Hemostatic Challenges in Neonates

Patricia Davenport, Martha Sola-Visner, Patricia Davenport, Martha Sola-Visner

Abstract

The neonatal hemostatic system is strikingly different from that of adults. Among other differences, neonates exhibit hyporeactive platelets and decreased levels of coagulation factors, the latter translating into prolonged clotting times (PT and PTT). Since pre-term neonates have a high incidence of bleeding, particularly intraventricular hemorrhages, neonatologists frequently administer blood products (i.e., platelets and FFP) to non-bleeding neonates with low platelet counts or prolonged clotting times in an attempt to overcome these "deficiencies" and reduce bleeding risk. However, it has become increasingly clear that both the platelet hyporeactivity as well as the decreased coagulation factor levels are effectively counteracted by other factors in neonatal blood that promote hemostasis (i.e., high levels of vWF, high hematocrit and MCV, reduced levels of natural anticoagulants), resulting in a well-balanced neonatal hemostatic system, perhaps slightly tilted toward a prothrombotic phenotype. While life-saving in the presence of active major bleeding, the administration of platelets and/or FFP to non-bleeding neonates based on laboratory tests has not only failed to decrease bleeding, but has been associated with increased neonatal morbidity and mortality in the case of platelets. In this review, we will present a clinical overview of bleeding in neonates (incidence, sites, risk factors), followed by a description of the key developmental differences between neonates and adults in primary and secondary hemostasis. Next, we will review the clinical tests available for the evaluation of bleeding neonates and their limitations in the context of the developmentally unique neonatal hemostatic system, and will discuss current and emerging approaches to more accurately predict, evaluate and treat bleeding in neonates.

Keywords: FFP transfusion; bleeding; hemostasis; neonate; platelet function; platelet transfusion.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Davenport and Sola-Visner.

Figures

Figure 1
Figure 1
Neonatal Hemostasis. The hemostatic system of neonates is characterized by decreased platelet reactivity and decreased levels of multiple coagulation factors, which would predict a bleeding phenotype. However, these findings are exquisitely equilibrated by other factors in neonatal blood that promote clotting, such as the increased hematocrit, MCV, VWF levels and the low levels of natural anticoagulants. The overall hemostatic balance in healthy term neonates is different from that of adults but well-balanced, and perhaps slightly tilted toward thrombosis, with shorter bleeding times and faster initiation of coagulation compared to healthy adults.

References

    1. Venkatesh V, Curley A, Khan R, Clarke P, Watts T, Josephson C, et al. . A novel approach to standardised recording of bleeding in a high risk neonatal population. Arch Dis Child Fetal Neonatal Ed. (2013) 98:F260–3. 10.1136/archdischild-2012-302443
    1. Poryo M, Boeckh JC, Gortner L, Zemlin M, Duppre P, Ebrahimi-Fakhari D, et al. . Ante-, peri- and postnatal factors associated with intraventricular hemorrhage in very premature infants. Early Hum Dev. (2018) 116:1–8. 10.1016/j.earlhumdev.2017.08010
    1. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatric Res. (2010) 67:1–8. 10.1203/PDR0b013e3181c1b176
