ABSTRACT
Inherited thrombophilia is defined as a genetically determined tendency to develop venous thromboembolism. In children, inherited thrombophilia contributes to the development of pediatric thromboembolic disease. As a consequence, pediatric hematologists are increasingly requested to test thrombophilia in pediatric patients with thrombosis or asymptomatic children from thrombophilic families. This article reviews the benefits and limitations of testing for thrombophilic disorders, for example, factor V Leiden, prothrombin mutation, and deficiencies of antithrombin, protein C, or protein S in childhood.
KEYWORDS
Thrombophilia - venous thromboembolism - pediatrics
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
(5)
1251-1257
-
2
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
-
3
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
-
4
Manco-Johnson M J.
Etiopathogenesis of pediatric thrombosis.
Hematology.
2005;
10
(Suppl 1)
167-170
-
5 Virchow R. Phlogose and thrombose im Gefässsystem. In: Virchow R, ed. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt: Von Meidinger Sohn; 1856: 458-636
-
6
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
-
7
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
-
8
Egeberg O.
Inherited antithrombin deficiency causing thrombophilia.
Thromb Diath Haemorrh.
1965;
13
516-530
-
9
Tait R C, Walker I D, Perry D J et al..
Prevalence of antithrombin deficiency in the healthy population.
Br J Haematol.
1994;
87
(1)
106-112
-
10
Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C.
Deficiency of protein C in congenital thrombotic disease.
J Clin Invest.
1981;
68
(5)
1370-1373
-
11
Tait R C, Walker I D, Reitsma P H et al..
Prevalence of protein C deficiency in the healthy population.
Thromb Haemost.
1995;
73
(1)
87-93
-
12
Kroiss S, Albisetti M.
Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency.
Biologics.
2010;
4
51-60
-
13
Comp P C, Nixon R R, Cooper M R, Esmon C T.
Familial protein S deficiency is associated with recurrent thrombosis.
J Clin Invest.
1984;
74
(6)
2082-2088
-
14
Mahasandana C, Suvatte V, Chuansumrit A et al..
Homozygous protein S deficiency in an infant with purpura fulminans.
J Pediatr.
1990;
117
(5)
750-753
-
15
Dahlbäck B, Carlsson M, Svensson P J.
Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.
Proc Natl Acad Sci U S A.
1993;
90
(3)
1004-1008
-
16
Bertina R M, Koeleman BPC, Koster T et al..
Mutation in blood coagulation factor V associated with resistance to activated protein C.
Nature.
1994;
369
(6475)
64-67
-
17
Rees D C, Cox M, Clegg J B.
World distribution of factor V Leiden.
Lancet.
1995;
346
(8983)
1133-1134
-
18
Poort S R, Rosendaal F R, Reitsma P H, Bertina R M.
A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
Blood.
1996;
88
(10)
3698-3703
-
19
Rosendaal F R, Doggen C J, Zivelin A et al..
Geographic distribution of the 20210 G to A prothrombin variant.
Thromb Haemost.
1998;
79
(4)
706-708
-
20
Tripodi A, Chantarangkul V, Menegatti M, Tagliabue L, Peyvandi F.
Performance of clinical laboratories for DNA analyses to detect thrombophilia mutations.
Clin Chem.
2005;
51
(7)
1310-1311
-
21
Favaloro E J, McDonald D, Lippi G.
Laboratory investigation of thrombophilia: the good, the bad, and the ugly.
Semin Thromb Hemost.
2009;
35
(7)
695-710
-
22
Monagle P, Barnes C, Ignjatovic V et al..
Developmental haemostasis. Impact for clinical haemostasis laboratories.
Thromb Haemost.
2006;
95
(2)
362-372
-
23
van Teunenbroek A, Peters M, Sturk A, Borm J J, Breederveld C.
Protein C activity and antigen levels in childhood.
Eur J Pediatr.
