Download PDF
Semin Thromb Hemost 2003; 29(4): 363-372
DOI: 10.1055/s-2003-42587
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Neonatal Platelet Function

Sara J. Israels1 , Margaret L. Rand2 , Alan D. Michelson3
  • 1Professor,Department of Pediatrics Child Health University of Manitoba Winnipeg, Manitoba Canada
  • 2Division of Haematology/Oncology The Hospital for Sick Children Departments of Laboratory Medicine & Pathobiology Biochemistry, University of Toronto Toronto, Ontario Canada
  • 3Center for Platelet Function Studies Departments of Pediatrics Medicine, and Pathology University of Massachusetts Medical School Worcester, Massachusetts
Further Information

Publication History

Publication Date:
30 September 2003 (online)

    Permissions and Reprints

ABSTRACT

Healthy newborns maintain normal circulating platelet counts, with a platelet ultrastructure that does not differ from adults. In vitro assessments of intrinsic platelet function, however, have demonstrated transient hyporesponsiveness that is most marked in platelets from preterm infants. Decreased responses were originally considered to be the result of platelet activation and degranulation during labor and delivery, but more recent studies of platelet activation markers have not supported this theory. Decreased activation responses are due to relative deficiencies of phospholipid metabolism, calcium mobilization, granule secretion, and aggregation. These result in turn from differences in intrinsic signal transduction in the neonatal platelet compared with the adult. In contrast, there is enhanced platelet adhesion due to the presence in neonatal plasma of larger, more functionally potent von Willebrand factor multimers. These ultralarge multimers may result from decreased activity of von Willebrand factor-cleaving protease in neonatal plasma and are associated with shorter bleeding times and Platelet Function Analyser-100 closure times in neonates. In the immediate newborn period, this enhanced platelet adhesion may compensate for the decreased intrinsic platelet activation in healthy neonates, but may leave sick neonates at increased risk of bleeding.

KEYWORDS

Platelets - platelet function - neonates

REFERENCES

  • 1 Andrew M, Paes B, Milner R. et al . The development of the human coagulation system in the full-term infant.  Blood . 1987;  70 165-172
    PubMedGoogle Scholar
  • 2 Andrew M, Paes B, Milner R. et al . Development of the human coagulation system in the healthy premature infant.  Blood . 1988;  72 1651-1657
    PubMedGoogle Scholar
  • 3 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 27-30
    PubMedGoogle Scholar
  • 4 Andrew M, Brooker L, Leaker M, Paes B, Weitz J. Fibrin clot lysis by thrombolytic agents is impaired in newborns due to low plasminogen concentration.  Thromb Haemost . 1992;  68 325-330
    PubMedGoogle Scholar
  • 5 Blanchette V S, Rand M L. Platelet disorders in newborn infants: diagnosis and management.  Semin Perinatol . 1997;  21 53-62
    PubMedGoogle Scholar
  • 6 Kuhne T, Imbach P. Neonatal platelet physiology and pathology.  Eur J Pediatr . 1998;  157 87-94
    CrossrefPubMedGoogle Scholar
  • 7 Michelson A D. Platelet function in the newborn.  Semin Thromb Hemost . 1998;  24 507-512
    PubMedGoogle Scholar
  • 8 Beverly D W, Inwood M J, Chance G W, Schaus M, O'Keefe B. “Normal” haemostasis parameters: a study in a well-defined inborn population of preterm infants.  Early Hum Dev . 1984;  9 249-257
    CrossrefPubMedGoogle Scholar
  • 9 Andrew M, Kelton J. Neonatal thrombocytopenia.  Clin Perinatol . 1984;  11 359-391
    PubMedGoogle Scholar
