxis” (usually UFH but at very different doses) The increasing incidence of thromboembolism in the PICU patient has led several institutions to develop risk stratification protocols to target patients at the highest risk.120,121 The most common risk factors remain the presence of CVAD, cardiac disease, and infants younger than year.122 There is a variety of practice depending on the center; currently, between 0% and 50% of children receive thromboprophylaxis.123–127 A prospective study examining pediatric trauma patients developed a risk stratification protocol and found a decrease by 65% in VTE with implementation of this protocol Of note in this study of 76 patients determined to be high risk for VTE, only two received pharmacologic thromboprophylaxis as per their protocol.128 Generalized routine thromboprophylaxis is unlikely to be of benefit in the PICU The development of risk assessment tools and their effectiveness remains an area of ongoing research Nonpharmacologic thromboprophylaxis should be encouraged Minimization of concurrent risk factors, early mobilization, and removal of CVADs as soon as feasible seem to be sensible strategies 1080.e1 • eFig 90.3 Preparations of unfractionated heparin (UFH) commonly found on an Australian pediatric ward Note the minimal differences in packaging and the significant differences in UFH concentration, such that there is potential for a 100-fold overdose should a selection error be made CHAPTER 90 Thrombosis in Pediatric Critical Care Conclusions Thromboembolic disease is now a major cause of mortality and morbidity in critically ill children in the context of children having marked differences in the hemostatic system compared with adults, which appear to be age related There remains much to be learned about the etiology and clinical presentations of thrombosis Diagnostic strategies are mostly extrapolated from adult studies but are likely suboptimal Similarly, management strategies and the use of anticoagulants in children for either treatment or primary prophylaxis are guided by minimal evidence; thus, there is a desperate need for further research In the meantime, clinical decisions must be made For the time being, these decisions require consideration of the individual risk-benefit ratios for each patient Key References Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L Maturation of the hemostatic system during childhood Blood 1992;80(8): 1998-2005 Arlikar SJ, Atchison CM, Amankwah EK, et al Development of a new risk score for hospital-associated venous thromboembolism in critically-ill children not undergoing cardiothoracic surgery Thromb Res 2015;136(4):717-722 Attard C, Huang J, Monagle P, Ignjatovic V Pathophysiology of thrombosis and anticoagulation post Fontan surgery Thromb Res 2018;172:204-213 Attard C, Huang J, Monagle P, Ignjatovic V Pathophysiology of thrombosis and anticoagulation post Fontan surgery Thromb Res 2018;172:204-213 Barton R, Ignjatovic V, Monagle P Anticoagulation during ECMO in neonatal and paediatric patients Thromb Res 2019;173:172-177 Chalmers EA Epidemiology of venous thromboembolism in neonates and children Thromb Res 2006;118(1):3-12 Fan H, Zhu JH A multifaceted anticoagulation strategy is needed for children supported with ECMO J Intensive Care Med 2018; 33(2):142 Hanson S, Punzalan R, Arca M Effectiveness of clinical guidelines for deep vein thrombosis prophylaxis in reducing the incidence of venous thromboembolism in critically ill children after trauma J Trauma 2014;72(5):1292-1297 Hanson SJ, Faustino EV, Mahajerin A, et al Recommendations for venous thromboembolism prophylaxis in pediatric trauma patients: A national, multidisciplinary consensus study J Trauma Acute Care Surg 2016;80(5):695-701 Hanson SJ, Lawson KA, Brown AM, et al Current treatment practices of venous thromboembolism in children admitted to pediatric intensive care units Paediatr Anaesth 2011;21(10):1052-1057 1081 Higgerson RA, Lawson