Semin Thromb Hemost 2023; 49(04): 391-401
DOI: 10.1055/s-0042-1758148
Review Article

Hemostasis in Neonates with Perinatal Hypoxia—Laboratory Approach: A Systematic Review

Marina Tsaousi*
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Zoi Iliodromiti*
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Nicoletta Iacovidou
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Eleni Karapati
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Alma Sulaj
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
2   Laboratory of Haematology and Blood Bank Unit, “Attiko” Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Chrysa Petropoulou
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Theodora Boutsikou
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
Argirios E. Tsantes
2   Laboratory of Haematology and Blood Bank Unit, “Attiko” Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
,
1   Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
3   Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikaia, Piraeus, Greece
› Author Affiliations

Abstract

Birth asphyxia, with an estimated prevalence of 1 to 6 per 1,000 live births, may lead to multiorgan dysfunction due to impaired oxygen and/or blood supply to various organ systems, including the hemostatic system. Coagulopathy, a common complication of perinatal asphyxia, has been described since the 1960s. The aim of this study was to systematically review the literature for records on the use of hemostasis tests in the evaluation of coagulation disorders, in neonates who had suffered from perinatal hypoxia or asphyxia. We identified published studies by searching PubMed and Scopus, up until April 2022. The literature search retrieved 37 articles fulfilling the inclusion criteria of the review. According to the bibliography, thrombocytopenia is commonly associated with perinatal hypoxia/asphyxia. The thrombocytopenia is usually described as mild and platelets return to normal levels by the 10th day of life. Additionally, hypoxic neonates usually present with a hypocoagulable profile, as reflected by the prolongation of standard coagulation tests, including prothrombin time, activated partial thromboplastin time, and international normalized ratio, findings commonly associated with disseminated intravascular coagulation, and by the reduction of the levels of the physiologic inhibition of coagulation system. A few studies thus far using ROTEM/TEG in hypoxic neonates have come to the same conclusion as well; hypoxic newborns seem to be characterized by a hypocoagulable profile compared with healthy neonates. It should be emphasized, however, that standard coagulation tests provide only a rough estimation of the true bleeding or thrombotic risk of hypoxic neonates. On the contrary, viscoelastic methods seem to be more precise in the early detection of hemostasis disorders in the neonatal population. However, until now, there was uncertainty as to the most appropriate coagulation assays for diagnosis and management of coagulation derangement in neonates with perinatal hypoxia indicating the need for further research on this field.

* These authors contributed equally to this work.