  • 10 Patrick C H, Lazarchick J, Stubbs T, Pittard W B. Mean platelet volume and platelet distribution width in the neonate.  Am J Pediatr Hematol Oncol . 1987;  9 130-132
    CrossrefPubMedGoogle Scholar
  • 11 Forestier F, Daffos F, Galacteros F, Bardakjian J, Rainaut M, Beuzard Y. Hematological values of 163 normal fetuses between 18 and 30 weeks of gestation.  Pediatr Res . 1986;  20 342-346
    PubMedGoogle Scholar
  • 12 Hohlfeld P, Forestier F, Kaplan C, Tissot J D, Daffos F. Fetal thrombocytopenia: a retrospective survey of 5194 fetal blood samplings.  Blood . 1994;  84 1851-1856
    PubMedGoogle Scholar
  • 13 Kipper S, Sieger L. Whole-blood platelet volumes in newborn infants.  J Pediatr . 1982;  101 763-766
    PubMedGoogle Scholar
  • 14 Arad I D, Alpan G, Sznajderman S D, Eldor A. The mean platelet volume (MPV) in the neonatal period.  Am J Perinatol . 1986;  3 1-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Clapp D W, Baley J E, Gerson S T. Gestational age-dependent changes in circulating hemopoietic stem cells in newborn infants.  J Lab Clin Med . 1989;  113 422-427
    PubMedGoogle Scholar
  • 16 Murray N A, Roberts I AG. Circulating megakaryocytes and their progenitors (BFU-MK and CFU-MK) in term and pre-term neonates.  Br J Haematol . 1995;  89 41-46
    PubMedGoogle Scholar
  • 17 Murray N A, Watts T L, Roberts I AG. Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies.  Pediatr Res . 1998;  43 148-151
    PubMedGoogle Scholar
  • 18 De Alarcon A P, Graeve J L. Analysis of megakaryocyte ploidy in fetal bone marrow biopsies using a new adaptation of the Feulgen technique to measure DNA content and estimate megakaryocyte ploidy from biopsy specimens.  Pediatr Res . 1996;  39 166-170
    PubMedGoogle Scholar
  • 19 Miyazaki R, Ogata H, Iguchi T. et al . Comparative analyses of megakaryoctyes derived from cord blood and bone marrow.  Br J Haematol . 2000;  108 602-609
    CrossrefPubMedGoogle Scholar
  • 20 Jilma-Stohlawetz P, Homoncik M, Jilma B. et al . High levels of reticulated platelets and thrombopoietin characterize fetal thrombopoiesis.  Br J Haematol . 2001;  112 466-468
    CrossrefPubMedGoogle Scholar
  • 21 Peterec S M, Brennan S A, Rinder H M, Wnek J L, Beardsley D S. Reticulated platelet values in normal and thrombocytopenic neonates.  J Pediatr . 1996;  129 269-274
    PubMedGoogle Scholar
  • 22 Joseph M A, Adams D, Maragos J, Saving K L. Flow cytometry of neonatal platelet RNA.  J Pediatr Hematol Oncol . 1996;  18 277-281
    CrossrefPubMedGoogle Scholar
  • 23 Kienast J, Schmitz G. Flow cytometric analysis of thiazole orange uptake by platelets: a diagnostic aid in the evaluation of thrombocytopenic disorders.  Blood . 1990;  75 116-121
    CrossrefPubMedGoogle Scholar
  • 24 Ault K A, Rinder H, Mitchell J, Carmody M B, Vary C PH, Hillman R S. The significance of platelets with increased RNA content (reticulated platelets): a measure of the rate of thrombopoiesis.  Am J Clin Pathol . 1992;  98 637-646
    CrossrefPubMedGoogle Scholar
  • 25 Sola M C, Juul S E, Li Y. et al . Thrombopoietin (Tpo) in the fetus and neonate: Tpo concentrations in preterm and term neonates, and organ distribution of Tpo and its receptor (c-mpl) during human fetal development.  Early Hum Dev . 1999;  53 239-250
    CrossrefPubMedGoogle Scholar
  • 26 Watts T L, Murray N A, Roberts I AG. Thrombopoietin has a primary role in the regulation of platelet production in preterm babies.  Pediatr Res . 1999;  46 28-32
    PubMedGoogle Scholar
  • 27 Sola M C, Calhoun D A, Hutson A D, Christensen R D. Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit.  Br J Haematol . 1999;  104 90-92
