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DOI: 10.1055/s-2001-15251
Thrombopoietin in Thrombocytopenias of Childhood
Publication History
Publication Date:
31 December 2001 (online)
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ABSTRACT
This review summarizes the biology of thrombopoietin (TPO) in childhood. Studies on TPO and its receptor (c-mpl) have improved the understanding of inherited and acquired thrombocytopenias in childhood. Data are presented in this review regarding the molecular biology of TPO, differences in cellular effects on megakaryopoiesis, the regulation of TPO production, and TPO concentrations in health and disease. For neonatal thrombocytopenia, the focus is on early-onset thrombocytopenia associated with maternal diabetes, pregnancy-induced hypertension, intrauterine growth retardation, hypoxia, and sepsis. Fetal alloimmune thrombocytopenia allows insight into the biology of TPO when fetal megakaryopoiesis is chronically stimulated. In the thrombocytopenia absent radii syndrome and congenital amegakaryocytic thrombocytopenia, thrombocytopenia is caused by a disorder in the signal transduction at the c-mpl level and respectively directly on c-mpl. TPO concentrations in other inherited thrombocytopenias such as Fanconi anemia, Shwachman syndrome, Wiskott-Aldrich syndrome, and Bernard-Soulier syndrome are discussed. For acquired thrombocytopenias, data on TPO in aplastic anemia, immune thrombocytopenia, human immunodeficiency virus infection, and liver disease are given. Possible indications for a treatment with recombinant TPO in childhood are discussed, but the criteria to identify patients who would benefit need detailed evaluation.
KEYWORD
Thrombopoietin - c-mpl, thrombocytopenia - children - thrombopoietin regulation
REFERENCES
- 1 Metcalf D. Blood. Thrombopoietin-at last. Nature . 1994; 369 519-520
- 2 de Sauvage J F, Hass P E, Spencer S D. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature . 1994; 369 533-538
- 3 Lok S, Kaushansky K, Holly R D. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature . 1994; 369 565-568
- 4 Bartley T D, Bogenberger J, Hunt P. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell . 1994; 77 1117-1124
- 5 Sohma Y, Akahori H, Seki N. Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Lett . 1994; 353 57-61
- 6 Kelemen E, Cserhati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol . 1958; 20 350-355
- 7 Leven R M, Yee M K. Megakaryocyte morphogenesis stimulated in vitro by whole and partially fractionated thrombocytopenic plasma: a model system for the study of platelet formation. Blood . 1987; 69 1046-1052
- 8 Penington D G, Olsen T E. Megakaryocytes in states of altered platelet production: cell numbers, size and DNA content. Br J Haematol . 1970; 18 447-463
- 9 McDonald T P, Clift R E, Cottrell M B. A four-step procedure for the purification of thrombopoietin. Exp Hematol . 1989; 17 865-871
- 10 Vannucchi A M, Grossi A, Rafanelli D, Rossi Ferrini P, Ramponi G. Partial purification and biochemical characterization of human plasma thrombopoietin. Leukemia . 1988; 2 236-240
- 11 Wendling F, Varlet P, Charon M, Tambourin P. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemic disorder in adult mice. Virology . 1986; 149 242-246
- 12 Souyri M, Vigon I, Penciolelli J F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell . 1990; 63 1137-1147
- 13 Vigon I, Mornon J P, Cocault L. Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci USA . 1992; 89 5640-5644
- 14 Kato T, Ogami K, Shimada Y. Purification and characterization of thrombopoietin. J Biochem (Tokyo) . 1995; 118 229-236
- 15 Kuter D J, Beeler D L, Rosenberg R D. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA . 1994; 91 11104-11108
- 16 Cwirla S E, Balasubramanian P, Duffin D J. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science . 1997; 276 1696-1699
- 17 de Serres M, Ellis B, Dillberger J E. Immunogenicity of thrombopoietin mimetic peptide GW395058 in BALB/c mice and New Zealand white rabbits: evaluation of the potential for thrombopoietin neutralizing antibody production in man. Stem Cells . 1999; 17 203-209