KA, Christie LM, et al Incidence and risk factors associated with venous thrombotic events in pediatric intensive care unit patients Pediatr Crit Care Med 2011;12(6):628-634 Huang JY, Ignjatovic V, Sheridan BJ, et al Bleeding and thrombotic events occur early in children on durable ventricular assist devices Thromb Res 2019;173:65-70 Huang JY, Monagle P, Massicotte MP, VanderPluym CJ Antithrombotic therapies in children on durable Ventricular Assist Devices: a literature review Thromb Res 2018;172:194-203 Jones S, Butt W, Monagle P, Cain T, Newall F The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children Blood 2019;133(8):857-866 Male C, Chait P, Ginsberg JS, et al Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study Prophylactic antithrombin replacement in kids with ALL treated with asparaginase, Thromb Haemost 2002;87(4):593-598 Manlhiot C, Brandão LR, Schwartz SM, et al Management and outcomes of patients with occlusive thrombosis after pediatric cardiac surgery J Pediatr 2016;169:146-153 Monagle P, Chan AK, Goldenberg NA, et al Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines Chest 2012;141(suppl 2):e737Se801S Monagle P, Cochrane A, Roberts R, et al A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for years after the Fontan procedure in children J Am Coll Cardiol 2011;58(6):645-651 Monagle P, Cuello CA, Augustine C, et al American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism Blood Adv 2018;2(22):3292-3316 Raffini L Anticoagulation with VADs and ECMO: walking the tightrope Hematology Am Soc Hematol Educ Program 2017;2017(1): 674-680 Rizzi M, Albisetti M Treatment of arterial thrombosis in children: methods and mechanisms Thromb Res 2018;169:113-119 Rizzi M, Goldenberg N, Bonduel M, Revel-Vilk S, Amankwah E, Albisetti M Catheter-related arterial thrombosis in neonates and children: a systematic review Thromb Haemost 2018;118(6): 1058-1066 Vidal E, Sharathkumar A, Glover J, Faustino EV Central venous catheterrelated thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis J Thromb Haemost 2014 ;12(7):1096-1109 Wessel DL, Berger F, Li JS, et al Clopidogrel in infants with systemic-topulmonary-artery shunts N Engl J Med 2013;368(25):2377-2384 The full reference list for this chapter is available at ExpertConsult.com e1 References Andrew M, Paes B, Milner R, et al Development of the human coagulation system in the full-term infant Blood 1987;70(1): 165-172 Andrew M, Paes B, Milner R, et al Development of the human coagulation system in the healthy premature infant Blood 1988;72(5):1651-1657 Andrew M, Paes B, Johnston M Development of the hemostatic system in the neonate and young infant Am J Pediatr Hematol Oncol 1990;12(1):95-104 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L Maturation of the hemostatic system during childhood Blood 1992;80(8):1998-2005 Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y Evolution of blood coagulation activators and inhibitors in the healthy human fetus Blood 1996;88(3):900-906 Ignjatovic V, Pelkmans L, Kelchtermans H, et al Differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults Thromb Res 2015;136(6):1303-1309 Karlaftis V, Perera S, Monagle P, Ignjatovic V Importance of posttranslational modifications on the function of key haemostatic proteins Blood Coagul Fibrinolysis 2016;27(1):1-4 Ignjatovic V, Lai C, Summerhayes R, et al Age-related differences in plasma proteins: how plasma proteins change from neonates to adults PLoS One 2011;6(2):e17213 Yip C, Ignjatovic V, Attard C, Monagle P, Linden MD First report of elevated monocyte-platelet aggregates in healthy children PLoS One 2013;8(6):e67416 10 Cini C, Yip C, Attard C, et al Differences in the resting platelet proteome and platelet releasate between healthy children and adults J Proteomics 2015;123:78-88 11 Andrew M, Mitchell L, Vegh P, Ofosu F Thrombin regulation in children differs from adults in the absence and presence of heparin Thromb