Blood Reviews
Volume 22, Issue 4 , Pages 173-186 , July 2008

Thrombocytopenia in the Neonate

  • Irene Roberts

      Affiliations

    • Professor of Paediatric Haematology and Honorary Consultant Paediatric Haematologist, Imperial College, London
    • Corresponding Author InformationCorresponding author. Tel.: +44 208 383 2163; fax: +44 208 742 9335.
  • ,
  • Simon Stanworth

      Affiliations

    • Consultant Haematologist, National Blood Service and Honorary Consultant Paediatric Haematologist, Oxford Radcliffe Hospitals, Oxford, UK
  • ,
  • Neil A Murray

      Affiliations

    • Senior Clinical Research Associate National Blood Service, Oxford, John Radcliffe Hospital, Headington, Oxford, UK

References 

  1. Murray NA, Howarth LJ, McCloy MP, et al. Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med. 2002;12:35–41
  2. Garcia MG, Duenas E, Sola MC, et al. Epidemiologic and outcome studies of patients who received platelet transfusions in the neonatal intensive care unit. J Perinatol. 2001;21:415–420
  3. Del Vecchio A, Sola MC, Theriaque DW, et al. Platelet transfusions in the neonatal intensive care unit: factors predicting which patients will require multiple transfusions. Transfusion. 2001;41:803–808
  4. Bonifacio L, Petrova A, Nanjundaswamy S, Mehta R. Thrombocytopenia related neonatal outcome in preterms. Indian J Pediatr. 2007;74:269–274
  5. Kenton AB, Hegemier S, Smith EO, et al. Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity. J Perinatol. 2005;25:173–177
  6. Pahal G, Jauniaux E, Kinnon C, Thrasher AJ, Rodeck CH. Normal development of human fetal hematopoiesis between eight and seventeen weeks’ gestation. Am J Obstet Gynecol. 2000;183:1029–1034
  7. Holmberg L, Gustavii B, Jonsson A. A prenatal study of fetal platelet count and size with application to the fetus at risk of Wiskott Aldrich syndrome. J Pediatr. 1983;102:773–781
  8. Forestier F, Daffos F, Galacteros F. Haematological values of 163 normal fetuses between 18 and 30 weeks of gestation. Pediatr Res. 1986;20:342–346
  9. Forestier F, Daffos F, Catherine N, Renard M, Andreux JP. Developmental hematopoiesis in normal human fetal blood. Blood. 1991;77:2360–2363
  10. Burrows RF, Kelton JG. Incidentally detected thrombocytopenia in healthy mothers and their infants. N Engl J Med. 1988;319:142–145
  11. Burrows RF, Kelton JG. Thrombocytopenia at delivery: A prospective survey of 6715 deliveries. Am J Obstet Gynecol. 1990;162:731–734
  12. Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med. 1993;329:1463–1466
  13. Sainio S, Jarvenpaa A-S, Renlund M, et al. Thrombocytopenia in term infants: A population-based study. Obstet Gynecol. 2000;95:441–446
  14. Christensen RD, Henry E, Wiedmeier SE, et al. Thrombocytopenia among extremely low birth weight neonates: data from a multihospital healthcare system. J Perinatol. 2006;26:348–353
  15. Castle V, Andrew M, Kelton J, et al. Frequency and mechanism of neonatal thrombocytopenia. J Pediatr. 1986;108:749–755
  16. Mehta P, Rohitkumar V, Neumann L, Karpatkin M. Thrombocytopenia in the high risk infant. J Pediatr. 1980;97:791–794
  17. Murray NA, Roberts IAG. Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res. 1996;40:112–119
  18. Watts TL, Roberts IAG. Haematological abnormalities in the growth-restricted infant. Semin Neonatol. 1999;4:41–54
  19. Roberts IAG, Murray NA. Neonatal thrombocytopenia: new insights into pathogenesis and implications for clinical management. Curr Opin Pediatr. 2001;13:16–21
  20. Watts TL, Murray NA, Roberts IAG. Thrombopoietin has a primary role in the regulation of platelet production in preterm babies. Pediatr Res. 1999;46:28–32
  21. Salvesen DR, Brudenell JM, Snijders RJ, Ireland RM, Nicolaides KH. Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Am J Obstet Gynecol. 1993;168:88–94
