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Semin Thromb Hemost 2009; 35(2): 181-188
DOI: 10.1055/s-0029-1220326
© Thieme Medical Publishers

Diagnostic Evaluation of Platelet Function Disorders in Neonates and Children: An Update

Sara J. Israels1 , 2 , 3
  • 1Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  • 2The Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada
  • 3Haemostasis Laboratory, Health Sciences Centre, Winnipeg, Manitoba, Canada
Further Information

Publication History

Publication Date:
30 April 2009 (online)

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ABSTRACT

Investigation of platelet function disorders in infants and small children requires the collaborative efforts of clinicians and clinical laboratories. A detailed personal, family, and medication history, and a search for additional clinical phenomena may help to direct diagnostic laboratory investigations. Testing for these disorders in young children presents several challenges: the requirement of relatively large volumes of blood, lack of standardization, and the absence of well-established age-specific reference ranges. Neonates show the most notable differences in platelet function compared to older children and adults; the decreased platelet activation responses persist for the first 2 to 4 weeks after delivery. Small studies of normal postneonatal pediatric populations have provided data on platelet function assays, including bleeding times, PFA-100 closure times, thromboelastography, aggregation, secretion, and flow cytometry. The majority of these studies, comparing normal children with adults, found only minor differences in platelet responses measured by these assays.