    CrossrefPubMedGoogle Scholar
  • 28 Albert T SE, Meng Y G, Simms P, Cohen R L, Phibbs R H. Thrombopoietin in the thrombocytopenic term and preterm newborn.  Pediatrics . 2000;  105 1286-1291
    CrossrefPubMedGoogle Scholar
  • 29 Oygur N, Tunga M, Mumcu Y. et al . Thrombopoietin levels of thrombocytopenic term and preterm newborns with infection.  Am J Perinatol . 2001;  18 279-286
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Matsubara K, Baba K, Nigami H. et al . Early elevation of serum thrombopoietin levels and subsequent thrombocytosis in healthy preterm infants.  Br J Haematol . 2001;  115 963-968
    CrossrefPubMedGoogle Scholar
  • 31 Traycoff C M, Abboud M R, Laver J. et al . Human umbilical cord blood hematopoietic progenitor cells: are they the same as their adult bone marrow counterparts?.  Blood Cells . 1994;  20 382-391
    PubMedGoogle Scholar
  • 32 Sola M C, Du Y, Hutson A D, Christensen R D. Dose-response relationship of megakaryocyte progenitors from the bone marrow of thrombocytopenic and non-thrombocytopenic neonates to recombinant thrombopoietin.  Br J Haematol . 2000;  110 449-453
    CrossrefPubMedGoogle Scholar
  • 33 Ts'ao C H, Green D, Schultz K. Function and ultrastructure of platelets of neonates: enhanced ristocetin aggregation of neonatal platelets.  Br J Haematol . 1976;  32 225-233
    PubMedGoogle Scholar
  • 34 Suarez C R, 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
    PubMedGoogle Scholar
  • 35 Saving K L, Jennings D E, Aldag J C, Caughey R C. Platelet ultrastructure of high-risk premature infants.  Thromb Res . 1994;  73 371-384
    CrossrefPubMedGoogle Scholar
  • 36 Saving K L, Aldag J, Jennings D, Caughey B, Regan M, Powers W. Electron microscopic characterization of neonatal platelet ultrastructure: effects of sampling techniques.  Thromb Res . 1991;  61 65-80
    PubMedGoogle Scholar
  • 37 Israels S J, Daniels M, McMillan E M. Deficient collagen-induced activation in the newborn platelet.  Pediatr Res . 1990;  27 337-343
    PubMedGoogle Scholar
  • 38 Gruel Y, Boizard B, Daffos F, Forestier F, Caen J, Wautier J L. Determination of platelet antigens and glycoproteins in the human fetus.  Blood . 1986;  68 488-492
    PubMedGoogle Scholar
  • 39 Shenkman B, Linder N, Savion N. et al . Increased neonatal platelet deposition on subendothelium under flow conditions: the role of plasma von Willebrand factor.  Pediatr Res . 1999;  45 270-275
    PubMedGoogle Scholar
  • 40 Corby D G, O'Barr T P. Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine.  Dev Pharmacol Ther . 1981;  2 215-225
    PubMedGoogle Scholar
  • 41 Davidson Ward L S, Schuetz S, Wachman L. et al . Elevated plasma norepinephrine levels in infants of substance-abusing mothers.  Am J Dis Child . 1991;  145 44-48
    PubMedGoogle Scholar
  • 42 Israels S J, Odaibo F S, Robertson C, McMillan E M, McNicol A. Deficient thromboxane synthesis and response in platelets from premature infants.  Pediatr Res . 1997;  41 218-223
    PubMedGoogle Scholar
  • 43 Corby D G, Zuck T F. Newborn platelet dysfunction: a storage pool and release defect.  Thromb Haemost . 1976;  36 200-207
    PubMedGoogle Scholar
  • 44 Whaun J M. The platelet of the newborn infant: 5-hydroxytryptamine uptake and release.  Thromb Diathes Haemorrhag . 1973;  30 327-333
    PubMedGoogle Scholar
  • 45 Whaun J M. Platelet function in the neonate: including qualitative platelet abnormalities associated with bleeding. In: Stockman JA, Pochedly C, eds. Developmental and Neonatal Hematology New York, NY: Raven 1988: 131-144
    Google Scholar