  22. Ghevaert C, Campbell K, Walton J, et al. Management and outcome of 200 cases of fetomaternal alloimmune thrombocytopenia. Transfusion. 2007;47:901–910
  23. Ouwehand WH, Smith G, Ranasinghe E. Management of severe alloimmune thrombocytopenia in the newborn. Arch Dis Child Fetal Neonatal Ed. 2000;82:F173–F175
  24. Bussel JB, Primiani A Fetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates. Blood Rev. 2007 Nov 2 [Epub ahead of print].
  25. Williamson LM, Hackett G, Rennie J, et al. The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood. 1998;92:2280–2287
  26. Mueller-Eckhardt C, Kiefel V, Grubert A, Kroll H, Weisheit M, Schmidt S, et al. 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet. 1989;1(8634):363–366
  27. Bussel JB, Zacharoulis S, Kramer K, et al. Clinical and diagnostic comparison of neonatal alloimmune thrombocytopenia to non-immune cases of thrombocytopenia. Pediatr Blood Cancer. 2005;45:176–183
  28. Giovangrandi Y, Daffos F, Kaplan C, et al. Very early intracranial haemorrhage in alloimmune fetal thrombocytopenia. Lancet. 1990;336(8710):310
  29. Bussel JB, Zabusky MR, Berkowitz RL, McFarland JG. Fetal alloimmune thrombocytopenia. N Engl J Med. 1997;337:22–26
  30. Singh SA, Pollard J, Singhal N. Fetomaternal alloimmune thrombocytopenia presenting as intracerebral bleeding in utero. Indian J Pediatr. 2005;72(3):269;Mar
  31. Sharif U, Kuban K. Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia. J Child Neurol. 2001;16:838–842
  32. te Pas AB, Lopriore E, van den Akker ES, et al. Postnatal management of fetal and neonatal alloimmune thrombocytopenia: the role of matched platelet transfusion and IVIG. Eur J Pediatr. 2007;166:1057–1063
  33. Ward MJ, Pauliny J, Lipper EG, Bussel JB. Long-term effects of fetal and neonatal alloimmune thrombocytopenia and its antenatal treatment on the medical and developmental outcomes of affected children. Am J Perinatol. 2006;23:487–492
  34. van den Akker ES, Oepkes D. Fetal and neonatal alloimmune thrombocytopenia. Best Pract Res Clin Obstet Gynaecol 2007 Oct 11; [Epub ahead of print].
  35. Murphy MF, Bussel JB. Advances in the management of alloimmune thrombocytopenia. Br J Haematol. 2007;136(3):366–378Feb
  36. Overton TG, Duncan KR, Jolly M, Letsky E, Fisk NM. Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol. 2002;186:826–831
  37. Berkowitz RL, Kolb EA, McFarland JG, et al. Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet Gynecol. 2006;107:91–96
  38. van den Akker ES, Oepkes D, Lopriore E, Brand A, Kanhai HH. Noninvasive antenatal management of fetal and neonatal alloimmune thrombocytopenia: safe and effective. BJOG. 2007;114:469–473
  39. Campbell K, Rishi K, Howkins G, Gilby D, Mushens R, Ghevaert C, et al. A modified rapid monoclonal antibody-specific immobilization of platelet antigen assay for the detection of human platelet antigen (HPA) antibodies: a multicentre evaluation. Vox Sanguinis. 2007;93:289–297
  40. Ghevaert C, Campbell K, Stafford P, Metcalfe P, Casbard A, Smith G, et al. HPA-1a antibody potency and bioactivity do not predict severity of fetomaternal alloimmune thrombocytopenia. Transfusion. 2007;47:1296–1305
  41. Bassler D, Greinacher A, Okascharoen C, et al. A systematic review and survey of the management of unexpected neonatal alloimmune thrombocytopenia. Transfusion. 2008;48:92–98
  42. Allen D, Verjee S, Rees S, Murphy MF, Roberts DJ. Platelet transfusion in neonatal alloimmune thrombocytopenia. Blood. 2007;109:388–389
  43. Kiefel V, Bassler D, Kroll H, Paes B, et al. Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT). Blood. 2006;107:3761–3763
  44. Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol. 2000;37:275–289
