Subscribe to RSS
DOI: 10.1055/s-0038-1660852
Hemostasis in the Very Young
Publication History
Publication Date:
18 June 2018 (online)
Abstract
Hemostasis is a dynamic process that starts in utero. The coagulation system evolves with age, as evidenced by marked physiological differences in the concentration of the majority of hemostatic proteins in early life compared with adulthood. This concept, known as “developmental hemostasis,” has important biological and clinical implications. Overall, impaired platelet function, along with physiologically reduced levels of vitamin K–dependent and contact coagulation factors, may cause poorer clot firmness even in healthy neonates. However, increased activity of von Willebrand factor and low levels of coagulation inhibitors that promote hemostasis counterbalance the delicate and immature hemostatic system. Since this hemostatic system has little reserve capacity, preterm neonates or sick infants are extremely vulnerable and predisposed to either hemorrhagic or thrombotic complications. This review will address the concept and manifestations of developmental hemostasis with respect to clinical disease phenotypes. It will discuss bleeding diagnosis in neonates, dealing especially with the devastating complications of intracerebral and pulmonary hemorrhage in preterm infants. Neonates, especially the sickest preterm ones, are also extremely susceptible to thrombotic complications; thus, thrombosis in neonates will be reviewed, with special focus on arterial ischemic perinatal stroke. Based on the concept of developmental hemostasis, the phenotypes of clinically relevant bleeding or thrombotic disorders among neonates may differ from those of older infants and children. Treatment options for these conditions will be suggested and reviewed.
-
References
- 1 Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996; 88 (03) 900-906
- 2 Andrew M, Paes B, Milner R. , et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72 (05) 1651-1657
- 3 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80 (08) 1998-2005
- 4 Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas. Blood Rev 2010; 24 (02) 63-68
- 5 Monagle P, Barnes C, Ignjatovic V. , et al. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95 (02) 362-372
- 6 Nowak-Göttl U, Limperger V, Kenet G. , et al. Developmental hemostasis: a lifespan from neonates and pregnancy to the young and elderly adult in a European white population. Blood Cells Mol Dis 2017; 67: 2-13
- 7 Attard C, van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013; 11 (10) 1850-1854
- 8 Ignjatovic V, Pelkmans L, Kelchtermans H. , et al. Differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults. Thromb Res 2015; 136 (06) 1303-1309
- 9 Kremers RM, Wagenvoord RJ, de Laat HB, Monagle P, Hemker HC, Ignjatovic V. Low paediatric thrombin generation is caused by an attenuation of prothrombin conversion. Thromb Haemost 2016; 115 (06) 1090-1100
- 10 Cvirn G, Gallistl S, Muntean W. Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma. Thromb Res 1999; 93 (04) 183-190
- 11 Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb Haemost 1990; 63 (01) 27-30
- 12 Summaria L. Comparison of human normal, full-term, fetal and adult plasminogen by physical and chemical analyses. Haemostasis 1989; 19 (05) 266-273
- 13 Saxonhouse MA, Sola MC. Platelet function in term and preterm neonates. Clin Perinatol 2004; 31 (01) 15-28
- 14 Levy-Shraga Y, Maayan-Metzger A, Lubetsky A. , et al. Platelet function of newborns as tested by cone and plate(let) analyzer correlates with gestational Age. Acta Haematol 2006; 115 (3-4): 152-156
- 15 Rajasekhar D, Barnard MR, Bednarek FJ, Michelson AD. Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997; 77 (05) 1002-1007
- 16 Israels SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A. Deficient thromboxane synthesis and response in platelets from premature infants. Pediatr Res 1997; 41 (02) 218-223
- 17 Del Vecchio A, Latini G, Henry E, Christensen RD. Template bleeding times of 240 neonates born at 24 to 41 weeks gestation. J Perinatol 2008; 28 (06) 427-431
- 18 Strauss T, Elisha N, Ravid B. , et al. Activity of Von Willebrand factor and levels of VWF-cleaving protease (ADAMTS13) in preterm and full term neonates. Blood Cells Mol Dis 2017; 67: 14-17
- 19 Strauss T, Levy-Shraga Y, Ravid B. , et al. Clot formation of neonates tested by thromboelastography correlates with gestational age. Thromb Haemost 2010; 103 (02) 344-350
- 20 Kenet G, Chan AK, Soucie JM, Kulkarni R. Bleeding disorders in neonates. Haemophilia 2010; 16 (Suppl. 05) 168-175
- 21 Yoffe G, Buchanan GR. Intracranial hemorrhage in newborn and young infants with hemophilia. J Pediatr 1988; 113 (02) 333-336
- 22 Abbondanzo SL, Gootenberg JE, Lofts RS, McPherson RA. Intracranial hemorrhage in congenital deficiency of factor XIII. Am J Pediatr Hematol Oncol 1988; 10 (01) 65-68
- 23 Struwe FE. Intracranial haemorrhage and occlusive hydrocephalus in hereditary bleeding disorders. Dev Med Child Neurol Suppl 1970; 22 (Suppl. 22) 22 , 165
- 24 Nowak-Göttl U, Limperger V, Bauer A, Kowalski D, Kenet G. Bleeding issues in neonates and infants - update 2015. Thromb Res 2015; 135 (Suppl. 01) S41-S43
- 25 Livnat T, Barg AA, Levy-Mendelovich S, Kenet G. Rare bleeding disorders-old diseases in the era of novel options for therapy. Blood Cells Mol Dis 2017; 67: 63-68