- 18 Carbonell F, Hoelzer D, Thiel E, Bartl R. Ph1-positive CML associated with megakaryocytic hyperplasia and thrombocythemia and an abnormality of chromosome no. 3. Cancer Genet Cytogenet . 1982; 6 153-161
- 19 Jenkins R B, Tefferi A, Solberg Jr A L, Dewald G W. Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3. Cancer Genet Cytogenet . 1989; 39 167-179
- 20 Foster D, Hunt P. The biological significance of truncated and full-length forms of mpl ligand. In: Kuter DJ, Hunt P, Sheridan W, Zucker-Franklin D, eds. Thrombopoiesis and Thrombopoietins: Molecular, Cellular, Preclinical and Clinical Biology Totowa, NJ: Humana Press 1997: 203-214
- 21 Gurney A L, Kuang W J, Xie M H. Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin. Blood . 1995; 85 981-988
- 22 Stoffel R, Wiestner A, Skoda R C. Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood . 1996; 87 567-573
- 23 Muto T, Feese M D, Shimada Y. Functional analysis of the C-terminal region of recombinant human thrombopoietin. C-terminal region of thrombopoietin is a ``shuttle'' peptide to help secretion. J Biol Chem . 2000; 275 12090-12094
- 24 Sola M C, Juul S E, Meng Y G. 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
- 25 Wolber E M, Dame C, Fahnenstich H. Expression of the thrombopoietin gene in human fetal and neonatal tissues. Blood . 1999; 94 97-105
- 26 Dame C, Fahnenstich H, Freitag P. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood . 1998; 92 3218-3225
- 27 Sungaran R, Markovic B, Chong B H. Localization and regulation of thrombopoietin mRNA expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood . 1997; 89 101-107
- 28 Debili N, Wendling F, Cosman D. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood . 1995; 85 391-401
- 29 Cardier J E, Dempsey J. Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial cells. Blood . 1998; 91 923-929
- 30 Vigon I, Dreyfus F, Melle J. Expression of the c-mpl proto-oncogene in human hematologic malignancies. Blood . 1993; 82 877-883
- 31 Sawai N, Koike K, Higuchi T, Ogami K, Oda M. Thrombopoietin enhances the production of myeloid cells, but not megakaryocytes, in juvenile chronic myelogenous leukemia. Blood . 1998; 91 4065-4073
- 32 Luo S S, Ogata K, Yokose N, Kato T, Dan K. Effect of thrombopoietin on proliferation of blasts from patients with myelodysplastic syndromes. Stem Cells . 2000; 18 112-119
- 33 Matsumura I, Kanakura Y, Kato T. The biologic properties of recombinant human thrombopoietin in the proliferation and megakaryocytic differentiation of acute myeloblastic leukemia cells. Blood . 1996; 88 3074-3082
- 34 Kaushansky K. Use of thrombopoietic growth factors in acute leukemia. Leukemia . 2000; 14 505-508
- 35 Schipper L F, Brand A, Reniers N C. Effects of thrombopoietin on the proliferation and differentiation of primitive and mature haemopoietic progenitor cells in cord blood. Br J Haematol . 1998; 101 425-435
- 36 Campagnoli C, Fisk N, Overton T. Circulating hematopoietic progenitor cells in first trimester fetal blood. Blood . 2000; 95 1967-1972
- 37 Murray N A, Watts T L, Roberts I A. Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res . 1998; 43 148-151
- 38 Watts T L, Murray N A, Roberts I A. Thrombopoietin has a primary role in the regulation of platelet production in preterm babies. Pediatr Res . 1999; 46 28-32
- 39 Nishihira H, Toyoda Y, Miyazaki H, Kigasawa H, Ohsaki E. Growth of macroscopic human megakaryocyte colonies from cord blood in culture with recombinant human thrombopoietin (c-mpl ligand) and the effects of gestational age on frequency of colonies. Br J Haematol . 1996; 92 23-28
- 40 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
- 41 Mwamtemi H H, Higuchi T, Sawai N, Hidaka E, Koike K. Quantitative and qualitative differences in thrombopoietin-dependent hematopoietic progenitor development between cord blood and bone marrow. Transplantation . 2000; 69 1645-1654