  45. George D, Bussel JB. Neonatal thrombocytopenia. Semin Thromb Hemost. 1995;21:276–293
  46. Kelton JGC. Idiopathic thrombocytopenic purpura complicating pregnancy. Blood Rev. 2002;16:43–46
  47. Bussel JB. Immune thrombocytopenia in pregnancy: autoimmune and alloimmune. J Reprod Immunol. 1997;37:35–61
  48. Payne SD, Resnik R, Moore TR, Hedriana HL, Kelly TF. Maternal characteristics and risk of severe neonatal thrombocytopenia and intracranial hemorrhage in pregnancies complicated by autoimmune thrombocytopenia. Am J Obstet Gynecol. 1997;177:149–155
  49. Valat AS, Caulier MT, Devos P, Rugeri L, Wibaut B, Vaast P, et al. Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia. Br J Haematol. 1998;103:397–401
  50. Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003;102:4306–4311
  51. Burrows RF, Kelton JG. Low fetal risks in pregnancies associated with idiopathic thrombocytopenic purpura. Am J Obstet Gynecol. 1990;163:1147–1150
  52. Ballin A, Andrew M, Ling E, Perlman M, Blanchette V. High dose intravenous gammaglobulin therapy for neonatal idiopathic autoimmune thrombocytopenia. J Pediatr. 1988;112:789–792
  53. Hohlfeld P, Forestier F, Kaplan C, Tissot JD, Daffos F. Fetal thrombocytopenia: a retrospective survey of 5,194 fetal blood samplings. Blood. 1994;84:1851–1856
  54. Sahoo T, Naeem R, Pham K, Chheng S, Noblin ST, Bacino CA, et al. A patient with isochromosome 18q, radial-thumb aplasia, thrombocytopenia, and an unbalanced 10;18 chromosome translocation. Am J Med Genet. 2005;133A:93–98
  55. Webb D, Roberts I, Vyas P. The haematology of Down syndrome. Arch Dis Child. 2007;
  56. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32:148–152
  57. Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood. 2003;101:4301–4304
  58. Groet J, McElwaine S, Spinelli M, et al. Acquired mutations in GATA1 in neonates with Down’s syndrome with transient myeloid disorder. Lancet. 2003;361:1617–1620
  59. Rainis L, et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood. 2003;102:981–986
  60. Xu G, et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood. 2003;102:2960–2968
  61. Ahmed M, Sternberg A, Hall G, Thomas A, Smith O, O’Marcaigh A, et al. Natural history of GATA1 mutations in Down syndrome. Blood. 2004;103:2480–2489
  62. Tunstall-Pedoe J, delaFuente P, Bennett NM, Fisk P, Vyas IAG, Roberts . Trisomy 21 expands the megakaryocyte-erythroid progenitor compartment in human fetal liver-implications for Down syndrome AMKL. Blood. 2006;108:170a
  63. Balduini CL, Savoia A. Inherited thrombocytopenias: molecular mechanisms. Semin Thromb Hemost. 2004;30:513–523
  64. Geddis AE, Kauchansky K. Inherited thrombocytopenias: toward a molecular understanding of disorders of platelet production. Curr Opin Pediatr. 2004;16:15–22
  65. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood. 1998;91:4397–4418
  66. Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Haematol. 2002;76:319–327
  67. Simsek S, Admiraal LG, Modderman PW, van der Schoot CE, von dem Borne AE. Identification of a homozygous single base pair deletion in the gene coding for the human platelet glycoprotein Ib alpha causing Bernard-Soulier syndrome. Thromb Haemost. 1994;72:444–449
  68. Fujimori K, Ohto H, Honda S, Sato A. Antepartum diagnosis of fetal intracranial hemorrhage due to maternal Bernard-Soulier syndrome. Obstet Gynecol. 1999;94:817–819
  69. Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, et al. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 1995;9:414–417
  70. Lutskiy MI, Rosen FS, Remold-O’Donnell E. Genotype-proteotype linkage in the Wiskott-Aldrich syndrome. J Immunol. 2005;175:1329–1336
  71. Ochs H. The Wiskott-Aldrich syndrome. Semin Hematol. 1998;35:332–345