    1. Handley SC, Passarella M, Lee HC, Lorch SA. Incidence Trends and Risk Factor Variation in Severe Intraventricular Hemorrhage across a Population Based Cohort. J Pediatr. (2018) 200:24–9. e3. 10.1016/j.jpeds.2018.04020
    1. Ahmad KA, Bennett MM, Ahmad SF, Clark RH, Tolia VN. Morbidity and mortality with early pulmonary haemorrhage in preterm neonates. Arch Dis Child Fetal Neonatal Ed. (2019) 104:F63–F8. 10.1136/archdischild-2017-314172
    1. Aziz A, Ohlsson A. Surfactant for pulmonary haemorrhage in neonates. Cochrane Database Syst Rev. (2020) 2:CD005254. 10.1002/14651858.CD005254pub4
    1. Suryawanshi P, Nagpal R, Meshram V, Malshe N, Kalrao V. Pulmonary hemorrhage (PH) in extremely low birth weight (ELBW) infants: successful treatment with surfactant. J Clin Diagn Res. (2015) 9:SD03–4. 10.7860/JCDR/2015/85965691
    1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. (2011) 364:255–64. 10.1056/NEJMra1005408
    1. Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, et al. . Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatric Surg. (2009) 44:1072–5. 10.1016/j.jpedsurg.2009.02013
    1. Namachivayam K, MohanKumar K, Shores DR, Jain SK, Fundora J, Everett AD, et al. . Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis. Proc Natl Acad Sci USA. (2020) 117:10958–69. 10.1073/pnas1912357117
    1. Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol. (2009) 29:130–6. 10.1038/jp.2008141
    1. Israels SJ, Cheang T, Robertson C, McMillan-Ward EM, McNicol A. Impaired signal transduction in neonatal platelets. Pediatr Res. (1999) 45:687–91. 10.1203/00006450-199905010-00014
    1. Sitaru AG, Holzhauer S, Speer CP, Singer D, Obergfell A, Walter U, et al. . Neonatal platelets from cord blood and peripheral blood. Platelets. (2005) 16:203–10. 10.1080/09537100400016862
    1. Hardy AT, Palma-Barqueros V, Watson SK, Malcor JD, Eble JA, Gardiner EE, et al. . Significant hypo-responsiveness to GPVI and CLEC-2 agonists in pre-term and full-term neonatal platelets and following immune thrombocytopenia. Thromb Haemost. (2018) 118:1009–20. 10.1055/s-0038-1646924
    1. Bednarek FJ, Bean S, Barnard MR, Frelinger AL, Michelson AD. The platelet hyporeactivity of extremely low birth weight neonates is age-dependent. Thromb Res. (2009) 124:42–5. 10.1016/j.thromres.2008.10004
    1. Schlagenhauf A, Schweintzger S, Birner-Grunberger R, Leschnik B, Muntean W. Comparative evaluation of PAR1, GPIb-IX-V, and integrin alphaIIbbeta3 levels in cord and adult platelets. Hamostaseologie. (2010) 30(Suppl. 1):S164–7. 10.1055/s-0037-1619105
    1. Israels SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A. Deficient thromboxane synthesis and response in platelets from premature infants. Pediatr Res. (1997) 41:218–23. 10.1203/00006450-199702000-00011
    1. Palma-Barqueros V, Torregrosa JM, Caparros-Perez E, Mota-Perez N, Bohdan N, Llanos MDC, et al. . Developmental differences in platelet inhibition response to prostaglandin E1. Neonatology. (2019) 117:15–23. 10.1159/000504173
    1. Urban D, Pluthero FG, Christensen H, Baidya S, Rand ML, Das A, et al. . Decreased numbers of dense granules in fetal and neonatal platelets. Haematologica. (2017) 102:e36–e8. 10.3324/haematol.2016152421
    1. Ts'ao CH, Green D, Schultz K. Function and ultrastructure of platelets of neonates: enhanced ristocetin aggregation of neonatal platelets. Br J Haematol. (1976) 32:225–33. 10.1111/j.1365-2141.1976.tb00925x
    1. Whaun JM. Platelet function in the neonate: including qualitative platelet abnormalities associated with bleeding. New York, NY: Raven Press; (1988).
