Age dependency for coagulation parameters in paediatric populations

Summary

Understanding of developmental haemostasis is critical to ensure optimal prevention, diagnosis, and treatment of haemorrhagic and thrombotic diseases in children. As coagulation test results are known to be dependent on the reagents/analysers used, it is recommended for each laboratory to define the age-dependent reference ranges by using its own technical condition. That study was carried out in seven centers to establish age-specific reference ranges using the same reagents and analyser. Plasma samples were obtained from 1437 paediatric patients from the following age groups: 15 days-4 weeks (n=36), 1–5 months (n=320), 6–12 months (n=176), 1–5 years (n=507), 6–10 years (n=132) and 11–17 years (n=262). Indication of coagulation testing was pre-operative screening for non-acute diseases in most cases. PT values were similar in the different age groups to those in adults, whereas longer aPTTs were demonstrated in the younger children. Plasma levels of all clotting factors, except for FV, were significantly decreased (p<0.0001) in the youngest children, adult values being usually reached before the end of the first year. The same applied to antithrombin, protein C/S, and plasminogen. In contrast, FVIII and VWF levels were elevated in the youngest children and returned to adult values within six months. The same applied to D-dimer levels, which were found elevated, particularly until six months of life, until puberty. These data suggest that most coagulation test results are highly dependent on age, mainly during the first year of life, and that age-specific reference ranges must be used to ensure proper evaluation of coagulation in children.

Keywords

Coagulation - childhood - paediatrics - reference ranges - developmental haemostasis