  72. Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111:5 Pt 1
  73. Faivre L, Guardiola P, Lewis C, et al. Association of complementation group and mutation type with clinical outcome in Fanconi anemia. Blood. 2000;96:4064–4070
  74. Gershanik JJ, Morgan SK, Akers R. Fanconi’s anemia in a neonate. Acta Paediatr Scand. 1972;61:623–625
  75. Gibson BES. Inherited disorders. In:  Hann IM,  Gibson BES,  Letsky E editor. Fetal and Neonatal Haematology. 1st ed.. London: Bailliere Tindall; 1991;p. 219–275
  76. Landmann E, Bluetters-Sawatzki R, Schindler D, Gortner L. Fanconi anemia in a neonate with pancytopenia. J Pediatr. 2004;145:125–127
  77. Auerbach AD, Rogatko A, Schroeder-Kurth TM. International Fanconi anemia registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood. 1989;73:391–396
  78. Dokal I, Vulliamy T. Inherited aplastic anaemias/bone marrow failure syndromes. Blood Rev. 2007;Epub Dec 28th
  79. Hedberg VA, Lipton JM. Thrombocytopenia with absent radii: A review of 100 cases. Am J Pediatr Hematol Oncol. 1988;10:51–64
  80. Hall JG. Thrombocytopenia and absent radius (TAR) syndrome. J Med Genet. 1987;24:79–83
  81. Greenhalgh KL, Howell RT, Bottani A, et al. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002;39:876–881
  82. Ballmaier M, Schulze H, Strauss G, et al. Thrombopoietin in patients with congenital thrombocytopenia and absent radii: elevated serum levels, normal receptor expression, but defective reactivity to thrombopoietin. Blood. 1997;90:612–619
  83. al-Jefri AH, Dror Y, Bussel JB, et al. Thrombocytopenia with absent radii: frequency of marrow megakaryocyte progenitors, proliferative characteristics, and megakaryocyte growth and development factor responsiveness. Pediatr Hematol Oncol. 2000;17:299–306
  84. Letestu R, Vitrat N, Masse A, et al. Existence of a differentiation blockage at the stage of a megakaryocyte precursor in the thrombocytopenia and absent radii (TAR) syndrome. Blood. 2000;95:1633–1641
  85. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nature Genetics. 2000;26:397–398
  86. Thompson AA, Woodruff K, Feig SA, et al. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome. Br J Haematol. 2001;113:866–870
  87. Freedman MH, Doyle JJ. Inherited bone marrow failure syndromes. In:  Lilleyman JS,  Hann IM,  Blanchette VS editor. Pediatric Hematology. London: Churchill Livingstone; 1999;p. 23–49
  88. Lackner A, Basu O, Bierings M, et al. Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia. Br J Haematol. 2000;109:773–775
  89. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA. 1999;96:3132–3136
  90. van den Oudenrijn S, Bruin M, Folman CC, et al. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol. 2000;110:441–448
  91. Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, et al. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001;97:139–146
  92. Tonelli R, Scardovi AL, Pession A, et al. Compound heterozygosity for two different amino-acid substitutions in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). Hum Genet. 2000;107:225–233
  93. Muraoka K, Ishii E, Tsuji K, et al. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol. 1997;96:287–292
  94. Freson K, Devriendt K, Matthijs G, et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood. 2001;98:85–92
  95. Mehaffey MG, Newton AL, Gandhi MJ, et al. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood. 2001;98:2681–2688
  96. Noris P, Spedini P, Belletti S, et al. Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May-Hegglin anomaly): clinical and laboratory findings. Am J Med. 1998;104:355–360
  97. Takashima T, Maeda H, Koyanagi T, et al. Prenatal diagnosis and obstetrical management of May-Hegglin anomaly: a case report. Fetal Diagn Ther. 1992;7:186–189