Haemost 1994;72(6):836-842 12 Chan AK, Berry LR, Monagle PT, Andrew M Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential Thromb Haemost 2002;87(4):606-613 13 Massicotte P, Leaker M, Marzinotto V, et al Enhanced thrombin regulation during warfarin therapy in children compared to adults Thromb Haemost 1998;80(4):570-574 14 Moalic P, Gruel Y, Body G, Foloppe P, Delahousse B, Leroy J Levels and plasma distribution of free and C4b-BP-bound protein S in human fetuses and full-term newborns Thromb Res 1988;49(5):471-480 15 Schwarz HP, Muntean W, Watzke H, Richter B, Griffin JH Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates Blood 1988;71(3):562-565 16 Ignjatovic V, Greenway A, Summerhayes R, Monagle P Thrombin generation: the functional role of alpha-2-macroglobulin and influence of developmental haemostasis Br J Haematol 2007; 138(3):366-368 17 Nako Y, Ohki Y, Harigaya A, Tomomasa T, Morikawa A Plasma thrombomodulin level in very low birthweight infants at birth Acta Paediatr 1997;86(10):1105-1109 18 Van Dreden P, et al Tissue factor pathway inhibitor in infants and children Thromb Haemost Suppl 2001;P2314 19 Monagle P, Cuello CA, Augustine C, et al American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism Blood Adv 2018;2(22):3292-3316 20 Attard C, Huang J, Monagle P, Ignjatovic V Pathophysiology of thrombosis and anticoagulation post Fontan surgery Thromb Res 2018;172:204-213 21 Huang JY, Monagle P, Massicotte MP, VanderPluym CJ Antithrombotic therapies in children on durable Ventricular Assist Devices: A literature review Thromb Res 2018;172:194-203 22 Huang JY, Ignjatovic V, Sheridan BJ, et al Bleeding and thrombotic events occur early in children on durable ventricular assist devices Thromb Res 2019;173:65-70 23 Barton R, Ignjatovic V, Monagle P Anticoagulation during ECMO in neonatal and paediatric patients Thromb Res 2019;173:172-177 24 MacLaren G, Monagle P Antithrombin administration in extracorporeal membrane oxygenation patients: putting the cart before the horse Pediatr Crit Care Med 2016;17(12):1188-1189 25 Fan H, Zhu JH A Multifaceted anticoagulation strategy is needed for children supported with ECMO J Intensive Care Med 2018; 33(2):142 26 Raffini L Anticoagulation with VADs and ECMO: walking the tightrope Hematology Am Soc Hematol Educ Program 2017;2017(1): 674-680 27 Koster A, Ljajikj E, Faraoni D Traditional and non-traditional anticoagulation management during extracorporeal membrane oxygenation Ann Cardiothorac Surg 2019;8(1):129-136 28 Chalmers EA Epidemiology of venous thromboembolism in neonates and children Thromb Res 2006;118(1):3-12 29 Faustino EV, Shabanova V, Pinto MG, et al Epidemiology of lower extremity deep venous thrombosis in critically ill adolescents J Pediatr 2018;201:176-183 30 Higgerson RA, Lawson KA, Christie LM, et al Incidence and risk factors associated with venous thrombotic events in pediatric intensive care unit patients Pediatr Crit Care Med 2011;12(6):628-634 31 Faustino EV Central venous catheter-associated deep venous thrombosis in critically ill children Semin Thromb Hemost 2018;44(1):52-56 32 Faustino EV, Raffini LJ Prevention of hospital-acquired venous thromboembolism in children: a review of published guidelines Front Pediatr 2017;5:9 33 Mannarino CN, Faustino EV Clinical equipoise on prophylaxis against catheter-associated thrombosis in critically ill children J Crit Care 2016;32:26-30 34 Vidal E, Sharathkumar A, Glover J, Faustino EV Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis J Thromb Haemost 2014;12(7):1096-1109 35 Jones S, Butt W, Monagle P, Cain T, Newall F The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children Blood 2019;133(8):857-866 36 O’Brien S A silent response to silent thrombosis Blood 2019; 133(8):776-777 37 Rizzi M, Goldenberg N, Bonduel M, Revel-Vilk S, Amankwah E, Albisetti M Catheter-related arterial thrombosis in neonates and children: a systematic review Thromb Haemost 2018;118(6):10581066 