The Coagulation System in Children: Developmental and Pathophysiological Considerations

ABSTRACT

The coagulation system in children is complex and ever changing, a fact encapsulated in the term developmental hemostasis. Studies confirm that there are quantitative and almost certainly qualitative differences in the coagulation system with age, and the control of these changes comes from something external to the liver. What remains uncertain is the magnitude of the qualitative changes and the implications of the changes for the growing child. At the very least, developmental hemostasis probably provides a protective mechanism for neonates and children and hence contributes to the decreased risk of thromboembolic and/or hemorrhagic events in these age groups. In addition, developmental hemostasis could also reflect the role that hemostatic proteins play in physiological development and hence the demand of other processes, such as angiogenesis. Finally, without doubt, developmental hemostasis affects the interactions of anticoagulant drugs with the coagulation system. This article will initially discuss the most recent evidence with respect to qualitative age-related changes in the coagulation system. Subsequently the article will discuss the coagulation system during childhood in light of the three aforementioned areas of clinical impact and suggest possible strategies to further understand this complex and exciting field of study.

KEYWORDS

Development - coagulation - plasma proteins - thromboembolism - children

REFERENCES

• 1 Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas.  Blood Rev. 2010;  24 (2) 63-68
• 2 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
• 3 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
• 4 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
• 5 Monagle P, Barnes C, Ignjatovic V et al.. Developmental haemostasis. Impact for clinical haemostasis laboratories.  Thromb Haemost. 2006;  95 (2) 362-372
• 6 Monagle P, Chan A, de Veber G, Massicotte P. Developmental Hemostasis. Pediatric Thromboembolism and Stroke Handbook. 3rd ed. Hamilton, Ontario: BC Decker Inc.; 2006: 3-30
• 7 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
• 8 Mari D, Mannucci P M, Coppola R, Bottasso B, Bauer K A, Rosenberg R D. Hypercoagulability in centenarians: the paradox of successful aging.  Blood. 1995;  85 (11) 3144-3149
• 9 Bock SC. Antithrombin III and heparin cofactor II. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 321-334
• 10 Monagle P, Hagstrom J. Developmental haemostasis. In: Fetal and Neonatal Physiology. 3rd ed. St. Louis: Elsevier; 2003: 1435-1447
• 11 Witt I, Müller H. Phosphorus and hexose content of human foetal fibrinogen.  Biochim Biophys Acta. 1970;  221 (2) 402-404
• 12 Hamulyák K, Nieuwenhuizen W, Devilée P P, Hemker H C. Reevaluation of some properties of fibrinogen, purified from cord blood of normal newborns.  Thromb Res. 1983;  32 (3) 301-310
• 13 Witt I, Müller H, Künzer W. Evidence for the existence of foetal fibrinogen.  Thromb Diath Haemorrh. 1969;  22 (1) 101-109
• 14 Miller B E, Tosone S R, Guzzetta N A, Miller J L, Brosius K K. Fibrinogen in children undergoing cardiac surgery: is it effective?.  Anesth Analg. 2004;  99 (5) 1341-1346
• 15 Martinez J, MacDonald K A, Palascak J E. The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains.  Blood. 1983;  61 (6) 1196-1202
• 16 Dang C V, Shin C K, Bell W R, Nagaswami C, Weisel J W. Fibrinogen sialic acid residues are low affinity calcium-binding sites that influence fibrin assembly.  J Biol Chem. 1989;  264 (25) 15104-15108
• 17 Ignjatovic V, Ilhan A, Monagle P. Evidence for age-related differences in human fibrinogen.  Blood Coagul Fibrinolysis. 2011;  22 (2) 110-117