    1. Suarez CR, Gonzalez J, Menendez C, Fareed J, Fresco R, Walenga J. Neonatal and maternal platelets: activation at time of birth. Am J Hematol. (1988) 29:18–21. 10.1002/ajh2830290105
    1. Caparros-Perez E, Teruel-Montoya R, Palma-Barquero V, Torregrosa JM, Blanco JE, Delgado JL, et al. . Down regulation of the Munc18b-syntaxin-11 complex and beta1-tubulin Impairs secretion and spreading in neonatal platelets. Thromb Haemost. (2017) 117:2079–91. 10.1160/TH17-04-0241
    1. Whaun JM. The platelet of the newborn infant. 5-hydroxytryptamine uptake and release. Thromb Diath Haemorrh. (1973) 30:327–33. 10.1055/s-0038-1649081
    1. Andrew M, Paes B, Bowker J, Vegh P. Evaluation of an automated bleeding time device in the newborn. Am J Hematol. (1990) 35:275–7. 10.1002/ajh2830350411
    1. Carcao MD, Blanchette VS, Dean JA, He L, Kern MA, Stain AM, et al. . The platelet function analyzer (PFA-100): a novel in-vitro system for evaluation of primary haemostasis in children. Br J Haematol. (1998) 101:70–3. 10.1046/j.1365-2141.1998.00656x
    1. Israels SJ, Cheang T, McMillan-Ward EM, Cheang M. Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyzer. J Pediatrics. (2001) 138:116–9. 10.1067/mpd.2001109794
    1. Roschitz B, Sudi K, Kostenberger M, Muntean W. Shorter PFA-100 closure times in neonates than in adults: role of red cells, white cells, platelets and von Willebrand factor. Acta Paediatr. (2001) 90:664–70. 10.1080/08035250119138
    1. Boudewijns M, Raes M, Peeters V, Mewis A, Cartuyvels R, Magerman K, et al. . Evaluation of platelet function on cord blood in 80 healthy term neonates using the Platelet Function Analyser (PFA-100); shorter in vitro bleeding times in neonates than adults. Eur J Pediatr. (2003) 162:212–3. 10.1007/s00431-002-1093-7
    1. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. . Development of the human coagulation system in the full-term infant. Blood. (1987) 70:165–72. 10.1182/blood.V70.1.165bloodjournal701165
    1. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al. . Development of the human coagulation system in the healthy premature infant. Blood. (1988) 72:1651–7. 10.1182/blood.V72.5.16511651
    1. Katz JA, Moake JL, McPherson PD, Weinstein MJ, Moise KJ, Carpenter RJ, et al. . Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma. Blood. (1989) 73:1851–8. 10.1182/blood.V73.7.18511851
    1. Weinstein MJ, Blanchard R, Moake JL, Vosburgh E, Moise K. Fetal and neonatal von willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura. Br J Haematol. (1989) 72:68–72. 10.1111/j.1365-2141.1989.tb07654x
    1. Gerrard JM, Docherty JC, Israels SJ, Cheang MS, Bishop AJ, Kobrinsky NL, et al. . A reassessment of the bleeding time: association of age, hematocrit, platelet function, von Willebrand factor, and bleeding time thromboxane B2 with the length of the bleeding time. Clin Invest Med. (1989) 12:165–71.
    1. Sola MC, del Vecchio A, Edwards TJ, Suttner D, Hutson AD, Christensen RD. The relationship between hematocrit and bleeding time in very low birth weight infants during the first week of life. J Perinatol. (2001) 21:368–71. 10.1038/sj.jp7210546
    1. Del V.ecchio A, Latini G, Henry E, Christensen RD. Template bleeding times of 240 neonates born at 24 to 41 weeks gestation. J Perinatol. (2008) 28:427–31. 10.1038/jp.200810
    1. Saxonhouse MA, Garner R, Mammel L, Li Q, Muller KE, Greywoode J, et al. . Closure times measured by the platelet function analyzer PFA-100 are longer in neonatal blood compared to cord blood samples. Neonatology. (2010) 97:242–9. 10.1159/000253755