1990;
149
(11)
774-778
-
24
Kenet G, Lütkhoff L K, Albisetti M et al..
Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies.
Circulation.
2010;
121
(16)
1838-1847
-
25
Revel-Vilk S, Chan A, Bauman M, Massicotte P.
Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease.
J Thromb Haemost.
2003;
1
(5)
915-921
-
26
van Ommen C H, Heijboer H, van den Dool E J, Hutten B A, Peters M.
Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome.
J Thromb Haemost.
2003;
1
(12)
2516-2522
-
27
Bezemer I D, van der Meer F J, Eikenboom J C, Rosendaal F R, Doggen C J.
The value of family history as a risk indicator for venous thrombosis.
Arch Intern Med.
2009;
169
(6)
610-615
-
28
van Sluis G L, Söhne M, El Kheir D Y, Tanck M W, Gerdes V E, Büller H R.
Family history and inherited thrombophilia.
J Thromb Haemost.
2006;
4
(10)
2182-2187
-
29
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
(6)
770-776
-
30
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
-
31
Lijfering W M, Brouwer J L, Veeger N J et al..
Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives.
Blood.
2009;
113
(21)
5314-5322
-
32
Baglin T, Luddington R, Brown K, Baglin C.
Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.
Lancet.
2003;
362
(9383)
523-526
-
33
Christiansen S C, Cannegieter S C, Koster T, Vandenbroucke J P, Rosendaal F R.
Thrombophilia, clinical factors, and recurrent venous thrombotic events.
JAMA.
2005;
293
(19)
2352-2361
-
34
Bates S M, Greer I A, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians .
Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest.
2008;
133
(6, Suppl)
844S-886S
-
35
Baglin T, Gray E, Greaves M British Committee for Standards in Haematology et al.
Clinical guidelines for testing for heritable thrombophilia.
Br J Haematol.
2010;
149
(2)
209-220
-
36
Tormene D, Simioni P, Prandoni P et al..
The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study.
Blood.
2002;
100
(7)
2403-2405
-
37
Langlois N J, Wells P S.
Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review.
Thromb Haemost.
2003;
90
(1)
17-26
-
38
Holzhauer S, Stoll M, Thedieck S et al..
Prevalence of thrombophilia and incidence of symptomatic thromboembolism in first degree relatives of pediatric index cases: a prospective cohort study.
J Thromb Haemost.
2009;
7
OC-TU-062
-
39
Calhoon M J, Ross C N, Pounder E, Cassidy D, Manco-Johnson M J, Goldenberg N A.
High prevalence of thrombophilic traits in children with family history of thromboembolism.
J Pediatr.
2010;
157
(3)
485-489
-
40
Green D.
Genetic hypercoagulability: screening should be an informed choice.
Blood.
2001;
98
(1)
20
-
41
O'Brien S H, Smith K J.
Using thrombophilia testing to determine anticoagulation duration in pediatric thrombosis is not cost-effective.
J Pediatr.
2009;
155
(1)
100-104
-
42
Wade C H, Wilfond B S, McBride C M.
Effects of genetic risk information on children's psychosocial wellbeing: a systematic review of the literature.
Genet Med.
2010;
12
(6)
317-326
-
43
Cohn D M, Vansenne F, Kaptein A A, De Borgie C A, Middeldorp S.
The psychological impact of testing for thrombophilia: a systematic review.
J Thromb Haemost.
2008;
6
(7)
1099-1104
-
44
Coppola A, Tufano A, Cerbone A M, Di Minno G.
Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism.
Semin Thromb Hemost.
2009;
35
(7)
683-694
-
45
Middeldorp S, van Hylckama Vlieg A.
Does thrombophilia testing help in the clinical management of patients?.
Br J Haematol.
2008;
143
(3)
321-335
C. Heleen van OmmenM.D. Ph.D.
Department of Paediatric Haematology, Emma Children's Hospital/Academic Medical Center
Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Email: c.h.vanommen@amc.nl