• 18 Manco-Johnson M J, Spedale S, Peters M et al.. Identification of a unique form of protein C in the ovine fetus: developmentally linked transition to the adult form.  Pediatr Res. 1995;  37 (3) 365-372
• 19 Niessen R W, Lamping R J, Peters M, Lamers W H, Sturk A. Fetal and neonatal development of antithrombin III plasma activity and liver messenger RNA levels in sheep.  Pediatr Res. 1996;  39 (4 Pt 1) 685-691
• 20 Lisman T, Platto M, Meijers J C, Haagsma E B, Colledan M, Porte R J. The hemostatic status of pediatric recipients of adult liver grafts suggests that plasma levels of hemostatic proteins are not regulated by the liver.  Blood. 2011;  117 (6) 2070-2072
• 21 Mosnier L O, Zlokovic B V, Griffin J H. The cytoprotective protein C pathway.  Blood. 2007;  109 (8) 3161-3172
• 22 Taylor Jr F B, Kinasewitz G T. The diagnosis and management of disseminated intravascular coagulation.  Curr Hematol Rep. 2002;  1 (1) 34-40
• 23 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
• 24 Gibson B E, Chalmers E, Bolton-Maggs P, Henderson D J, Lynn R. Thrombembolism in childhood: a prospective 2 year BPSU study in the United Kingdom.  Thromb Haemost. 2003;  1 (Suppl 1) OC422
• 25 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
• 26 Mitchell L G, Andrew M, Hanna K Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase Group (PARKAA) 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 (2) 508-516
• 27 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 (6) 763-766
• 28 Newall F, Wallace T, Crock C et al.. Venous thromboembolic disease: a single-centre case series study.  J Paediatr Child Health. 2006;  42 (12) 803-807
• 29 Nowak-Göttl U, Heinecke A, von Kries R, Nürnberger W, Münchow N, Junker R. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration.  Thromb Res. 2001;  103 (3) 165-172
• 30 Nowak-Göttl U, von Kries R, Göbel U. Neonatal symptomatic thromboembolism in Germany: two year survey.  Arch Dis Child Fetal Neonatal Ed. 1997;  76 (3) F163-F167
• 31 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry.  Pediatrics. 1995;  96 (5 Pt 1) 939-943
• 32 van Ommen C H, Heijboer H, Büller H R, Hirasing R A, Heijmans H S, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands.  J Pediatr. 2001;  139 (5) 676-681
• 33 White R H. The epidemiology of venous thromboembolism.  Circulation. 2003;  107 (23, Suppl 1) I4-I8
• 34 Kuhle S, Massicotte P, Chan A et al.. Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service.  Thromb Haemost. 2004;  92 (4) 722-728
• 35 Raffini L, Huang Y S, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007.  Pediatrics. 2009;  124 (4) 1001-1008
• 36 Bjarke B, Herin P, Blombäck M. Neonatal aortic thrombosis. A possible clinical manifestation of congenital antithrombin 3 deficiency.  Acta Paediatr Scand. 1974;  63 (2) 297-301
• 37 De Stefano V, Leone G, Ferrelli R et al.. Severe deep vein thrombosis in a 2-year-old child with protein S deficiency.  Thromb Haemost. 1987;  58 (4) 1089
• 38 Israels S J, Seshia S S. Childhood stroke associated with protein C or S deficiency.  J Pediatr. 1987;  111 (4) 562-564
• 39 Mannino F L, Trauner D A. Stroke in neonates.  J Pediatr. 1983;  102 (4) 605-610
• 40 Shapiro M E, Rodvien R, Bauer K A, Salzman E W. Acute aortic thrombosis in antithrombin III deficiency.  JAMA. 1981;  245 (17) 1759-1761
• 41 Andrassy K, Ritz E, Bommer J. Hypercoagulability in the nephrotic syndrome.  Klin Wochenschr. 1980;  58 (19) 1029-1036
• 42 Kanfer A, Kleinknecht D, Broyer M, Josso F. Coagulation studies in 45 cases of nephrotic syndrome without uremia.  Thromb Diath Haemorrh. 1970;  24 (3) 562-571
• 43 Kauffmann R H, Veltkamp J J, Van Tilburg N H, Van Es L A. Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome.  Am J Med. 1978;  65 (4) 607-613
• 44 Kuhlmann U, Blättler W, Pouliadis G, Siegenthaler W. [Complications of nephrotic syndrome with special reference to thromboembolic accidents].  Schweiz Med Wochenschr. 1979;  109 (6) 200-209
