Thromb Haemost 2006; 95(02): 362-372
DOI: 10.1160/TH05-01-0047
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Developmental haemostasis

Impact for clinical haemostasis laboratories
Paul Monagle
1   Department of Haematology
4   Department of Pathology, University of Melbourne, Australia
Chris Barnes
1   Department of Haematology
Vera Ignjatovic
1   Department of Haematology
5   Murdoch Children’s Research Institute, Melbourne, Australia
Janine Furmedge
1   Department of Haematology
Fiona Newall
1   Department of Haematology
Anthony Chan
6   Department of Paediatrics, McMaster University, Hamilton, Canada
Lidia De Rosa
1   Department of Haematology
Simone Hamilton
1   Department of Haematology
Philip Ragg
2   Department of Anaesthetics
Stephen Robinson
2   Department of Anaesthetics
Alex Auldist
3   Department of Surgery, Royal Children’s Hospital, Melbourne, Australia
Cathy Crock
1   Department of Haematology
Neil Roy
7   Department of Neonatology
Shelley Rowlands
8   Department of Obstetrics, Royal Women’s Hospital, Melbourne, Australia
› Author Affiliations
Financial support: The authors thank Diagnostica Stago, France and Bayer Diagnostics, Australia for supply of relevant reagents.
Further Information

Publication History

Received 20 January 2005

Accepted after resubmission 02 January 2005

Publication Date:
28 November 2017 (online)


Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980’s. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whethera current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to agerelated changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.

  • References

  • 1 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-72.
  • 2 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-7.
  • 3 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
  • 4 Royston P, Wright E. Goodness-of-fit statistics for age-specific reference intervals. Statist Med 2000; 19: 2943-62.
  • 5 Monagle P, Andrew M. Developmental Hemostasis: Relevance to Newborns and Infants. In: Nathan DG, Oski FA. eds. Hematology of Infancy and Childhood. Vol 1. 6th Edition. Philadelphia, PA: Saunders; 2003: 121-69.
  • 6 Barnes C, Newall F, Harvey S. et al. Interpretation of thrombophilia in childhood stroke; a cautionary tale. J Child Neurol 2004; 19: 218-9.
  • 7 Monagle P, Ignjatovic V, Barnes C. et al. The importance of age appropriate haemostasis reference ranges. Blood 2002; 100: 94-95 (a).
  • 8 Olson J, Arkin C, Brandt J. et al. College of American Pathologists conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122: 782-98.
  • 9 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12: 95-104.
  • 10 Hirsh J, Raschke R. Heparin and Low Molecular Weight Heparin. The seventh ACCP conference on antithrombotic and thrombolytic therapy. CHEST 2004; 126: 188S-203S.
  • 11 Laffan MA. Manning RA: Investigation of haemostasis. In: Lewis SM, Bain BJ, Bates I. eds. Dacie and Lewis Practical Haematology. 9th Edition. Churchill Livingstone; 2001: 347-48.
  • 12 Berry L, Andrew M, Post M. et al. A549 lung epithelial cell line synthesize anticoagulant molecules on the cell surface, matrix, and in conditioned media. Am J Resp Cell Mol Biol 1991; 04: 338-46.
  • 13 Jaffe E, Nachman R, Becker C. et al. Culture of human endothelial cells derived from umbilical veins: Identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-56.
  • 14 Walenga J, Fareed J. Automation and quality control in the coagulation laboratory. Thromb Haemost 1994; 14: 709-28.
  • 15 White G. The partial thromboplastin time: defining an era in coagulation. J Thromb Haemost 2003; 01: 2267-70.
  • 16 Williams N. et al. The STA Haemostasis Analyser - an evaluation. 4th South Pacific Congress of Medical Scientists. Gold Coast; Australia: 1995
  • 17 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 204S-233S.
  • 18 Monagle P, Andrew MJ. Coagulation abnormalities following Fontan procedures. Thorac Cardiovasc Surg 1998; 115: 732-3.
  • 19 Barnes C, Monagle P. Hemostatic changes following the modified Fontan procedure. Thromb Haemost 2001; 86: 1341-2.
  • 20 Brill-Edwards P, Ginsburg JS, Johnston M. et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993; 119: 104-9.
  • 21 D’Angelo A, Seveso M, D’Angelo S. et al. Effect of clot-detection methods and reagents on APTT-implications in heparin monitoring by APTT. Am J Clin Path 1990; 94: 297-306.
  • 22 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-75.
  • 23 Stevenson KJ, Easton AC, Curry A. The reliability of activated partial thromboplastin time methods and the relationship to lipid composition and ultrastructure. Thromb Haemost 1986; 55: 250-8.
  • 24 Gram J, Declerck P, Sidelmann J. et al. Mulitcentre evaluation of commercial kit methods: plasminogen activator inhibitor activity. Thromb Haemost 1993; 70: 852-7.
  • 25 Declerck P, Moreau H, Jespersen J. et al. Multicentre evaluation of commercially available methods for the immunological determination of plasminogen activator inhibitor-1 (PAI-1). Thromb Haemost 1993; 70: 858-63.
  • 26 Libeer J-C. Good medical laboratory services - guidelines. Vol. 1, 2nd ed. Dordrecht: Kluwer Academic Publishers BV; 1999
  • 27 Dacie J, Lewis S. Practical Haematology. Vol. 7th . Edinburgh: Churchill Livingstone; 1991
  • 28 Monagle P, Michelson AD, Chan A. et al. Antithrombotic therapy in children. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 645S-687S.
  • 29 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74: 415-25.
  • 30 Monagle P, Hagstrom JN. Developmental Haemostasis. In: Polin Fox. and Abman, eds. Fetal and Neonatal Physiology. 3rd Edition. Elsevier St: Louis; 2003: 1435-46.
  • 31 Folkman J. Angiogenesis and proteins of the hemostatic system. J Thromb Haemost 2003; 01: 1681-2.
  • 32 Zhang W, Chuang Y, Swanson R. et al. Antiangiogenic antithrombin down regulates the expression of the proangiogenic heparan sulphate proteoglycan, perlecan, in endothelial cells. Blood 2004; 103: 1185-91.