KEYWORDS

Platelet function - platelet disorders - platelet aggregation - newborn - child

REFERENCES

  • 1 Khair K, Liesner R. Bruising and bleeding in infants and children – a practical approach.  Br J Haematol. 2006;  133 221-231
    CrossrefPubMedGoogle Scholar
  • 2 Nosek-Cenkowska B, Cheang M S, Pizzi N J, Israels E D, Gerrard J M. Bruising/bleeding symptomatology in children with and without bleeding disorders.  Thromb Haemost. 1991;  65 237-241
    PubMedGoogle Scholar
  • 3 Katsanis E, Luki K-H, Hsu E, Li M, Lillicrap D. Prevalence and significance of mild bleeding disorders in children with recurrent epistaxis.  J Pediatr. 1988;  113 73-76
    CrossrefPubMedGoogle Scholar
  • 4 Hedlund-Treutiger I, Revel-Vilk S, Blanchette V S, Curtin J A, Lillicrap D, Rand M L. Reliability and reproducibility of classification of children as “bleeders” versus “non-bleeders” using a questionnaire for significant mucocutaneous bleeding.  J Pediatr Hematol Oncol. 2004;  26 488-491
    CrossrefPubMedGoogle Scholar
  • 5 Biss T T, Blanchette V, Bowman M et al.. Quantitation of bleeding symptoms in children with von Willebrand disease (VWD) or a platelet function disorder: use of a standardized pediatric bleeding score.  Blood. 2007;  110 2137 [abstract]
    PubMedGoogle Scholar
  • 6 Israels S J, Daniels M, McMillan E M. Deficient collagen-induced activation in the newborn platelet.  Pediatr Res. 1990;  27 337-343
    PubMedGoogle Scholar
  • 7 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
  • 8 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
  • 9 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
  • 10 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
  • 11 Carcao M D, Blanchette V S, Dean J A 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 70-73
    CrossrefPubMedGoogle Scholar
  • 12 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
  • 13 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
  • 14 Stuart M J, Allen J B. Arachidonic acid metabolism in the neonatal platelet.  Pediatrics. 1982;  69 714-718
    PubMedGoogle Scholar
  • 15 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
  • 16 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
  • 17 Michelson A D. Platelet function in the newborn.  Semin Thromb Hemost. 1998;  24 507-512
    PubMedGoogle Scholar
  • 18 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
  • 19 Ucar T, Gurman C, Arsan S, Kemahli S. Platelet aggregation in term and preterm newborns.  Pediatr Hematol Oncol. 2005;  22 139-145
    CrossrefPubMedGoogle Scholar
  • 20 Sitaru A G, Holzhauer S, Speer C P et al.. Neonatal platelets from cord blood and peripheral blood.  Platelets. 2005;  16 203-210
    CrossrefPubMedGoogle Scholar
  • 21 Hezard N, Potron G, Schlegel N, Amory C, Leroux B, Nguyen P. Unexpected persistence of platelet hyporeactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children.  Thromb Haemost. 2003;  90 116-123
    PubMedGoogle Scholar
  • 22 Ichinose F, Uezono S, Muto R et al.. Platelet hyporeactivity in young infants during cardiopulmonary bypass.  Anesth Analg. 1999;  88 258-262
    PubMedGoogle Scholar
  • 23 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
  • 24 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
  • 25 Kipper S L, Sieger L. Whole blood platelet volumes in newborn infants.  J Pediatr. 1982;  101 763-766
    PubMedGoogle Scholar
  • 26 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
  • 27 Witkop C J, Krumwiede M, Sedano H, White J G. Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome.  Am J Hematol. 1987;  26 305-311
    PubMedGoogle Scholar
  • 28 White J G, Krumwiede M. Some contributions of electron microscopy to knowledge of human platelets.  Thromb Haemost. 2007;  98 69-72
    PubMedGoogle Scholar
  • 29 Saving K, 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
  • 30 Andrew M, Castle V, Mitchell L, Paes B. Modified bleeding time in the infant.  Am J Hematol. 1989;  30 190-191
    PubMedGoogle Scholar
  • 31 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
  • 32 Del Vecchio A. Use of the bleeding time in the neonatal intensive care unit.  Acta Paediatr Suppl. 2002;  91 82-86
    PubMedGoogle Scholar
  • 33 Del Vecchio A, Ltina G, Henry E, Christensen R D. Template bleeding times of 240 neonates born at 24 to 41 weeks gestation.  J Perinatol. 2008;  28 427-431