• 45 Schrader J, Köstering H, Züchner C, Kaiser H, Kramer P, Scheler F. Antithrombin III-Bestimmungim Schnelltest: Ein Vergleich mit Partigen-Platten undeinem chromogenen Substrat.  Lab Med. 1981;  5 211-218
• 46 Thaler E, Balzar E, Kopsa H, Pinggera W F. Acquired antithrombin III deficiency in patients with glomerular proteinuria.  Haemostasis. 1978;  7 (5) 257-272
• 47 Hirsh J. Heparin.  N Engl J Med. 1991;  324 (22) 1565-1574
• 48 Olson S T, Björk I, Shore J D. Kinetic characterization of heparin-catalyzed and uncatalyzed inhibition of blood coagulation proteinases by antithrombin.  Methods Enzymol. 1993;  222 525-559
• 49 Carrell R W, Stein P E, Fermi G, Wardell M R. Biological implications of a 3 A structure of dimeric antithrombin.  Structure. 1994;  2 (4) 257-270
• 50 Schreuder H A, de Boer B, Dijkema R et al.. The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions.  Nat Struct Biol. 1994;  1 (1) 48-54
• 51 Levi M. All heparins are equal, but some are more equal than others.  J Thromb Haemost. 2003;  1 (5) 884-885
• 52 Schedin-Weiss S, Richard B, Hjelm R, Olson S T. Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence.  Biochemistry. 2008;  47 (51) 13610-13619
• 53 Chan A K, Berry L R, Paredes N, Parmar N. Isoform composition of antithrombin in a covalent antithrombin-heparin complex.  Biochem Biophys Res Commun. 2003;  309 (4) 986-991
• 54 Picard V, Ersdal-Badju E, Bock S C. Partial glycosylation of antithrombin III asparagine-135 is caused by the serine in the third position of its N-glycosylation consensus sequence and is responsible for production of the beta-antithrombin III isoform with enhanced heparin affinity.  Biochemistry. 1995;  34 (26) 8433-8440
• 55 Carlson T H, Atencio A C, Simon T L. Comparison of the behaviour in vivo of two molecular forms of antithrombin III.  Biochem J. 1985;  225 (3) 557-564
• 56 Witmer M R, Hatton M W. Antithrombin III-beta associates more readily than antithrombin III-alpha with uninjured and de-endothelialized aortic wall in vitro and in vivo.  Arterioscler Thromb. 1991;  11 (3) 530-539
• 57 Turk B, Brieditis I, Bock S C, Olson S T, Björk I. The oligosaccharide side chain on Asn-135 of alpha-antithrombin, absent in beta-antithrombin, decreases the heparin affinity of the inhibitor by affecting the heparin-induced conformational change.  Biochemistry. 1997;  36 (22) 6682-6691
• 58 Schedin-Weiss S, Richard B, Hjelm R, Olson S T. Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence.  Biochemistry. 2008;  47 (51) 13610-13619
• 59 Adcock D M, Fink L M, Marlar R A, Cavallo F, Zangari M. The hemostatic system and malignancy.  Clin Lymphoma Myeloma. 2008;  8 (4) 230-236
• 60 Akl E A, van Doormaal F F, Barba M et al.. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.  Cochrane Database Syst Rev. 2007;  (3) CD006652
• 61 Wojtukiewicz M Z, Sierko E, Rak J. Contribution of the hemostatic system to angiogenesis in cancer.  Semin Thromb Hemost. 2004;  30 (1) 5-20
• 62 Schmidt B, Gillie P, Mitchell L, Andrew M, Caco C, Roberts R. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome.  Am J Respir Crit Care Med. 1998;  158 (2) 470-476
• 63 Ganrot P O. Inhibition of plasmin activity by alpha-2-macroglobulin.  Clin Chim Acta. 1967;  16 (2) 328-329
• 64 Sottrup-Jensen L. Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation.  J Biol Chem. 1989;  264 (20) 11539-11542
• 65 Blacker D, Wilcox M A, Laird N M et al.. Alpha-2 macroglobulin is genetically associated with Alzheimer disease.  Nat Genet. 1998;  19 (4) 357-360
• 66 Baker A H, Edwards D R, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities.  J Cell Sci. 2002;  115 (Pt 19) 3719-3727