  • 46 Qutob M S, Conway A, Stein D T, Ohler S, Lachant N A, Gunning W T. Dense granule number and adenine nucleotide content in umbilical cord platelets (Abst).  Blood . 2002;  100 691a
    PubMedGoogle Scholar
  • 47 Mankin P, Maragos J, Akhand M, Saving K L. Impaired platelet dense granule release in neonates.  J Pediatr Hematol Oncol . 2000;  22 143-147
    CrossrefPubMedGoogle Scholar
  • 48 Israels S J, Gowen B, Gerrard J M. Contractile activity of neonatal platelets.  Pediatr Res . 1987;  21 293-295
    PubMedGoogle Scholar
  • 49 Andrew M, Castle V, Mitchell L, Paes B. Modified bleeding time in the infant.  Am J Hematol . 1989;  30 190-191
    PubMedGoogle Scholar
  • 50 Andrew M, Paes B, Bowker J, Vegh P. Evaluation of an automated bleeding time device in the newborn.  Am J Hematol . 1990;  35 275-277
    CrossrefPubMedGoogle Scholar
  • 51 Katz J A, Moake J L, McPherson P D. et al . Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma.  Blood . 1989;  73 1851-1858
    PubMedGoogle Scholar
  • 52 Weinstein M J, Blanchard R, Moake J L, 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
    CrossrefPubMedGoogle Scholar
  • 53 Gerrard J M, Docherty J C, Israels S J. 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;  12 165-171
    PubMedGoogle Scholar
  • 54 Kundu S K, Heilmann E J, Sio R, Garcia C, Ostgaard R A. Characterization of an in vitro platelet function analyzer, PFA-100;rM .  Clin Appl Thromb Hemost . 1996;  2 241-249
    CrossrefPubMedGoogle Scholar
  • 55 Favalaro E J, Facey D, Henniker A. Use of a novel platelet function analyzer (PFA-100™) with a high sensitivity to disturbances in von Willebrand factor to screen for von Willebrand's disease and other disorders.  Am J Hematol . 1999;  62 165-174
    CrossrefPubMedGoogle Scholar
  • 56 Fressinaud E, Veyradier A, Truchaud F. et al . Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases.  Blood . 1998;  91 1325-1331
    CrossrefPubMedGoogle Scholar
  • 57 Israels S J, Cheang T, McMillan-Ward E M, Houston D. Comparison of the PFA-100;rM platelet function analyzer and the template bleeding time in evaluation of patients with a clinical bleeding history (Abst).  Blood . 1999;  94(Suppl 1) 452a
    PubMedGoogle Scholar
  • 58 Carcao M D, Blanchette V S, Dean J A. et al . The platelet function analyzer (PFA-100;rM): a novel in vitro system for evaluation of primary haemostasis in children.  Br J Haematol . 1998;  101 70-73
    CrossrefPubMedGoogle Scholar
  • 59 Israels S J, Cheang T, McMillan-Ward E M, Cheang M. Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyzer.  J Pediatr . 2001;  138 116-119
    CrossrefPubMedGoogle Scholar
  • 60 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;  90 664-670
    PubMedGoogle Scholar
  • 61 Mull M M, Hathaway W E. Altered platelet function in newborns.  Pediatr Res . 1970;  4 229-237
    PubMedGoogle Scholar
  • 62 Corby D G, Schulman I. The effects of antenatal drug administration on aggregation of platelets of newborn infants.  J Pediatr . 1971;  79 307-313
    PubMedGoogle Scholar
  • 63 Corby D G, O'Barr T P. Neonatal platelet function: a membrane-related phenomenon?.  Haemostasis . 1981;  10 177-185
    PubMedGoogle Scholar
  • 64 Louden K A, Broughton Pipkin F, Heptinstall S. et al . Neonatal platelet reactivity and serum thromboxane B2 production in whole blood: the effect of maternal low-dose aspirin.  Br J Obstet Gynaecol . 1994;  101 203-208
    PubMedGoogle Scholar
  • 65 Israels S J, Andrew M. Neonatal haemostasis. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and Thrombosis 3rd ed. Edinburgh, Scotland: Churchill Livingstone 1994: 1017-1055
    Google Scholar