38 Rizzi M, Albisetti M Treatment of arterial thrombosis in children: Methods and mechanisms Thromb Res 2018;169:113-119 39 Rizzi M, Kroiss S, Kretschmar O, Forster I, Brotschi B, Albisetti M Long-term outcome of catheter-related arterial thrombosis in infants with congenital heart disease J Pediatr 2016;170:181-187 40 Brotschi B, Hug MI, Kretschmar O, Rizzi M, Albisetti M Incidence and predictors of cardiac catheterisation-related arterial thrombosis in children Heart 2015;101(12):948-953 41 Albisetti M, Rizzi M, Bonduel M, Revel-Vilk S, Goldenberg N; Pediatric and Neonatal Thrombosis and Haemostasis Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Official communication of the SSC: Recommendations for future research in catheter-related arterial thrombosis in children Res Pract Thromb Haemost 2019;3(2):193-196 42 Manlhiot C, Brandão LR, Schwartz SM, et al Management and outcomes of patients with occlusive thrombosis after pediatric cardiac surgery J Pediatr 2016;169:146-153 43 Agarwal A, Firdouse M, Brar N, et al Incidence and management of thrombotic and thromboembolic complications following the Norwood procedure: a systematic review Clin Appl Thromb Hemost 2017;23(8):911-921 e2 44 Monagle P Thrombosis in pediatric cardiac patients Semin Thromb Hemost 2003;29(6):547-555 45 Chittithavorn V, Duangpakdee P, Rergkliang C, Pruekprasert N Risk factors for in-hospital shunt thrombosis and mortality in patients weighing less than kg with functionally univentricular heart undergoing a modified Blalock-Taussig shunt Interact Cardiovasc Thorac Surg 2017;25(3):407-413 46 Vitanova K, Leopold C, von Ohain JP, et al Reasons for failure of systemic-to-pulmonary artery shunts in neonates Thorac Cardiovasc Surg 2019;67(1):2-7 47 Wessel DL, Berger F, Li JS, et al Clopidogrel in infants with systemic-to-pulmonary-artery shunts N Engl J Med 2013;368(25): 2377-2384 48 Attard C, Huang J, Monagle P, Ignjatovic V Pathophysiology of thrombosis and anticoagulation post Fontan surgery Thromb Res 2018;172:204-213 49 Monagle P, Cochrane A, McCrindle B, Benson L, Williams W, Andrew M Thromboembolic complications after Fontan procedures– the role of prophylactic anticoagulation J Thorac Cardiovasc Surg 1998;115(3):493-498 50 Monagle P, Karl TR Thromboembolic problems after the Fontan operation Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:36-47 51 McCrindle BW, Manlhiot C, Cochrane A, et al Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary thromboprophylaxis for years after the Fontan procedure J Am Coll Cardiol 2013;61(3):346-353 52 Pina LM, Dong X, Zhang L, et al Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: Rationale and design of a prospective, randomized trial (the UNIVERSE study) Am Heart J 2019;213:97-104 53 Payne RM, Burns KM, Glatz AC, et al A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study Am Heart J 2019;217:52-63 54 Monagle P, Cochrane A, Roberts R, et al A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for years after the Fontan procedure in children J Am Coll Cardiol 2011;58(6):645-651 55 Miletich JP, et al: Inherited predisposition to thrombosis Cell 72(4):477–480, 1993 56 Prins MH, Hirsh J A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism Arch Intern Med 1991;151(9):1721-1731 57 Seligsohn U, Zivelin A Thrombophilia as a multigenic disorder Thromb Haemost 1997;78(1):297-301 58 Nowak-Göttl U, van Ommen H, Kenet G Thrombophilia testing in children: What and when should be tested? Thromb Res 2018;164:75-78 59 Hedegaard SS, Klein AC, Hvas AM The significance of thrombophilia in paediatric thromboembolism Scand J Clin Lab Invest 2018;78(7-8):551-555 60 deVeber G, Kirkham F, Shannon K, et al Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population Haematologica 2019;104(8):1676-1681 61 Bock ME, Bobrowski AE, Bhat R Utility of thrombophilia screening in pediatric renal transplant recipients Pediatr Transplant 2019;23(1):e13314 62 Young G, Albisetti