    1. Pal S, Curley A, Stanworth SJ. Interpretation of clotting tests in the neonate. Arch Dis Child Fetal Neonatal Ed. (2015) 100:F270–4. 10.1136/archdischild-2014-306196
    1. Achey MA, Nag UP, Robinson VL, Reed CR, Arepally GM, Levy JH, et al. . The developing balance of thrombosis and hemorrhage in pediatric surgery: clinical implications of age-related changes in hemostasis. Clin Appl. Thromb. Hemost. (2020) 26:1076029620929092. 10.1177/1076029620929092
    1. Pichler E, Pichler L. The neonatal coagulation system and the vitamin K deficiency bleeding - a mini review. Wien Med Wochenschr. (2008) 158:385–95. 10.1007/s10354-008-0538-7
    1. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood. (1992) 80:1998–2005. 10.1182/blood.V80.8.19981998
    1. Christensen RD, Baer VL, Lambert DK, Henry E, Ilstrup SJ, Bennett ST. Reference intervals for common coagulation tests of preterm infants (CME). Transfusion. (2014) 54:627–32. 10.1111/trf12322
    1. Neary E, Okafor I, Al-Awaysheh F, Kirkham C, Sheehan K, Mooney C, et al. . Laboratory coagulation parameters in extremely premature infants born earlier than 27 gestational weeks upon admission to a neonatal intensive care unit. Neonatology. (2013) 104:222–7. 10.1159/000353366
    1. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, et al. . Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. (2006) 95:362–72. 10.1160/TH05-01-0047
    1. Neary E, McCallion N, Kevane B, Cotter M, Egan K, Regan I, et al. . Coagulation indices in very preterm infants from cord blood and postnatal samples. J Thromb Haemost. (2015) 13:2021–30. 10.1111/jth13130
    1. Monagle P, Massicotte P. Developmental haemostasis: secondary haemostasis. Semin Fetal Neonatal Med. (2011) 16:294–300. 10.1016/j.siny.2011.07007
    1. Catford K, Muthukumar P, Reddy C, Al Atrash H, Clarke P, Venkatesh V, et al. . Routine neonatal coagulation testing increases use of fresh-frozen plasma. Transfusion. (2014) 54:1444–5. 10.1111/trf12610
    1. Cvirn G, Gallistl S, Rehak T, Jurgens G, Muntean W. Elevated thrombin-forming capacity of tissue factor-activated cord compared with adult plasma. J Thromb Haemost. (2003) 1:1785–90. 10.1046/j.1538-7836.2003.00320x
    1. Blanchette VS, Chen L, de Friedberg ZS, Hogan VA, Trudel E, Decary F. Alloimmunization to the PlA1 platelet antigen: results of a prospective study. Br J Haematol. (1990) 74:209–15. 10.1111/j.1365-2141.1990.tb02567x
    1. Johnson JA, Ryan G, al-Musa A, Farkas S, Blanchette VS. Prenatal diagnosis and management of neonatal alloimmune thrombocytopenia. Seminars Perinatol. (1997) 21:45–52. 10.1016/S0146-0005(97)80019-5
    1. Sparger KA, Assmann SF, Granger S, Winston A, Christensen RD, Widness JA, et al. . Platelet transfusion practices among very-low-birth-weight infants. JAMA Pediatrics. (2016) 170:687–94. 10.1001/jamapediatrics.20160507
    1. Muthukumar P, Venkatesh V, Curley A, Kahan BC, Choo L, Ballard S, et al. . Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions. Transfus Med. (2012) 22:338–43. 10.1111/j.1365-3148.2012.01171x
    1. Stanworth SJ, Clarke P, Watts T, Ballard S, Choo L, Morris T, et al. . Prospective, observational study of outcomes in neonates with severe thrombocytopenia. Pediatrics. (2009) 124:e826–34. 10.1542/peds2009-0332
    1. von Lindern JS, van den Bruele T, Lopriore E, Walther FJ. Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort study. BMC Pediatr. (2011) 11:16. 10.1186/1471-2431-11-16
    1. Deschmann E, Saxonhouse MA, Feldman HA, Norman M, Barbian M, Sola-Visner M. Association between in vitro bleeding time and bleeding in preterm infants with thrombocytopenia. JAMA Pediatrics. (2019) 173:393–4. 10.1001/jamapediatrics.20190008