  • 66 Johnson S S, Montgomery R R, Hathaway W E. Newborn factor VIII complex: elevated activities in term infants and alterations in electrophoretic mobility related to illness and activated coagulation.  Br J Haemotol . 1981;  47 597-606
    PubMedGoogle Scholar
  • 67 Gatti L, Guarneri D, Caccamo M L, Gianotti G A, Marini A. Platelet activation in newborns detected by flow-cytometry.  Biol Neonate . 1996;  70 322-327
    PubMedGoogle Scholar
  • 68 Kuhne T, Ryan G, Blanchette V. et al . Platelet-surface glycoproteins in healthy and pre-eclamptic mothers and their newborn infants.  Pediatr Res . 1996;  40 876-880
    CrossrefPubMedGoogle Scholar
  • 69 Rajasekhar D, Kestin A S, Bednarek F J, Ellis P A, Barnard M R, Michelson A D. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood.  Thromb Haemost . 1994;  72 957-963
    PubMedGoogle Scholar
  • 70 Rajasekhar D, Barnard M R, Bednarek F J, Michelson A D. Platelet hyporeactivity in very-low-birth-weight neonates.  Thromb Haemost . 1997;  77 1002-1007
    PubMedGoogle Scholar
  • 71 Hezard N, Amory C, Leroux B, Schlegel N, Potron G, Nguyen P. Platelet hyporeactivity in healthy children remains beyond the neonatal period (Abst).  Blood . 2002;  100 69a
    PubMedGoogle Scholar
  • 72 Ichinose F, Uezono S, Muto R. et al . Platelet hyporeactivity in young infants during cardiopulmonary bypass.  Anesth Analg . 1999;  88 258-262
    PubMedGoogle Scholar
  • 73 Nicolini U, Guarneri D, Gianotti G A, Campagnoli C, Crosignani P G, Gatti L. Maternal and fetal platelet activation in normal pregnancy.  Obstet Gynecol . 1994;  83 65-69
    PubMedGoogle Scholar
  • 74 Grosshaupt B, Muntean W, Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth.  Eur J Pediatr . 1997;  156 944-948
    CrossrefPubMedGoogle Scholar
  • 75 Irken G, Uysal K M, Olgun N. et al . Platelet activation during the early neonatal period.  Biol Neonate . 1998;  73 166-171
    CrossrefPubMedGoogle Scholar
  • 76 Mannucci P M, Canciani T, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.  Blood . 2001;  98 2730-2735
    CrossrefPubMedGoogle Scholar
  • 77 Tsai H M, Sarode R, Downes K A. Ultralarge von Willebrand factor multimers and normal ADAMTS13 activity in the umbilical cord blood.  Thromb Res . 2002;  108 121-125
    CrossrefPubMedGoogle Scholar
  • 78 Schmugge M, Dunn M, Amankwah K, Blanchette V S, Freedman J, Rand M L. von Willebrand factor ultralarge multimers and the activity of the cleaving protease activity in healthy neonates and children (Abst).  J Pediatr Hematol Oncol . 2002;  24 A14
    CrossrefPubMedGoogle Scholar
  • 79 Fischer B E, Thomas K B, Dorner F. von Willebrand factor: measuring its antigen or function?.  <~>Correlation between the level of antigen, activity, and multimer size using various detection systems. Thromb Res . 1998;  91 39-43
    PubMedGoogle Scholar
  • 80 Linder N, Shenkman B, Levin E. et al . Deposition of whole blood platelets on extracellular matrix under flow conditions in preterm infants.  Arch Dis Child . 2002;  86 127-130
    CrossrefPubMedGoogle Scholar
  • 81 Stuart M J, Allen J B. Arachidonic acid metabolism in the neonatal platelet.  Pediatrics . 1982;  69 714-718
    PubMedGoogle Scholar
  • 82 Stuart M J, Dusse J, Clark D A, Walenga R W. Differences in thromboxane production between neonatal and adult platelets in response to arachidonic acid and epinephrine.  Pediatr Res . 1984;  18 823-826
    PubMedGoogle Scholar
  • 83 Stuart M J, Oski F A. Vitamin E and platelet function.  Am J Ped Hematol Oncol . 1979;  1 77-82
    PubMedGoogle Scholar
  • 84 Brass L F, Manning D R, Cichowski K, Abrams C S. Signaling through G proteins in platelets: to integrins and beyond.  Thromb Haemost . 1997;  78 581-589