Publication History

Article published online:
11 November 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 de Haan M, Wyatt JS, Roth S, Vargha-Khadem F, Gadian D, Mishkin M. Brain and cognitive-behavioural development after asphyxia at term birth. Dev Sci 2006; 9 (04) 350-358
  • 2 Morales P, Bustamante D, Espina-Marchant P. et al. Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?. EPMA J 2011; 2 (02) 211-230
  • 3 Rainaldi MA, Perlman JM. Pathophysiology of birth asphyxia. Clin Perinatol 2016; 43 (03) 409-422
  • 4 Hankins GDV, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol 2003; 102 (03) 628-636
  • 5 Gravett C, Eckert LO, Gravett MG. et al; Brighton Collaboration Non-Reassuring Fetal Status Working Group. Non-reassuring fetal status: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2016; 34 (49) 6084-6092
  • 6 Christensen RD, Baer VL, Yaish HM. Thrombocytopenia in late preterm and term neonates after perinatal asphyxia. Transfusion 2015; 55 (01) 187-196
  • 7 Bauman ME, Cheung PY, Massicotte MP. Hemostasis and platelet dysfunction in asphyxiated neonates. J Pediatr 2011; 158 (2, Suppl): e35-e39
  • 8 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 (04) F319-F323
  • 9 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62 (10) 1006-1012
  • 10 Boutaybi N, Steggerda SJ, Smits-Wintjens VEHJ, van Zwet EW, Walther FJ, Lopriore E. Early-onset thrombocytopenia in near-term and term infants with perinatal asphyxia. Vox Sang 2014; 106 (04) 361-367
  • 11 Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C. Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 1986; 108 (5, Pt 1): 749-755
  • 12 Ören H, Irken G, Ören B, Olgun N, Özkan H. Assessment of clinical impact and predisposing factors for neonatal thrombocytopenia. Indian J Pediatr 1994; 61 (05) 551-558
  • 13 Ulusoy E, Tüfekçi O, Duman N, Kumral A, İrken G, Ören H. Thrombocytopenia in neonates: causes and outcomes. Ann Hematol 2013; 92 (07) 961-967
  • 14 Resch E, Hinkas O, Urlesberger B, Resch B. Neonatal thrombocytopenia-causes and outcomes following platelet transfusions. Eur J Pediatr 2018; 177 (07) 1045-1052
  • 15 Mehta P, Vasa R, Neumann L, Karpatkin M. Thrombocytopenia in the high-risk infant. J Pediatr 1980; 97 (05) 791-794
  • 16 Nadkarni J, Patne SK, Kispotta R. Hypoxia as a predisposing factor for the development of early onset neonatal thrombocytopenia. J Clin Neonatol 2012; 1 (03) 131-134
  • 17 Ahmad S, Hussain N, Ali A, Saleem R, Akbar A, Rafiq T. Etiology and outcome of thrombocytopenia in sick neonates. Med Forum Mon 2020; 31 (01) 54-57
  • 18 Kumar Ray R, Panda S, Patnaik R, Sarangi G. A study of neonatal thrombocytopenia in a tertiary care hospital: a prospective study. J Neonatol 2018; 32 (01) 6-11
  • 19 Sharma A, Thapar K. A prospective observational study of thrombocytopenia in high risk neonates in a tertiary care teaching hospital. Sri Lanka J Child Health 2015; 44 (04) 213-219
  • 20 Gupta A, Mathai SS, Kanitkar M. Incidence of thrombocytopenia in the neonatal intensive care unit. Med J Armed Forces India 2011; 67 (03) 234-236
  • 21 Chakkarapani E, Davis J, Thoresen M. Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 2014; 99 (06) F458-F463
  • 22 Boutaybi N, Razenberg F, Smits-Wintjens VEHJ. et al. Neonatal thrombocytopenia after perinatal asphyxia treated with hypothermia: a retrospective case control study. Int J Pediatr 2014; 2014: 760654
  • 23 Shankaran S, Pappas A, Laptook AR. et al; NICHD Neonatal Research Network. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2008; 122 (04) e791-e798
  • 24 Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998; 102 (4, Pt 1): 885-892
  • 25 Kääpä P, Viinikka L, Ylikorkala O. Thromboxane B2 production by fetal and neonatal platelets: effect of idiopathic respiratory distress syndrome and birth asphyxia. Pediatr Res 1984; 18 (08) 756-758
  • 26 Christensen RD, Sheffield MJ, Lambert DK, Baer VL. Effect of therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy on platelet function. Neonatology 2012; 101 (02) 91-94
  • 27 Pakvasa MA, Winkler AM, Hamrick SE, Josephson CD, Patel RM. Observational study of haemostatic dysfunction and bleeding in neonates with hypoxic-ischaemic encephalopathy. BMJ Open 2017; 7 (02) e013787
  • 28 Chessells JM, Wigglesworth JS. Coagulation studies in severe birth asphyxia. Arch Dis Child 1971; 46 (247) 253-256
  • 29 Chadd MA, Elwood PC, Gray OP, Muxworthy SM. Coagulation defects in hypoxic full-term newborn infants. BMJ 1971; 4 (5786): 516-518
  • 30 Sweetman D, Kelly LA, Zareen Z. et al. Coagulation profiles are associated with early clinical outcomes in neonatal encephalopathy. Front Pediatr 2019; 7 (October): 399
  • 31 Forman KR, Diab Y, Wong ECC, Baumgart S, Luban NLC, Massaro AN. Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia: a retrospective case-control study. BMC Pediatr 2014; 14 (01) 277
  • 32 Oncel MY, Erdeve O, Calisici E. et al. The effect of whole-body cooling on hematological and coagulation parameters in asphyxic newborns. Pediatr Hematol Oncol 2013; 30 (03) 246-252
  • 33 Sarkar S, Barks JD, Bhagat I, Donn SM. Effects of therapeutic hypothermia on multiorgan dysfunction in asphyxiated newborns: whole-body cooling versus selective head cooling. J Perinatol 2009; 29 (08) 558-563