    1. Baer VL, Lambert DK, Henry E, Christensen RD. Severe thrombocytopenia in the NICU. Pediatrics. (2009) 124:e1095–100. 10.1542/peds2009-0582
    1. Josephson CD, Granger S, Assmann SF, Castillejo MI, Strauss RG, Slichter SJ, et al. . Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia. Blood. (2012) 120:748–60. 10.1182/blood-2011-11-389569
    1. Waller AK, Lantos L, Sammut A, Salgin B, McKinney H, Foster HR, et al. . Flow cytometry for near-patient testing in premature neonates reveals variation in platelet function: a novel approach to guide platelet transfusion. Pediatric Res. (2019) 85:874–84. 10.1038/s41390-019-0316-9
    1. Deschmann E, Saxonhouse MA, Feldman HA, Norman M, Barbian M, Sola-Visner M. Association of bleeding scores and platelet transfusions with platelet counts and closure times in response to adenosine diphosphate (CT-ADPs) among preterm neonates with thrombocytopenia. JAMA Netw Open. (2020) 3:e203394. 10.1001/jamanetworkopen.20203394
    1. Fustolo-Gunnink SF, Fijnvandraat K, Putter H, Ree IM, Caram-Deelder C, Andriessen P, et al. . Dynamic prediction of bleeding risk in thrombocytopenic preterm neonates. Haematologica. (2019) 104:2300–6. 10.3324/haematol.2018208595
    1. Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemost. (1995) 21:317–29. 10.1055/s-2007-1000653
    1. Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. (2009) 23:49–59. 10.1016/j.blre.2008.06001
    1. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic disease: a pooled data analysis. J Paediatr Child Health. (1993) 29:177–81. 10.1111/j.1440-1754.1993.tb00480x
    1. Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev. (1992) 6:92–104. 10.1016/0268-960X(92)90011-E
    1. Kenet G, Chan AK, Soucie JM, Kulkarni R. Bleeding disorders in neonates. Haemophilia. (2010) 16(Suppl. 5):168–75. 10.1111/j.1365-2516.2010.02316x
    1. Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol. (2001) 112:264–74. 10.1046/j.1365-2141.2001.02362x
    1. Chambost H, Gaboulaud V, Coatmelec B, Rafowicz A, Schneider P, Calvez T, et al. . What factors influence the age at diagnosis of hemophilia? Results of the French hemophilia cohort. J Pediatrics. (2002) 141:548–52. 10.1067/mpd.2002128115
    1. Chalmers EA. Haemophilia and the newborn. Blood Rev. (2004) 18:85–92. 10.1016/S0268-960X(03)00062-6
    1. Kulkarni R, Lusher JM. Intracranial and extracranial hemorrhages in newborns with hemophilia: a review of the literature. J Pediatr Hematol Oncol. (1999) 21:289–95. 10.1097/00043426-199907000-00009
    1. Conway JH, Hilgartner MW. Initial presentations of pediatric hemophiliacs. Arch Pediatr Adolesc Med. (1994) 148:589–94. 10.1001/archpedi.199402170060043007
    1. Ljung R, Lindgren AC, Petrini P, Tengborn L. Normal vaginal delivery is to be recommended for haemophilia carrier gravidae. Acta Paediatr. (1994) 83:609–11. 10.1111/j.1651-2227.1994.tb13090x
    1. Klinge J, Auberger K, Auerswald G, Brackmann HH, Mauz-Korholz C, Kreuz W. Prevalence and outcome of intracranial haemorrhage in haemophiliacs–a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr. (1999) 158(Suppl. 3):S162–5. 10.1007/PL00014346
    1. Walker ID, Walker JJ, Colvin BT, Letsky EA, Rivers R, Stevens R. Investigation and management of haemorrhagic disorders in pregnancy. Haemostasis and Thrombosis Task Force. J Clin Pathol. (1994) 47:100–8. 10.1136/jcp.47.2100
    1. Kulkarni R, Lusher JM, Henry RC, Kallen DJ. Current practices regarding newborn intracranial haemorrhage and obstetrical care and mode of delivery of pregnant Haemophilia carriers: a survey of obstetricians, neonatologists and haematologists in the United States, on behalf of the National Hemophilia Foundation's Medical and Scientific Advisory Council. Haemophilia. (1999) 5:410–5. 10.1046/j.1365-2516.1999.00357x
