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

 

 Buy Article Permissions and Reprints

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.

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