  • 34 Herrera TI, Edwards L, Malcolm WF. et al. Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy. Early Hum Dev 2018; 125: 1-7
  • 35 Elsadek AE, FathyBarseem N, Suliman HA. et al. Hepatic injury in neonates with perinatal asphyxia. Glob Pediatr Health 2021; 8: X20987781
  • 36 Choudhary M, Sharma D, Dabi D, Lamba M, Pandita A, Shastri S. Hepatic dysfunction in asphyxiated neonates: prospective case-controlled study. Clin Med Insights Pediatr 2015; 9: 1-6
  • 37 Mautone A, Giordano P, Montagna O, Quercia M, Altomare M, De Mattia D. Coagulation and fibrinolytic systems in the ill preterm newborn. Acta Paediatr 1997; 86 (10) 1100-1104
  • 38 Konstantinidi A, Sokou R, Tsantes AG. et al. Thromboelastometry variables in neonates with perinatal hypoxia. Semin Thromb Hemost 2020; 46 (04) 428-434
  • 39 Forman KR, Wong E, Gallagher M, McCarter R, Luban NLC, Massaro AN. Effect of temperature on thromboelastography and implications for clinical use in newborns undergoing therapeutic hypothermia. Pediatr Res 2014; 75 (05) 663-669
  • 40 Suzuki S. Blood coagulation and fibrinolysis of the newborn viewed as perinatal factors. I. Blood coagulation and fibrinolysis of the newborn viewed as obstetrical factors. J Perinat Med 1977; 5 (06) 274-283
  • 41 Golub IE, Zarubin AA, Micheeva NI, Vanyarkina AS, Ivanova OG. The effect of severe birth asphyxia on the hemostasis system in newborns during the first hour of life. General Reanimatology 2017; 13 (01) DOI: 10.15360/1813-9779-2017-1-17-23.
  • 42 Hathaway WE, Mahasandana C, Makowski EL. Cord blood coagulation studies in infants of high-risk pregnant women. Am J Obstet Gynecol 1975; 121 (01) 51-57
  • 43 El Beshlawy A, Hussein HA, Abou-Elew HH, Abdel Kader MS. Study of protein C, protein S, and antithrombin III in hypoxic newborns. Pediatr Crit Care Med 2004; 5 (02) 163-166
  • 44 Canbal A, Yildirim Yilmaz L. The effects of perinatal asphyxia on hemostasis. Duzce Med J. 2012; 14 (01) 31-36
  • 45 Gursel T, Kocak U, Kaya Z, Bukulmez A, Atalay Y. Activated protein C resistance in cord blood from healthy and complicated newborns. J Matern Fetal Neonatal Med 2007; 20 (11) 797-801
  • 46 Carr R, Kelly AM, Williamson LM. Neonatal thrombocytopenia and platelet transfusion - a UK perspective. Neonatology 2015; 107 (01) 1-7
  • 47 Meberg A. Transitory thrombocytopenia in newborn mice after intrauterine hypoxia. Pediatr Res 1980; 14 (09) 1071-1073
  • 48 Saxonhouse MA, Rimsza LM, Christensen RD. et al. Effects of anoxia on megakaryocyte progenitors derived from cord blood CD34pos cells. Eur J Haematol 2003; 71 (05) 359-365
  • 49 Ören H, Duman N, Abacioglu H, Özkan H, Irken G. Association between serum macrophage colony-stimulating factor levels and monocyte and thrombocyte counts in healthy, hypoxic, and septic term neonates. Pediatrics 2001; 108 (02) 329-332
  • 50 Ikeno K, Koike K, Fukuromoto T, Shimizu T, Nagatomo M, Komiyama A. Increased macrophage-colony stimulating factor levels in neonates with perinatal complications. Early Hum Dev 1996; 46 (03) 229-237
  • 51 Baker GR, Levin J. Transient thrombocytopenia produced by administration of macrophage colony-stimulating factor: investigations of the mechanism. Blood 1998; 91 (01) 89-99
  • 52 Aly H, El Beshlawy A, Badrawi N. et al. Thrombopoietin level is increased in the serum of asphyxiated neonates: a prospective controlled study. J Perinatol 2005; 25 (05) 320-324
  • 53 Del Vecchio A, Motta M, Christensen RD. The neonate at risk for thrombocytopenia. Early Hum Dev 2013; 89 (Suppl. 04) S33-S36
  • 54 Tekin M, Konca C, Kahramaner Z. et al. The association between mean platelet volume and infants with meconium stained amniotic fluid. Eur Rev Med Pharmacol Sci 2016; 20 (14) 2983-2987
  • 55 MacQueen BC, Christensen RD, Henry E. et al. The immature platelet fraction: creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias. J Perinatol 2017; 37 (07) 834-838
  • 56 Sola-Visner M, Sallmon H, Brown R. New insights into the mechanisms of nonimmune thrombocytopenia in neonates. Semin Perinatol 2009; 33 (01) 43-51
  • 57 Nako Y, Tomomasa T, Morikawa A. Plasma thrombomodulin level in newborn infants with and without perinatal asphyxia. Acta Paediatr 1997; 86 (01) 91-95
  • 58 Parastatidou S, Sokou R, Tsantes AG. et al. The role of ROTEM variables based on clot elasticity and platelet component in predicting bleeding risk in thrombocytopenic critically ill neonates. Eur J Haematol 2021; 106 (02) 175-183
  • 59 Sokou R, Tsantes AG, Konstantinidi A. et al. Rotational thromboelastometry in neonates admitted to a Neonatal Intensive Care Unit. A large cross-sectional study. Semin Thromb Hemost 2021; 47 (07) 875-884
  • 60 Davenport P, Sola-Visner M. Hemostatic challenges in neonates. Front Pediatr 2021; 9: 627715
  • 61 Favaloro EJ, Lippi G. Translational aspects of developmental hemostasis: infants and children are not miniature adults and even adults may be different. Ann Transl Med 2017; 5 (10) 212
  • 62 Sokou R, Parastatidou S, Konstantinidi A. et al. Fresh frozen plasma transfusion in the neonatal population: a systematic review. Blood Rev 2022; 55: 100951