    1. Cattivelli K, Distefano C, Bonetti L, Testa S, Siboni SM, Plebani A, et al. . Recurrent bleedings in newborn: a factor VII deficiency case report. Transfus Med Hemother. (2018) 45:104–6. 10.1159/000481993
    1. Khair K, Liesner R. Bruising and bleeding in infants and children–a practical approach. Br J Haematol. (2006) 133:221–31. 10.1111/j.1365-2141.2006.06016x
    1. Jaffray J, Young G, Ko RH. The bleeding newborn: a review of presentation, diagnosis, and management. Semin Fetal Neonatal Med. (2016) 21:44–9. 10.1016/j.siny.2015.12002
    1. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood. (2015) 125:2052–61. 10.1182/blood-2014-08-532820
    1. Herrmann FH, Wulff K, Auerswald G, Schulman S, Astermark J, Batorova A, et al. . Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene. Haemophilia. (2009) 15:267–80. 10.1111/j.1365-2516.2008.01910x
    1. Di Minno MN, Dolce A, Mariani G, Group SS. Bleeding symptoms at disease presentation and prediction of ensuing bleeding in inherited FVII deficiency. Thromb Haemost. (2013) 109:1051–9. 10.1160/TH12-10-0740
    1. Miller BE, Bailey JM, Mancuso TJ, Weinstein MS, Holbrook GW, Silvey EM, et al. . Functional maturity of the coagulation system in children: an evaluation using thrombelastography. Anesth Analg. (1997) 84:745–8. 10.1097/00000539-199704000-00008
    1. Kettner SC, Pollak A, Zimpfer M, Seybold T, Prusa AR, Herkner K, et al. . Heparinase-modified thrombelastography in term and preterm neonates. Anesth Analg. (2004) 98:1650–2, table of contents. 10.1213/01.ANE.0000115149.25496DD
    1. Oswald E, Stalzer B, Heitz E, Weiss M, Schmugge M, Strasak A, et al. . Thromboelastometry (ROTEM) in children: age-related reference ranges and correlations with standard coagulation tests. Br J Anaesth. (2010) 105:827–35. 10.1093/bja/aeq258
    1. Radicioni M, Bruni A, Bini V, Villa A, Ferri C. Thromboelastographic profiles of the premature infants with and without intracranial hemorrhage at birth: a pilot study. J Matern Fetal Neonatal Med. (2015) 28:1779–83. 10.3109/14767058.2014968773
    1. Edwards RM, Naik-Mathuria BJ, Gay AN, Olutoye OO, Teruya J. Parameters of thromboelastography in healthy newborns. Am J Clin Pathol. (2008) 130:99–102. 10.1309/LABNMY41RUD099J2
    1. Sewell EK, Forman KR, Wong EC, Gallagher M, Luban NL, Massaro AN. Thromboelastography in term neonates: an alternative approach to evaluating coagulopathy. Arch Dis Child Fetal Neonatal Ed. (2017) 102:F79–F84. 10.1136/archdischild-2016-310545
    1. Strauss T, Levy-Shraga Y, Ravid B, Schushan-Eisen I, Maayan-Metzger A, Kuint J, et al. . Clot formation of neonates tested by thromboelastography correlates with gestational age. Thromb Haemost. (2010) 103:344–50. 10.1160/TH09-05-0282
    1. Sokou R, Giallouros G, Konstantinidi A, Pantavou K, Nikolopoulos G, Bonovas S, et al. . Thromboelastometry for diagnosis of neonatal sepsis-associated coagulopathy: an observational study. Eur J Pediatr. (2018) 177:355–62. 10.1007/s00431-017-3072-z
    1. Lampridou M, Sokou R, Tsantes AG, Theodoraki M, Konstantinidi A, Ioakeimidis G, et al. . ROTEM diagnostic capacity for measuring fibrinolysis in neonatal sepsis. Thromb Res. (2020) 192:103–8. 10.1016/j.thromres.2020.05028
    1. Rudolph AM, Nadas AS, Borges WH. Hematologic adjustments to cyanotic congenital heart disease. Pediatrics. (1953) 11:454–65.
    1. Bahnson HT, Ziegler RF. A consideration of the causes of death following operation for congenital heart disease of the cyanotic type. Surg Gynecol Obstet. (1950) 90:60–76.