    PubMedGoogle Scholar
  • 85 Israels S J, Cheang T, Robertson C, McMillan-Ward E M, McNicol A. Impaired signal transduction in neonatal platelets.  Pediatr Res . 1999;  45 687-691
    PubMedGoogle Scholar
  • 86 Gelman B, Setty B NY, Chen D, Amin-Hanjani S A, Stuart M J. Impaired mobilization of intracellular calcium in neonatal platelets.  Pediatr Res . 1996;  39 692-696
    PubMedGoogle Scholar
  • 87 Michelson A D, Rajasekhar D, Bednarek F J, Barnard M R. Platelet and platelet-derived microparticle surface factor V/Va binding in whole blood: differences between neonates and adults.  Thromb Haemost . 2000;  84 689-694
    PubMedGoogle Scholar
  • 88 Israels S J, McMillan-Ward E. Neonatal platelet procoagulant activity (Abst).  Blood . 2002;  100 78b
    PubMedGoogle Scholar
  • 89 Stuart M J, Dusse J. In vitro comparison of the efficacy of cyclo-oxygenase inhibitors on the adult versus neonatal platelet.  Biol Neonate . 1985;  47 265-269
    PubMedGoogle Scholar
  • 90 Bleyer W A, Brekenridge R T. Studies on the detection of adverse drug reactions in the newborn II. The effects of prenatal aspirin on newborn hemostasis.  JAMA . 1970;  213 2049-2053
    CrossrefPubMedGoogle Scholar
  • 91 Stuart M J, Gross S J, Elrad H, Graeber J E. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis.  N Engl J Med . 1982;  307 909-912
    PubMedGoogle Scholar
  • 92 Norton M E, Merrill J, Cooper B, Kullaer J, Clyman R I. Neonatal complications after the administration of indomethacin for preterm labor.  N Engl J Med . 1993;  329 1602-1607
    CrossrefPubMedGoogle Scholar
  • 93 Benigni A, Gregorini G, Frusca T. et al . Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension.  N Engl J Med . 1989;  321 357-362
    CrossrefPubMedGoogle Scholar
  • 94 Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review.  Br Med J . 2001;  322 329-333
    CrossrefPubMedGoogle Scholar
  • 95 Unsworth J, d'Assis-Fonseca A, Beswick D T, Blake D R. Serum salicylate levels in a breastfed infant.  Ann Rheum . 1987;  46 638-639
    PubMedGoogle Scholar
  • 96 Ylikorkala O, Halmesmaki E, Viinikka L. Effect of ethanol on thromboxane and prostacyclin synthesis by fetal platelets and umbilical artery.  Life Sci . 1987;  41 371-376
    CrossrefPubMedGoogle Scholar
  • 97 Cheung P Y, Salas E, Schulz R, Radomski M W. Nitric oxide and platelet function: implications for neonatology.  Semin Perinatol . 1997;  21 409-417
    PubMedGoogle Scholar
  • 98 Varels A F, Runge A, Ignano L J, Chandhuri G. Nitric oxide and prostacyclin inhibit fetal platelet aggregation: a response similar to that observed in adults.  Am J Obstet Gynecol . 1992;  167 1599-1604
    PubMedGoogle Scholar
  • 99 George T N, Johnson K J, Bates J N, Segar J L. The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates.  J Pediatr . 1998;  132 731-734
    PubMedGoogle Scholar
  • 100 Cheung P Y, Salas E, Etches P C, Phillipos E, Schulz R, Radomski M W. Inhaled nitric oxide and inhibition of platelet aggregation in critically ill neonates.  Lancet . 1998;  351 1181-1182
    PubMedGoogle Scholar
  • 101 Keh D, Kurer I, Dudenhausen J W, Woltmann W, Falke K J, Gerlach H. Response of neonatal platelets to nitric oxide in vitro.  Intensive Care Med . 2001;  27 283-286
    CrossrefPubMedGoogle Scholar
  • 102 Hoehn T, Krause M F, Buhrer C. Inhaled nitric oxide in premature infants-a meta-analysis.  J Perinat Med . 2000;  28 7-13
    CrossrefPubMedGoogle Scholar
  • 103 Israels, S J. Platelet function in the newborn. In: Michelson AD, ed. Platelets San Diego CA: Academic 2002: 267-272
    Google Scholar
      >