    CrossrefPubMedGoogle Scholar
  • 34 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
  • 35 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
  • 36 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
  • 37 Sola M C, del Vecchio A, Edwards T J, Suttner D, Hutson A D, Christensen R D. The relationship between hematocrit and bleeding time in very low birth weight infants during the first week of life.  J Perinatol. 2001;  21 368-371
    CrossrefPubMedGoogle Scholar
  • 38 Kundu S K, Heilmann E J, Sio R, Garcia C, Ostgaard R A. Characterization of an in vitro platelet function analyzer, PFA-100® .  Clin Appl Thromb Hemost. 1996;  2 241-249
    CrossrefPubMedGoogle Scholar
  • 39 Favaloro 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
  • 40 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
  • 41 Israels S J, Cheang T, McMillan-Ward E M, Houston D. Comparison of the PFA-100® platelet function analyzer and the template bleeding time in evaluation of patients with a clinical bleeding history.  Blood. 1999;  94(Suppl 1) 452 [abstract]
    PubMedGoogle Scholar
  • 42 Carcao M D, Blanchette V S, Dean J A 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 70-73
    CrossrefPubMedGoogle Scholar
  • 43 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
  • 44 Boudewijns M, Raes M, Peeters V 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;  162 212-213
    PubMedGoogle Scholar
  • 45 Lippi G, Manzato F, Franchini M, Brocco G, Florenziani G, Guidi G. Establishment of reference values for the PFA-100 platelet function analyzer in pediatrics.  Clin Exp Med. 2001;  1 69-70
    CrossrefPubMedGoogle Scholar
  • 46 Perel J M, Just S, Rowell J, Williams B, Kennedy G A. Utility of the PFA-100 analyser in the evaluation of primary haemostasis in a paediatric population.  Int J Lab Hematol. 2007;  29 480-481
    CrossrefPubMedGoogle Scholar
  • 47 Hayward C PM, Harrison P, Cattaneo M, Ortel T L, Rao A K. Platelet function analyzer (PFA)-100® closure time in the evaluation of platelet disorders and platelet function.  J Thromb Haemost. 2006;  4 312-319
    CrossrefPubMedGoogle Scholar
  • 48 Roschitz B, Thaller S, Koestenberger M et al.. PFA-100 closure times in preoperative screening in 500 pediatric patients.  Thromb Haemost. 2007;  98 243-247
    PubMedGoogle Scholar
  • 49 Harrison P. The role of PFA-100® testing in the investigation and management of haemostatic defects in children and adults.  Br J Haematol. 2005;  130 3-10
    CrossrefPubMedGoogle Scholar
  • 50 Cariappa R, Wilhite T R, Parvin C A, Luchtman-Jones L. Comparison of PFA-100 and bleeding time testing in pediatric patients with suspected hemorrhagic problems.  J Pediatr Hematol Oncol. 2003;  25 474-479
    CrossrefPubMedGoogle Scholar
  • 51 Hanebutt F L, Rolf N, Loesel A, Kuhlisch E, Siegert G, Knoefler R. Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders.  Haemophilia. 2008;  14 524-530
    CrossrefPubMedGoogle Scholar
  • 52 Pivalizza E G, Pivalizza P J, Gottschalk L I, Kee S, Szmuk P, Abramson D C. Celite-activated thromboelastography in children.  J Clin Anesth. 2001;  13 20-23
    CrossrefPubMedGoogle Scholar
  • 53 Rajwal S, Richards M, O'Meara M. The use of recalcified citrated whole blood—a pragmatic approach for thromboelastography in children.  Paediatr Anaesth. 2004;  14 656-660
    PubMedGoogle Scholar
  • 54 Yee D L, Edwards R M, Mueller B U, Teruya J. Thromboelastographic and hemostatic characteristics in pediatric patients with sickle cell disease.  Arch Pathol Lab Med. 2005;  129 760-765
    PubMedGoogle Scholar
  • 55 Chan K L, Summerhayes R G, Ignajavtovic V, Horton S B, Monagle P T. Reference values for kaolin-activated thromboelastography in healthy children.  Anesth Analg. 2007;  105 1610-1613
    CrossrefPubMedGoogle Scholar
  • 56 Miller B E, Bailey J M, Mancuso T J et al.. Functional maturity of the coagulation system in children: an evaluation using thrombelastography.  Anesth Analg. 1997;  84 745-748
    CrossrefPubMedGoogle Scholar
  • 57 Kettner S C, Pollak A, Zimpfer M et al.. Heparinase-modified thrombelastography in term and preterm neonates.  Anesth Analg. 2004;  98 1650-1652
    PubMedGoogle Scholar