    1. Osthaus WA, Boethig D, Johanning K, Rahe-Meyer N, Theilmeier G, Breymann T, et al. . Whole blood coagulation measured by modified thrombelastography (ROTEM) is impaired in infants with congenital heart diseases. Blood Coagul Fibrinolysis. (2008) 19:220–5. 10.1097/MBC0b013e3282f54532
    1. Cremer M, Sola-Visner M, Roll S, Josephson CD, Yilmaz Z, Buhrer C, et al. . Platelet transfusions in neonates: practices in the United States vary significantly from those in Austria, Germany, and Switzerland. Transfusion. (2011) 51:2634–41. 10.1111/j.1537-2995.2011.03208x
    1. Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory MR, et al. . Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. Pediatrics. (2009) 123:278–85. 10.1542/peds2007-2850
    1. Andrew M, Vegh P, Caco C, Kirpalani H, Jefferies A, Ohlsson A, et al. . A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatrics. (1993) 123:285–91. 10.1016/S0022-3476(05)81705-6
    1. Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh V, Hudson C, et al. . Randomized trial of platelet-transfusion thresholds in neonates. N Engl J Med. (2019) 380:242–51. 10.1056/NEJMoa1807320
    1. von Lindern JS, Hulzebos CV, Bos AF, Brand A, Walther FJ, Lopriore E. Thrombocytopaenia and intraventricular haemorrhage in very premature infants: a tale of two cities. Arch Dis Child Fetal Neonatal Ed. (2012) 97:F348–52. 10.1136/fetalneonatal-2011-300763
    1. Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD. Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system. J Perinatol. (2007) 27:790–6. 10.1038/sj.jp7211833
    1. Del Vecchio A, Sola MC, Theriaque DW, Hutson AD, Kao KJ, Wright D, et al. . Platelet transfusions in the neonatal intensive care unit:factors predicting which patients will require multiple transfusions. Transfusion. (2001) 41:803–8. 10.1046/j.1537-2995.2001.41060803x
    1. Patel RM, Josephson CD, Shenvi N, Maheshwari A, Easley KA, Stowell S, et al. . Platelet transfusions and mortality in necrotizing enterocolitis. Transfusion. (2018) 59:981–8. 10.1111/trf15112
    1. Kenton AB, Hegemier S, Smith EO, O'Donovan DJ, Brandt ML, Cass DL, et al. . Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity. J Perinatol. (2005) 25:173–7. 10.1038/sj.jp7211237
    1. Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth S, Curley AE, Onland W, et al. . Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood. (2019) 134:2354–60. 10.1182/blood2019000899
    1. Ferrer-Marin F, Chavda C, Lampa M, Michelson AD, Frelinger AL, 3rd, Sola-Visner M. Effects of in vitro adult platelet transfusions on neonatal hemostasis. J Thromb Haemost. (2011) 9:1020–8. 10.1111/j.1538-7836.2011.04233x
    1. Smith TL, Weyrich AS. Platelets as central mediators of systemic inflammatory responses. Thromb Res. (2011) 127:391–4. 10.1016/j.thromres.2010.10013
    1. Weyrich AS. Platelets: more than a sack of glue. Hematology. (2014) 2014:400–3. 10.1182/asheducation-2014.1400
    1. Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA, Miner C, et al. . Adherence to NICU transfusion guidelines: data from a multihospital healthcare system. J Perinatol. (2008) 28:492–7. 10.1038/jp.200823
    1. Puetz J, Darling G, McCormick KA, Wofford JD. Fresh frozen plasma and recombinant factor VIIa use in neonates. J Pediatr Hematol Oncol. (2009) 31:901–6. 10.1097/MPH0b013e3181c29c25
    1. Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy MF, et al. . The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion. (2011) 51:62–70. 10.1111/j.1537-2995.2010.02798x
    1. Altuntas N, Yenicesu I, Beken S, Kulali F, Burcu B.elen F, Hirfanoglu IM, et al. . Clinical use of fresh-frozen plasma in neonatal intensive care unit. Transfus Apher Sci. (2012) 47:91–4. 10.1016/j.transci.2012.05007
