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DOI: 10.1055/s-0031-1297162
The Coagulation System in Children: Developmental and Pathophysiological Considerations
Publikationsverlauf
Publikationsdatum:
20. Dezember 2011 (online)

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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 5
Monagle P, Barnes C, Ignjatovic V et al..
Developmental haemostasis. Impact for clinical haemostasis laboratories.
Thromb Haemost.
2006;
95
(2)
362-372
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 10 Monagle P, Hagstrom J. Developmental haemostasis. In: Fetal and Neonatal Physiology. 3rd ed. St. Louis: Elsevier; 2003: 1435-1447
MissingFormLabel
- 11
Witt I, Müller H.
Phosphorus and hexose content of human foetal fibrinogen.
Biochim Biophys Acta.
1970;
221
(2)
402-404
MissingFormLabel
- 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
MissingFormLabel
- 13
Witt I, Müller H, Künzer W.
Evidence for the existence of foetal fibrinogen.
Thromb Diath Haemorrh.
1969;
22
(1)
101-109
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 17
Ignjatovic V, Ilhan A, Monagle P.
Evidence for age-related differences in human fibrinogen.
Blood Coagul Fibrinolysis.
2011;
22
(2)
110-117
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 21
Mosnier L O, Zlokovic B V, Griffin J H.
The cytoprotective protein C pathway.
Blood.
2007;
109
(8)
3161-3172
MissingFormLabel
- 22
Taylor Jr F B, Kinasewitz G T.
The diagnosis and management of disseminated intravascular coagulation.
Curr Hematol Rep.
2002;
1
(1)
34-40
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 31
Schmidt B, Andrew M.
Neonatal thrombosis: report of a prospective Canadian and international registry.
Pediatrics.
1995;
96
(5 Pt 1)
939-943
MissingFormLabel
- 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
MissingFormLabel
- 33
White R H.
The epidemiology of venous thromboembolism.
Circulation.
2003;
107
(23, Suppl 1)
I4-I8
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 38
Israels S J, Seshia S S.
Childhood stroke associated with protein C or S deficiency.
J Pediatr.
1987;
111
(4)
562-564
MissingFormLabel
- 39
Mannino F L, Trauner D A.
Stroke in neonates.
J Pediatr.
1983;
102
(4)
605-610
MissingFormLabel
- 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
MissingFormLabel
- 41
Andrassy K, Ritz E, Bommer J.
Hypercoagulability in the nephrotic syndrome.
Klin Wochenschr.
1980;
58
(19)
1029-1036
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 47
Hirsh J.
Heparin.
N Engl J Med.
1991;
324
(22)
1565-1574
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 51
Levi M.
All heparins are equal, but some are more equal than others.
J Thromb Haemost.
2003;
1
(5)
884-885
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 63
Ganrot P O.
Inhibition of plasmin activity by alpha-2-macroglobulin.
Clin Chim Acta.
1967;
16
(2)
328-329
MissingFormLabel
- 64
Sottrup-Jensen L.
Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation.
J Biol Chem.
1989;
264
(20)
11539-11542
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 75
Ignjatovic V, Furmedge J, Newall F et al..
Age-related differences in heparin response.
Thromb Res.
2006;
118
(6)
741-745
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 89
Evans D I, Rowlands M, Poller L.
Survey of oral anticoagulant treatment in children.
J Clin Pathol.
1992;
45
(8)
707-708
MissingFormLabel
- 90
Bonduel M, Sciuccati G, Hepner M et al..
Acenocoumarol therapy in pediatric patients.
J Thromb Haemost.
2003;
1
(8)
1740-1743
MissingFormLabel
- 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
MissingFormLabel
Paul MonagleM.D. M.B.B.S. M.Sc. F.C.C.P. F.R.C.P.A. F.R.A.C.P.
Professor, Department of Clinical Haematology, Department of Paediatrics, University
of Melbourne
Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia
eMail: paul.monagle@rch.org.au