• References

• 1 Lippi G, Franchini M, Montagnana M. et al. Coagulation testing in pediatric patients: the young are not just miniature adults. Semin Thromb Hemost 2007; 33: 816-820.
• 2 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172.
• 3 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-1657.
• 4 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
• 5 Andrew M. Developmental hemostasis: relevance to hemostatic problems during childhood. Semin Thromb Hemost 1995; 21: 341-356.
• 6 Flanders MM, Crist RA, Roberts WL. et al. Pediatric reference intervals for seven common coagulation assays. Clin Chem 2005; 51: 1738-1742.
• 7 Flanders MM, Phansalkar AR, Crist RA. et al. Pediatric reference intervals for uncommon bleeding and thrombotic disorders. J Pediatr 2006; 149: 275-277.
• 8 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
• 9 Monagle P, Massicotte P. Developmental haemostasis: secondary haemostasis. Semin Fetal Neonatal Med 2011; 16: 294-300.
• 10 Appel IM, Grimminck B, Geerts J. et al. Age dependency of coagulation parameters during childhood and puberty. J Thromb Haemost 2012; 10: 2254-2263.
• 11 Attard C, van der Straaten T, Karlaftis V. et al. Developmental hemostasis: agespecific differences in the levels of hemostatic proteins. J Thromb Haemost 2013; 11: 1850-1854.
• 12 Male C, Johnston M, Sparling C. et al. The influence of developmental haemostasis on the laboratory diagnosis and management of haemostatic disorders during infancy and childhood. Clin Lab Med 1999; 19: 39-69.
• 13 Chandler WL. Initial evaluation of hemostasis: reagent and method selection. In: Quality in laboratory hemostasis and thrombosis. Wiley-Blackwell: Chichester, UK; 2009: 63-71.
• 14 Ignjatovic V, Kenet G, Monagle P. Perinatal and Paediatric Haemostasis Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Developmental haemostasis: recommendations for laboratories reporting pediatric samples. J Thromb Haemost 2012; 10: 298-300.
• 15 Horowitz GL, Altaie S, Boyd JC. et al. CLSI Document C28-A3. Defining, establishing, and verifying reference intervals in the clinical laboratory. approved guideline-Third edition. Clinical and Laboratory Standards Institute; Wayne, PA, USA: 2009. Vol.28 no 30.
• 16 Molliex S, Pierre S, Bléry C. et al. Routine preinterventional tests. Ann Fr Anesth Reanim 2012; 31: 752-763 Erratum in: Ann Fr Anesth Reanim 2014; 33: 200.
• 17 Feely MA, Collins CS. et al. Preoperative testing before noncardiac surgery: guidelines and recommendations. Am Fam Physician 2013; 87: 414-418.
• 18 Kirkham KR, Wijeysundera DN, Pendrith C. et al. Preoperative testing before low-risk surgical procedures. CMAJ 2015; 187: E349-358.
• 19 Kirkham KR, Wijeysundera DN, Pendrith C. et al. Preoperative Laboratory Investigations: Rates and Variability Prior to Low-risk Surgical Procedures. Anesthesiology. 2016 Epub ahead of print..
• 20 WHO. Guidelines for thromboplastin and plasma used to control oral anticoagulant therapy. WHO Technical Report series 1999; 889: 64-93.
• 21 Gosselin RC, Janatpour K, Larkin EC. et al. Comparison of samples obtained from 3.2 % sodium citrate glass and two 3.2 % sodium citrate plastic blood collection tubes used in coagulation testing. Am J Clin Pathol 2004; 122: 843-848.
• 22 Toulon P, Abecassis L, Ternisien C. et al. Monitoring unfractionated heparin treatments: CTAD must be used instead of citrate as the anticoagulant solution when using partial-draw collection tubes. Thromb Res 2010; 126: 536-542.
• 23 Desconclois C, Eschwège V, Proulle V. et al. Underestimation of unfractionated heparin therapy assessment due to platelet activation when using partial-draw (pediatric) citrate collection tubes. Thromb Res 2014; 134: 1117-1122.
• 24 Walker ID. Blood collection and sample preparation: pre-analytical variation. In: Jespersen J, Bertina RM, Haverkate F. eds. Laboratory techniques in thrombosis - A manual. 2nd. revised edition of ECAT assay procedures Kluwer Academic Publishers, Dordrecht; The Netherlands: 1999: 21-28.
• 25 Polack B, Schved J-F, Boneu B. on behalf of the ‘Groupe d’Etude sur l’Hémostase et la Thrombose’ [GEHT]. Preanalytical recommendations of the ‘Groupe d’Etude sur l’Hémostase et la Thrombose’ (GEHT) for venous blood testing in hemostasis laboratories. Haemostasis 2001; 31: 61-68.
• 26 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246.
• 27 Bodo I, Eikenboom J, Montgomery R. et al. and on behalf of the SSC Subcommittee on von Willebrand Factor Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13: 1345-1350.
• 28 Gallistl S, Muntean W, Leschnik B. et al. Longer aPTT values in healthy children than in adults: no single cause. Thromb Res 1997; 88: 355-359.
• 29 Toulon P, Eloit Y, Smahi M. et al. Detection of mild clotting factor deficiencies. Critical role of the activated partial thromboplastin time (aPTT) reagent. Blood 2015; 126: 3281 (Abstract).
• 30 Currimbhoy Z. Transitory anticoagulants in healthy children. Am J Pediatr Hematol Oncol 1984; 06: 210-212.
• 31 Male C, Lechner K, Eichinger S. et al. Clinical significance of lupus anticoagulants in children. J Pediatr 1999; 134: 199-205.
• 32 Casais P, Meschengieser SS, Gennari LC. et al. Morbidity of lupus anticoagulants in children: a single institution experience. Thromb Res 2004; 114: 245-249.
• 33 Mizumoto H, Maihara T, Hiejima E. et al. Transient antiphospholipid antibodies associated with acute infections in children: a report of three cases and a review of the literature. Eur J Pediatr 2006; 165: 484-488.
• 34 Li J, Lai X, Yan C. et al. Age-associated developmental changes in the activated partial thromboplastin time (APTT) and causes of prolonged APTT values in healthy Chinese children. Clin Chem Lab Med 2009; 47: 1531-1537.
• 35 Mackie IJ, Kitchen S, Machin SJ. et al. Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology Guidelines on fibrinogen assays. Br J Haematol 2003; 121: 396-404.
• 36 Klarmann D, Eggert C, Geisen C. et al. Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents. Transfusion 2010; 50: 1571-1580.
• 37 Reber G, De Moerloose P. Standardization of D-dimer testing. In: Quality in laboratory haemostasis and thrombosis. Kitchen S, JD Olson. and FE Preston eds. Wiley-Blackwell; Chichester, UK: 2009: 99-109.
• 38 Reverdiau-Moalic P, Delahousse B, Body G. et al. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996; 88: 900-906.
• 39 Salonvaara M, Riikonen P, Kekomäki R. et al. Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants. Arch Dis Child Fetal Neonatal Ed 2003; 88: F319-F323.
• 40 Salonvaara M, Riikonen P, Vahtera E. et al. Development of selected coagulation factors and anticoagulants in preterm infants by the age of six months. Thromb Haemost 2004; 92: 688-696.
• 41 Mitsiakos G, Giougi E, Chatziioannidis I. et al. Haemostatic profile of healthy premature small for gestational age neonates. Thromb Res 2010; 126: 103-106.
• 42 Monagle P, Newall F, Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas. Blood Rev 2010; 24: 151-162.