    1. Gross SJ, Filston HC, Anderson JC. Controlled study of treatment for disseminated intravascular coagulation in the neonate. J Pediatr. (1982) 100:445–8. 10.1016/S0022-3476(82)80457-5
    1. Hambleton G, Appleyard WJ. Controlled trial of fresh frozen plasma in asphyxiated low birthweight infants. Arch Dis Child. (1973) 48:31–5. 10.1136/adc.48.131
    1. Beverley DW, Pitts-Tucker TJ, Congdon PJ, Arthur RJ, Tate G. Prevention of intraventricular haemorrhage by fresh frozen plasma. Arch Dis Child. (1985) 60:710–3. 10.1136/adc.60.8710
    1. Ekblad H, Kero P, Shaffer SG, Korvenranta H. Extracellular volume in preterm infants: influence of gestational age and colloids. Early Hum Dev. (1991) 27:1–7. 10.1016/0378-3782(91)90022-U
    1. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma gelatin or glucose on early mortality and morbidity in preterm babies . The Northern neonatal nursing initiative [NNNI] trial group. Eur J Pediatr. (1996) 155:580–8. 10.1007/BF01957909
    1. Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. (2004) 2:CD002055. 10.1002/14651858.CD002055pub2
    1. Acunas BA, Peakman M, Liossis G, Davies ET, Bakoleas B, Costalos C, et al. . Effect of fresh frozen plasma and gammaglobulin on humoral immunity in neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. (1994) 70:F182–7. 10.1136/fn.70.3F182
    1. Krediet TG, Beurskens FJ, van Dijk H, Gerards LJ, Fleer A. Antibody responses and opsonic activity in sera of preterm neonates with coagulase-negative staphylococcal septicemia and the effect of the administration of fresh frozen plasma. Pediatric Res. (1998) 43:645–51. 10.1203/00006450-199805000-00013
    1. Gottuso MA, Williams ML, Oski FA. The role of exchange transfusions in the management of low-birth-weight infants with and without severe respiratory distress syndrome. II. Further observations and studies of mechanisms of action. J Pediatr. (1976) 89:279–85. 10.1016/S0022-3476(76)80468-4
    1. Emery EF, Greenough A, Gamsu HR. Randomised controlled trial of colloid infusions in hypotensive preterm infants. Arch Dis Child. (1992) 67:1185–8. 10.1136/adc.67.10_Spec_No1185
    1. Forman KR, Diab Y, Wong EC, Baumgart S, Luban NL, Massaro AN. Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia: a retrospective case-control study. BMC Pediatr. (2014) 14:277. 10.1186/1471-2431-14-277
    1. Gkiougki E, Mitsiakos G, Chatziioannidis E, Papadakis E, Nikolaidis N. Predicting response to rFVIIa in neonates with intractable bleeding or severe coagulation disturbances. J Pediatr Hematol Oncol. (2013) 35:221–6. 10.1097/MPH0b013e318286d27e
    1. Young G, Wicklund B, Neff P, Johnson C, Nugent DJ. Off-label use of rFVIIa in children with excessive bleeding: a consecutive study of 153 off-label uses in 139 children. Pediatr Blood Cancer. (2009) 53:179–83. 10.1002/pbc22053
    1. Puetz J, Darling G, Brabec P, Blatny J, Mathew P. Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma. Pediatr Blood Cancer. (2009) 53:1074–8. 10.1002/pbc22160
    1. Rech MA, Wittekindt L, Friedman SD, Kling K, Ubogy D. Prothrombin complex concentrate for intracerebral hemorrhage secondary to vitamin K deficiency bleeding in a 6-week-old child. J Pediatr. (2015) 167:1443–4. 10.1016/j.jpeds.2015.09030
    1. Ashikhmina E, Said S, Smith MM, Rodriguez V, Oliver WC, Jr, Nuttall GA, et al. . Prothrombin complex concentrates in pediatric cardiac surgery: the current state and the future. Ann Thorac Surg. (2017) 104:1423–31. 10.1016/j.athoracsur.2017.04009
    1. Mitsiakos G, Karametou M, Gkampeta A, Karali C, Papathanasiou AE, Papacharalambous E, et al. . Effectiveness and safety of 4-factor prothrombin complex concentrate (4PCC) in neonates with intractable bleeding or severe coagulation disturbances: a retrospective study of 37 cases. J Pediatric Hematol Oncol. (2019) 41:e135–e40. 10.1097/MPH0000000000001397

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