Role of protein S deficiency in children with venous thromboembolism

Ulrich C. Klostermeier; Verena Limperger; Gili Kenet; Karin Kurnik; Martine Alhenc Gelas; Ulrich Finckh; Ralf Junker; Christine Heller; Barbara Zieger; Ralf Knöfler; Susanne Holzhauer; Rolf Mesters; Anne Krümpel; Ulrike Nowak-Göttl

doi:10.1160/TH14-06-0533

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 113(02): 426-433
DOI: 10.1160/TH14-06-0533

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Role of protein S deficiency in children with venous thromboembolism

An observational international cohort study

Autoren

Ulrich C. Klostermeier^*

¹Institute of Clinical Chemistry, Univ. Hospital of Kiel & Lübeck, Germany
Verena Limperger^*

¹Institute of Clinical Chemistry, Univ. Hospital of Kiel & Lübeck, Germany
Gili Kenet

²Thrombosis Unit, National Hemophilia Center, Tel Hashomer and the Sackler Medical School, Tel Aviv University, Israel
Karin Kurnik

³Department of Pediatrics, Univ. Children Hospital Munich, Germany
Martine Alhenc Gelas

⁴Service d’hématologie biologique, AP-HP, Hôpital Europeen Georges Pompidou, Paris, France
Ulrich Finckh

⁵Medizinisches Versorgungszentrum Eberhard & Partner, Dortmund, Germany
Ralf Junker

¹Institute of Clinical Chemistry, Univ. Hospital of Kiel & Lübeck, Germany
Christine Heller

⁶Department of Pediatric Hemostaseology, Frankfurt, Germany
Barbara Zieger

⁷Department Pediatrics, Univ. Children Hospital Freiburg, Germany
Ralf Knöfler

⁸Department of Pediatric Hemostaseology, Dresden, Germany
Susanne Holzhauer

⁹Department of Pediatric Hematology/Oncology, Charité, Berlin, Germany
Rolf Mesters

¹⁰Department of Medicine/ Hematology & Oncology, Univ. Hospital of Münster, Germany
Anne Krümpel

¹¹Univ. Children Hospital, Münster, Germany
Ulrike Nowak-Göttl

¹¹Univ. Children Hospital, Münster, Germany

¹²Center of Thrombosis and Hemostasis, Department of Clinical Chemistry, Univ. Hospital of Kiel & Lübeck, Germany

Abstract

Summary

Venous thromboembolism [TE] is a multifactorial disease, and protein S deficiency [PSD] constitutes a major risk factor. In the present study the prevalence of PSD and the clinical presentation at TE onset in a cohort of children is reported. In 367 unselected paediatric patients with TE (age 0.1–18 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Thirty of 367 paediatric patients (8.2 %) derived from 27 families had PSD. Mean age at first TE onset was 14.5 years (range 0.1 to 18). Thrombotic locations were cerebral veins (n=8), calf vein TE (n=3) deep veins (DVT) of the leg (n=12), DVT & pulmonary embolism (n=5) and intra-cardiac veins (n=1) or purpura fulminans (n=1). PSD co-occurred with the factor 5 mutation at rs6025 or the homozygous factor 2 susceptibility variant at rs1799963 in one case each. The Heerlen polymorphism detected in five children presented with milder PSD. In 18 patients (60 %) a concomitant risk factor for TE was identified. A second TE event within primarily healthy siblings occurred in three of 27 PSD families (11.0 %). In this cohort of children with symptomatic TE, the prevalence of PSD adjusted for family status was 7.4 %. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.