M, Bonduel M, et al Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies Circulation 2008;118(13):1373-1382 63 Neshat-Vahid S, Pierce R, Hersey D, Raffini LJ, Faustino EV Association of thrombophilia and catheter-associated thrombosis in children: a systematic review and meta-analysis J Thromb Haemost 2016;14(9):1749-1758 64 Avila ML, Amiri N, Stanojevic S, et al Can thrombophilia predict recurrent catheter-related deep vein thrombosis in children? Blood 2018;131(24):2712-2719 65 Warkentin TE, Greinacher A, Koster A, Lincoff AM Treatment and prevention of heparin-induced thrombocytopenia Chest 2008; 133(suppl 6):340S-380S 66 Klement D, Rammos S, v Kries R, Kirschke W, Kniemeyer HW, Greinacher A Heparin as a cause of thrombus progression Heparinassociated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts Eur J Pediatr 1996;155(1):11-14 67 Magnani HN Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172) Thromb Haemost 1993;70(4):554-561 68 Murdoch IA, Beattie RM, Silver DM Heparin-induced thrombocytopenia in children Acta Paediatr 1993;82(5):495-497 69 Potter C, Gill JC, Scott JP, McFarland JG Heparin-induced thrombocytopenia in a child J Pediatr 1992;121(1):135-138 70 Severin T, Sutor AH Heparin-induced thrombocytopenia in pediatrics Semin Thromb Hemost 2001;27(3):293-299 71 Boshkov L, et al Heparin-induced thrombocytopenia (HIT) in neonates and very young children undergoing congenital cardiac surgery: a likely under-recognized complication with significant morbidity and mortality: report of sequential cases, J Thromb Haemost 2003;1(suppl 1):1494a 72 Etches W, Stang L, Conradi A Incidence of Heparin-Induced Thrombocytopenia in a pediatric intensive care population Blood 2003;102(Suppl):536a 73 Klenner AF, Fusch C, Rakow A, et al Benefit and risk of heparin for maintaining peripheral venous catheters in neonates: a placebocontrolled trial J Pediatr 2003;143(6):741-745 74 Newall F, Barnes C, Ignjatovic V, Monagle P Heparin-induced thrombocytopenia in children J Paediatr Child Health 2003; 39(4):289-292 75 Schmugge M, Risch L, Huber AR, Benn A, Fischer JE Heparininduced thrombocytopenia-associated thrombosis in pediatric intensive care patients Pediatrics 2002;109(1):E10 76 Spadone D Heparin induced thrombocytopenia in the newborn J Vasc Surg 1996;15:306-312 77 Lo GK, Sigouin CS, Warkentin TE What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007;82(12):1037-1043 78 Klenner AF, Lubenow N, Raschke R, Greinacher A Heparininduced thrombocytopenia in children: 12 new cases and review of the literature Thromb Haemost 2004;91(4):719-724 79 Risch L, Fischer JE, Herklotz R, Huber AR Heparin-induced thrombocytopenia in paediatrics: clinical characteristics, therapy and outcomes Intensive Care Med 2004;30(8):1615-1624 80 Saxon BR, Black MD, Edgell D, Noel D, Leaker MT Pediatric heparin-induced thrombocytopenia: management with Danaparoid (orgaran) Ann Thorac Surg 1999;68(3):1076-1078 81 Severin T, Zieger B, Sutor AH Anticoagulation with recombinant hirudin and danaparoid sodium in pediatric patients Semin Thromb Hemost 2002;28(5):447-454 82 Chan VH, Monagle P, Massicotte P, Chan AK Novel paediatric anticoagulants: a review of the current literature Blood Coagul Fibrinolysis 2010;21(2):144-151 83 Buck ML Bivalirudin as an alternative to heparin for anticoagulation in infants and children J Pediatr Pharmacol Ther 2015;20(6):408-417 84 Obeng EA, Harney KM, Moniz T, Arnold A, Neufeld EJ, Trenor CC III Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system J Pediatr 2015;166(1):144-150 85 Male C, Chait P, Ginsberg JS, et al Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study Prophylactic antithrombin replacement in kids with ALL treated with asparaginase Thromb Haemost 2002;87(4):593-598 ... systemic-topulmonary-artery shunts N Engl J Med 2013;368(25):2377-2384 The full reference list for this chapter is available at ExpertConsult.com e1 References Andrew M, Paes B, Milner R, et al