  • 58 Varon D, Dardik R, Shenkman B et al.. A new method for quantitative analysis of whole blood platelet interaction with the extracellular matrix under flow conditions.  Thromb Res. 1997;  85 283-294
    CrossrefPubMedGoogle Scholar
  • 59 Levy-Shraga Y, Maayan-Metzber A, Lubtsky A et al.. Platelet function of newborns as tested by cone and plate(let) analyzer correlates with gestational age.  Acta Haematol. 2006;  115 152-156
    CrossrefPubMedGoogle Scholar
  • 60 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
  • 61 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 Fetal Neonatal Ed. 2002;  86 F127-F130
    CrossrefPubMedGoogle Scholar
  • 62 Mull M M, Hathaway W E. Altered platelet function in newborns.  Pediatr Res. 1970;  4 229-237
    PubMedGoogle Scholar
  • 63 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
  • 64 Corby D G, O'Barr T P. Neonatal platelet function: a membrane-related phenomenon?.  Haemostasis. 1981;  10 177-185
    PubMedGoogle Scholar
  • 65 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
  • 66 Israels S J, Andrew M. Neonatal hemostasis. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD Haemostasis and Thrombosis, 3rd ed. Edinburgh, United Kingdom; Churchill Livingstone 1994: 1017-1055
    Google Scholar
  • 67 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 Haematol. 1981;  47 597-606
    PubMedGoogle Scholar
  • 68 Bonduel M, Frontroth J P, Hepner M, Sciuccati G, Feliu-Torres A. Platelet aggregation and adenosine triphosphate release values in children and adults.  J Thromb Haemost. 2007;  5 1782-1787
    CrossrefPubMedGoogle Scholar
  • 69 Kuhne T, Ryan G, Blanchette V et al.. Platelet-surface glycoproteins in healthy and preeclamptic mothers and their newborn infants.  Pediatr Res. 1996;  40 876-880
    CrossrefPubMedGoogle Scholar
  • 70 Gunay-Aygun M, Huizing M, Gahl W A. Molecular defects that affect platelet dense granules.  Semin Thromb Hemost. 2004;  30 537-547
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Nurden P, Nurden A T. Congenital disorders associated with platelet dysfunctions.  Thromb Haemost. 2008;  99 253-263
    PubMedGoogle Scholar
  • 72 Walker M, Payne J, Wagner B, Vora A. Hermansky-Pudlak syndrome.  Br J Haematol. 2007;  138 671
    CrossrefPubMedGoogle Scholar
  • 73 Hayward C P. Diagnostic approach to platelet function disorders.  Transfus Apher Sci. 2008;  38 65-76
    CrossrefPubMedGoogle Scholar
  • 74 Litalien C, Jacqz-Aigrain E. Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol.  Paediatr Drugs. 2001;  3 817-858
    CrossrefPubMedGoogle Scholar
  • 75 Acharya S, Bussel J B. Hematologic toxicity of sodium valproate.  J Pediatr Hematol Oncol. 2000;  22 62-65
    CrossrefPubMedGoogle Scholar
  • 76 Koenig S, Gerstner T, Keller A, Teich M, Longin E, Dempfle C E. High incidence of valproate-induced coagulation disorders in children receiving valproic acid: a prospective study.  Blood Coagul Fibrinolysis. 2008;  19 375-382
    CrossrefPubMedGoogle Scholar
  • 77 Halperin D, Reber G. Influence of anti-depressants on hemostasis.  Dialogues Clin Neurosci. 2007;  9 47-59
    PubMedGoogle Scholar
  • 78 Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure.  Semin Thromb Hemost. 2004;  30 579-589
    Article in Thieme ConnectPubMedGoogle Scholar
  • 79 Gerrard J M, McNicol A. Platelet storage pool deficiency, leukemia, and myelodysplastic syndromes.  Leuk Lymphoma. 1992;  8 277-281
    CrossrefPubMedGoogle Scholar
  • 80 Manoharan A, Brighton T, Gemmell R, Lopez K, Moran S, Kyle P. Platelet dysfunction in myelodysplastic syndromes: a clinicopathological study.  Int J Hematol. 2002;  76 272-278
    CrossrefPubMedGoogle Scholar
  • 81 Gurbel P A, Becker R C, Mann K G, Steinhubl S R, Michelson A D. Platelet function monitoring in patients with coronary artery disease.  J Am Coll Cardiol. 2007;  50 1822-1834
    CrossrefPubMedGoogle Scholar
  • 82 Yee D L, Dinu B R, Sun C W et al.. Low prevalence and assay discordance of “aspirin resistance” in children.  Pediatr Blood Cancer. 2008;  51 86-92
    CrossrefPubMedGoogle Scholar
  • 83 Li J S, Yow E, Berezny K Y et al.. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial.  Circulation. 2008;  117 553-559
    CrossrefPubMedGoogle Scholar

Dr. Sara J Israels

Pediatric Hematology/Oncology, CancerCare Manitoba

675 McDermot Ave., Winnipeg, Manitoba, Canada, R3E 0V9

Email: israels@cc.umanitoba.ca