Keywords

Protein S deficiency - genetics - children

Volltext

Referenzen

References
1 Comp PC, Nixon RR, Cooper MR. et al. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088.
2 Schwarz HP, Fischer M, Hopmeier P. et al. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
3 Fair DS, Marlar RA. Biosynthesis and secretion of factor VII, protein C, protein S, and the Protein C inhibitor from a human hepatoma cell line. Blood 1986; 67: 64-70.
4 Stern D, Brett J, Harris K. et al. Participation of endothelial cells in the protein C-protein S anticoagulant pathway: the synthesis and release of protein S. J Cell Biol 1986; 102: 1971-1978.
5 Gandrille S, Borgel D, Eschwege-Gufflet V. et al. Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 1995; 85: 130-138.
6 Dahlbäck B, Frohm B, Nelsestuen G. High affinity interaction between C4b-binding protein and vitamin K–dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction. J Biol Chem 1990; 265: 16082-16087.
7 Dahlbäck B. The tale of protein S and C4b-binding protein, a story of affection. Thromb Haemost 2007; 98: 90-96.
8 Hackeng TM, Seré KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A 2006; 103 (09) 3106-11.
9 Maurissen LF, Thomassen MCLGD, Nicolaes G. et al. Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation. Blood 2008; 111: 3034-3041.
10 Castoldi E, Simioni P, Tormene D. et al. Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost 2010; 08: 294-300.
11 Ploos van Amstel HK, Reitsma PH, van der Logt CP. et al. Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution. Biochemistry 1990; 29: 7853-7861.
12 Beauchamp NJ, Makris M, Preston FE. et al. Major structural defects in the anti-thrombin gene in four families with type I antithrombin deficiency--partial/ complete deletions and rearrangement of the antithrombin gene. Thromb Hae-most 2000; 83: 715-721.
13 García de Frutos P, Fuentes-Prior P, Hurtado B. et al. Molecular basis of protein S deficiency. Thromb Haemost 2007; 98: 543-556.
14 Pintao MC, Garcia AA, Borgel D. et al. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum Genet 2009; 126: 449-456.
15 Mustafa S, Pabinger I, Mannhalter C. Protein S deficiency type I: identification of point mutations in 9 of 10 families. Blood 1995; 86: 3444-3451.
16 Gandrille S, Borgel D, Sala N. et al. Protein S deficiency: a database of mutations--summary of the first update. Thromb Haemost 2000; 84: 918.
17 Alhenc-Gelas M, Canonico M, Morange PE. et al. Protein S inherited qualitative deficiency: novel mutations and phenotypic influence. J Thromb Haemost 2010; 08: 2718-2726.
18 Caspers M, Pavlova A, Driesen J. et al. Deficiencies of antithrombin, protein C and protein S – practical experience in genetic analysis of a large patient cohort. Thromb Haemost 2012; 108: 247-257.
19 Pegelow CH, Ledford M, Young JN. et al. Severe protein S deficiency in a newborn. Paediatrics 1992; 89: 674-676.
20 Martinelli I, Bucciarelli P, Artoni A. et al. Anticoagulant treatment with rivaroxaban in severe protein S deficiency. Paediatrics 2013; 132: e1435-1439.
21 Pabinger I, Kyrle PA, Heistinger M. et al. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study. Thromb Haemost 1994; 71: 441-445.
22 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
23 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: 1373-1382.
24 Kenet G, Lütkhoff LK, 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: 1838-1847.
25 Kosch A, Junker R, Wermes C. et al. Recurrent pulmonary embolism in a 13-year-old male homozygous for the prothrombin G20210A mutation combined with protein S deficiency and increased lipoprotein (a). Thromb Res 2002; 105: 49-53.
26 Ehrenforth S, Junker R, Koch HG. et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr 1999; 158 Suppl S97-104.
27 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
28 Stenson PD, Mort M, Ball EV. et al. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014; 133: 1-9.
29 Goodeve AC, Reitsma PH, McVey JH. Nomenclature of genetic variants in hemostasis. J Thromb Haemost 2011; 09: 852-855.
30 Den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000; 15: 7-12.
31 Kromeyer-Hauschild K, Wabitsch M, Kunze D. et al. Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschrift Kinderheilkd 2001; 149: 807-818.
32 Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 1992; 11: 1305-1319.
33 Holzhauer S, Goldenberg N, Junker R. et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood 2012; 120: 1510-1515.
34 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-662.
35 Van Ommen CH, Heijboer H, Büller HR. et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139: 676-681.
36 Whitlatch NL, Ortel TL. Thrombophilias: when should we test and how does it help?. Semin Respir Crit Care Med 2008; 29: 25-39.
37 Clagett GP, Anderson FA, Heit J. et al. Prevention of venous thromboembolism. Chest 1995; 108 (Suppl. 04) 312S-334S.
38 Coppola A, Tufano A, Cerbone AM. et al. Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb He-most 2009; 35: 683-694.
39 Lijfering WM, Brouwer J-LP, Veeger NJGM. 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: 5314-5322.
40 Couturaud F, Kearon C. Predictors of thrombosis in relatives of patients with venous thromboembolism. Curr Opin Pulm Med 2010; 16: 453-458.
41 Cohn DM, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing. Semin Thromb Hemost 2007; 33: 573-581.
42 Limperger V, Franke A, Kenet G. et al. Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and anti-thrombin deficiency: An observational multicenter cohort study. Thromb Hae-most 2014; 112: 478-485.
43 Limperger V, Klostermeier U, Kenet G. et al. Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study. Br J Haematol 2014; 167: 385-393.
44 Zöller B, García de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-3531.
45 Castoldi E, Maurissen LF, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
46 Simmonds RE, Zöller B, Ireland H. et al. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89: 4364-4370.

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