• 67 French K, Yerbury J J, Wilson M R. Protease activation of alpha2-macroglobulin modulates a chaperone-like action with broad specificity.  Biochemistry. 2008;  47 (4) 1176-1185
• 68 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
• 69 Mitchell L, Piovella F, Ofosu F, Andrew M. Alpha-2-macroglobulin may provide protection from thromboembolic events in antithrombin III-deficient children.  Blood. 1991;  78 (9) 2299-2304
• 70 Schmidt B, Mitchell L, Ofosu F A, Andrew M. Alpha-2-macroglobulin is an important progressive inhibitor of thrombin in neonatal and infant plasma.  Thromb Haemost. 1989;  62 (4) 1074-1077
• 71 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
• 72 Ling X, Delorme M, Berry L et al.. alpha 2-Macroglobulin remains as important as antithrombin III for thrombin regulation in cord plasma in the presence of endothelial cell surfaces.  Pediatr Res. 1995;  37 (3) 373-378
• 73 Guzzetta N A, Miller B E, Todd K et al.. Clinical measures of heparin's effect and thrombin inhibitor levels in pediatric patients with congenital heart disease.  Anesth Analg. 2006;  103 (5) 1131-1138
• 74 Albisetti M, Chan A K, McCrindle B W, Wong D, Monagle P, Andrew M. Impaired fibrinolytic activity is present in children with dyslipidemias.  Pediatr Res. 2004;  55 (4) 576-580
• 75 Ignjatovic V, Furmedge J, Newall F et al.. Age-related differences in heparin response.  Thromb Res. 2006;  118 (6) 741-745
• 76 Ignjatovic V, Summerhayes R, Newall F, Monagle P T. The in vitro response to low-molecular-weight heparin is not age-dependent in children.  Thromb Haemost. 2010;  103 (4) 855-856
• 77 Newall F, Ignjatovic V, Summerhayes R et al.. In vivo age dependency of unfractionated heparin in infants and children.  Thromb Res. 2009;  123 (5) 710-714
• 78 Ignjatovic V, Straka E, Summerhayes R, Monagle P. Age-specific differences in binding of heparin to plasma proteins.  J Thromb Haemost. 2010;  8 (6) 1290-1294
• 79 Andrew M, Ofosu F, Schmidt B, Brooker L, Hirsh J, Buchanan M R. Heparin clearance and ex vivo recovery in newborn piglets and adult pigs.  Thromb Res. 1988;  52 (6) 517-527
• 80 McDonald M M, Jacobson L J, Hay Jr W W, Hathaway W E. Heparin clearance in the newborn.  Pediatr Res. 1981;  15 (7) 1015-1018
• 81 Turner Gomes S, Nitschmann E, Benson L, Burrows P, Andrew M. Heparin is cleared faster in children with congenital heart disease than adults.  J Am Coll Cardiol. 1993;  21 (2) 59a
• 82 Newall F, Ignjatovic V, Johnston L et al.. Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin.  Thromb Haemost. 2010;  103 (5) 1085-1090
• 83 Ignjatovic V, Najid S, Newall F, Summerhayes R, Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.  Br J Haematol. 2010;  149 (5) 734-738
• 84 Trame M N, Mitchell L, Krümpel A, Male C, Hempel G, Nowak-Göttl U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.  J Thromb Haemost. 2010;  8 (9) 1950-1958
• 85 Andrew M, Marzinotto V, Brooker L A et al.. Oral anticoagulation therapy in pediatric patients: a prospective study.  Thromb Haemost. 1994;  71 (3) 265-269
• 86 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 (9) 3007-3014
• 87 Carpentieri U, Nghiem Q X, Harris L C. Clinical experience with an oral anticoagulant in children.  Arch Dis Child. 1976;  51 (6) 445-448
• 88 Doyle J J, Koren G, Cheng M Y, Blanchette V S. Anticoagulation with sodium warfarin in children: effect of a loading regimen.  J Pediatr. 1988;  113 (6) 1095-1097
• 89 Evans D I, Rowlands M, Poller L. Survey of oral anticoagulant treatment in children.  J Clin Pathol. 1992;  45 (8) 707-708
• 90 Bonduel M, Sciuccati G, Hepner M et al.. Acenocoumarol therapy in pediatric patients.  J Thromb Haemost. 2003;  1 (8) 1740-1743
• 91 Piquet P, Losay J, Doubine S. [Acenocoumarol (Sintrom) and fluinidione (Previscan) in pediatrics after cardiac surgical procedures].  Arch Pediatr. 2002;  9 (11) 1137-1144