- 26 Peterson JA, McFarland JG, Curtis BR, Aster RH. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol 2013; 161 (01) 3-14
- 27 Kuperman AA, Brenner B, Kenet G. Intraventricular hemorrhage in preterm infants and coagulation--ambivalent perspectives?. Thromb Res 2013; 131 (Suppl. 01) S35-S38
- 28 Strauss T, Rozenzweig N, Rosenberg N. , et al. Surfactant impairs coagulation in-vitro: a risk factor for pulmonary hemorrhage?. Thromb Res 2013; 132 (05) 599-603
- 29 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96 (5, Pt 1): 939-943
- 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 (03) F163-F167
- 31 Lau KK, Stoffman JM, Williams S. , et al; Canadian Pediatric Thrombosis and Hemostasis Network. Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006. Pediatrics 2007; 120 (05) e1278-e1284
- 32 van Ommen CH, Heijboer H, Büller HR, Hirasing RA, Heijmans HS, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139 (05) 676-681
- 33 Massicotte MP, 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 (06) 770-776
- 34 Limperger V, Klostermeier UC, 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 (03) 385-393
- 35 Fruchtman Y, Strauss T, Rubinstein M. , et al. Skin necrosis and purpura fulminans in children with and without thrombophilia--a tertiary center's experience. Pediatr Hematol Oncol 2015; 32 (07) 505-510
- 36 Klostermeier UC, Limperger V, Kenet G. , et al. Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study. Thromb Haemost 2015; 113 (02) 426-433
- 37 Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124 (04) 1001-1008
- 38 Setty BA, O'Brien SH, Kerlin BA. Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases. Pediatr Blood Cancer 2012; 59 (02) 258-264
- 39 Kenet G, Nowak-Göttl U. Venous thromboembolism in neonates and children. Best Pract Res Clin Haematol 2012; 25 (03) 333-344
- 40 Nowak-Göttl U, Junker R, Kreuz W. , et al; Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97 (04) 858-862
- 41 Limperger V, Franke A, Kenet G. , et al. Clinical and laboratory characteristics of paediatric and adolescent index cases with venous thromboembolism and antithrombin deficiency. An observational multicentre cohort study. Thromb Haemost 2014; 112 (03) 478-485
- 42 Limperger V, Kenet G, Goldenberg NA. , et al. Impact of high-risk thrombophilia status on recurrence among children with a first non-central-venous-catheter-associated VTE: an observational multicentre cohort study. Br J Haematol 2016; 175 (01) 133-140
- 43 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
- 44 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74 (01) 415-425
- 45 Berfelo FJ, Kersbergen KJ, van Ommen CH. , et al. Neonatal cerebral sinovenous thrombosis from symptom to outcome. Stroke 2010; 41 (07) 1382-1388
- 46 Nelson KB. Perinatal ischemic stroke. Stroke 2007; 38 (2, Suppl): 742-745
- 47 Kirton A, Armstrong-Wells J, Chang T. , et al; International Pediatric Stroke Study Investigators. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics 2011; 128 (06) e1402-e1410
- 48 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 (16) 1838-1847
- 49 Berkun Y, Simchen MJ, Strauss T, Menashcu S, Padeh S, Kenet G. Antiphospholipid antibodies in neonates with stroke–a unique entity or variant of antiphospholipid syndrome?. Lupus 2014; 23 (10) 986-993
- 50 Curtis C, Mineyko A, Massicotte P. , et al. Thrombophilia risk is not increased in children after perinatal stroke. Blood 2017; 129 (20) 2793-2800
- 51 Monagle P, Chan AKC, Goldenberg NA. , et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e737S-e801S . Erratum in Chest 2014;146(5):1422; Chest 2014;146(6):1694
- 52 Kosch A, Kuwertz-Bröking E, Heller C, Kurnik K, Schobess R, Nowak-Göttl U. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up. Blood 2004; 104 (05) 1356-1360
- 53 Williams V, Pham C, Suppiah R, Melville A. Liquid warfarin formulation for oral anticoagulation of a neonate with a renal vein thrombosis. J Paediatr Child Health 2013; 49 (01) E106-E107
- 54 Michaels LA, Gurian M, Hegyi T, Drachtman RA. Low molecular weight heparin in the treatment of venous and arterial thromboses in the premature infant. Pediatrics 2004; 114 (03) 703-707
- 55 Dix D, Andrew M, Marzinotto V. , et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136 (04) 439-445
- 56 Schloemer NJ, Abu-Sultaneh S, Hanson SJ. , et al. Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*. Pediatr Crit Care Med 2014; 15 (07) e294-e299
- 57 Malowany JI, Monagle P, Knoppert DC. , et al; Canadian Paediatric Thrombosis and Hemostasis Network. Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates. Thromb Res 2008; 122 (06) 826-830
- 58 Avila ML, Shah V, Brandão LR. Systematic review on heparin-induced thrombocytopenia in children: a call to action. J Thromb Haemost 2013; 11 (04) 660-669
- 59 Young G, Tarantino MD, Wohrley J, Weber LC, Belvedere M, Nugent DJ. Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost 2007; 5 (08) 1654-1659
- 60 von Vajna E, Alam R, So TY. Current clinical trials on the use of direct oral anticoagulants in the pediatric population. Cardiol Ther 2016; 5 (01) 19-41
- 61 Attard C, Monagle P, Kubitza D, Ignjatovic V. The in vitro anticoagulant effect of rivaroxaban in children. Thromb Res 2012; 130 (05) 804-807