  98. Urato AC, Repke JT. May-Hegglin anomaly: a case of vaginal delivery when both mother and fetus are affected. Am J Obstet Gynecol. 1998;179:260–261
  99. Kelley MJ, Jawian W, Ortel TL, Korczak KF. Mutation of MY H9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nat Genet. 2000;26:106–108
  100. Toren A, Rozenfeld-Granot G, Rocca B, et al. Autosomal-dominant giant platelet syndromes: a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13. Blood. 2000;96:3447–3451
  101. Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol. 2001;112:851–862
  102. Haisley-Royster C, Enjolas O, Frieden IJ, et al. Kasabach-Merritt phenomenon: a retrospective study of treatment with vincristine. J Pediatr Hematol Oncol. 2002;24:459–462
  103. Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol. 2000;42:225–235
  104. Pampin C, Devillers A, Treguier C. Intratumoral consumption of indium-111-labeled platelets in a child with splenic hemangioma and thrombocytopenia. J Pediatr Hematol Oncol. 2000;22:256–258
  105. Seo SK, Suh JC, Na GY. Kasabach-Merritt syndrome: identification of platelet trapping in a tufted angioma by immunohistochemistry technique using monoclonal antibody to CD61. Pediatr Dermatol. 1999;16:392–394
  106. Jubinsky PT, Moraille R, Tsai HM. Thrombotic thrombocytopenic purpura in a newborn. J Perinatol. 2003;23:85–87
  107. Schiff DE, Roberts WD, Willert J, Tsai HM. Thrombocytopenia and severe hyperbilirubinemia in the neonatal period secondary to congenital thrombotic thrombocytopenic purpura and ADAMTS13 deficiency. J Pediatr Hematol Oncol. 2004;26:535–538
  108. Berner R, Krause MF, Gordjani N, et al. Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis. Pediatr Nephrol. 2002;17:190–192
  109. Spadone D, Clark F, James E, et al. Heparin-induced thrombocytopenia in the newborn. J Vasc Surg. 1992;15:306–311
  110. Ranze O, Ranze P, Magnani HN, Greinacher A. Heparin-induced thrombocytopenia in paediatric patients--a review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr. 1999;158:S130–S133
  111. Frost J, Mureebe L, Russo P, et al. Pediatr Crit Care Med. 2005;6:216–219
  112. Marks SD, Massocote MP, Steele BT, et al. Neonatal renal venous thrombosis: clinical outcomes and prevalence of prothrombotic disorders. J Pediatr. 2005;146:811–816
  113. Burlina AB, Bonafe L, Zacchello F. Clinical and biochemical approach to the neonate with a suspected inborn error of amino acid and organic acid metabolism. Semin Perinatol. 1999;23:162–173
  114. Gilbert-Barness E, Barness LA. Isovaleric acidemia with promyelocytic myeloproliferative syndrome. Pediatr Dev Pathol. 1999;2:286–291
  115. Roth P, Sklower Brooks S, Potaznik D, et al. Neonatal Gaucher disease presenting as persistent thrombocytopenia. J Perinatol. 2005;25:356–358
  116. Debillon T, Daoud P, Durand P, et al. Whole-body cooling after perinatal asphyxia: a pilot study in term neonates. Dev Med Child Neurol. 2003;45:17–23
  117. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32:18–24
  118. Andrew M, Castle V, Saigal S, et al. Clinical impact of neonatal thrombocytopenia. J Pediatr. 1987;110:457–464
  119. Murray N, Ballard S, Casbard A, et al. A multi-centre prospective observational study of platelet transfusion practice in neonates with severe thrombocytopenia. Blood. 2006;108:287a
  120. Andrew M, Vegh P, Caco C. A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr. 1993;123:285–291
  121. www.bcshguidelines.com.
  122. Josephson CD, Su LL, Christensen RD, et al. Platelet transfusion practice among neonatologists in the U.S. and Canada: Results of a survey. Transfusion 2006; 46: Abstract S19-030E.

PII: S0268-960X(08)00023-4

doi: 10.1016/j.blre.2008.03.004

Blood Reviews
Volume 22, Issue 4 , Pages 173-186 , July 2008