- 42 Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood . 1995; 86 419-431
- 43 Debili N, Masse J M, Katz A. Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34+ cells. Blood . 1993; 82 84-95
- 44 Howarth L J, McCloy M, Roberts I AG, Murray N A. Thrombopoietin mimetic peptide (GW395058) is a potent stimulant of neonatal megakaryocyte colony production. Ann Hematol(Abst). 2000; 79 B12
- 45 Solar G P, Kerr W G, Zeigler F C. Role of c-mpl in early hematopoiesis. Blood . 1998; 92 4-10
- 46 Ritchie A, Vadhan-Raj S, Broxmeyer H E. Thrombopoietin suppresses apoptosis and behaves as a survival factor for the human growth factor-dependent cell line, M07e. Stem Cells . 1996; 14 330-336
- 47 Ritchie A, Gotoh A, Gaddy J, Braun S E, Broxmeyer H E. Thrombopoietin upregulates the promoter conformation of p53 in a proliferation-independent manner coincident with a decreased expression of Bax: potential mechanisms for survival enhancing effects. Blood . 1997; 90 4394-4402
- 48 Kaushansky K, Broudy V C, Grossmann A. Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. J Clin Invest . 1995; 96 1683-1687
- 49 Sawai N, Koike K, Mwamtemi H H. Thrombopoietin enhances neutrophil production by bone marrow hematopoietic progenitors with the aid of stem cell factor in congenital neutropenia. J Leukoc Biol . 2000; 68 137-143
- 50 Grossmann A, Lenox J, Ren H P. Thrombopoietin accelerates platelet, red blood cell, and neutrophil recovery in myelosuppressed mice. Exp Hematol . 1996; 24 1238-1246
- 51 Liu W, Wang M, Tang D C, Ding I, Rodgers G P. Thrombopoietin has a differentiative effect on late-stage human erythropoiesis. Br J Haematol . 1999; 105 459-469
- 52 Kuter D J, Rosenberg R D. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood . 1995; 85 2720-2730
- 53 Fielder P J, Gurney A L, Stefanich E. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood . 1996; 87 2154-2161
- 54 Nagata Y, Shozaki Y, Nagahisa H. Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis. Thromb Haemost . 1997; 77 808-814
- 55 Murone M, Carpenter D A, de Sauvage J F. Hematopoietic deficiencies in c-mpl and TPO knockout mice. Stem Cells . 1998; 16 1-6
- 56 Yamashita K, Matsuoka H, Ochiai T. Hepatocyte growth factor/scatter factor enhances the thrombopoietin mRNA expression in rat hepatocytes and cirrhotic rat livers. J Gastroenterol Hepatol . 2000; 15 83-90
- 57 Wolber E M, Jelkmann W. Interleukin-6 increases thrombopoietin production in human hepatoma cells HepG2 and Hep3B. J Interferon Cytokine Res . 2000; 20 499-506
- 58 Sungaran R, Chisholm O T, Markovic B. The role of platelet alpha-granular proteins in the regulation of thrombopoietin messenger RNA expression in human bone marrow stromal cells. Blood . 2000; 95 3094-3101
- 59 Allen T D, Dexter T M. The essential cells of the hemopoietic microenvironment. Exp Hematol . 1984; 12 517-521
- 60 Sainio S, Javela K, Kekomaki R, Teramo K. Thrombopoietin levels in cord blood plasma and amniotic fluid in fetuses with alloimmune thrombocytopenia and healthy controls. Br J Haematol . 2000; 109 330-335
- 61 Dame C, Fahnenstich H, Cremer M, Bartmann P. Regulation der Thrombopoiese durch Thrombopoietin and Interleukin-11 bei Neugeborenen mit einer praepartal bestehenden Thrombozytopenie. Z Geburtsh Neonatol (Abst). 1998; 202 S14
- 62 Walka M M, Sonntag J, Dudenhausen J W, Obladen M. Thrombopoietin concentration in umbilical cord blood of healthy term newborns is higher than in adult controls. Biol Neonate . 1999; 75 54-58
- 63 Albert T S, Meng Y G, Simms P, Cohen R L, Phibbs R H. Thrombopoietin in the thrombocytopenic term and preterm newborn. Pediatrics . 2000; 105 1286-1291
- 64 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
- 65 Ishiguro A, Nakahata T, Matsubara K. Age-related changes in thrombopoietin in children: reference interval for serum thrombopoietin levels. Br J Haematol . 1999; 106 884-888
- 66 Ikeno K, Koike K, Takeshita A. Stressful delivery influences circulating thrombopoietin (TPO) levels in newborns: possible role for cortisol in TPO-mpl binding. Early Hum Dev . 2000; 58 225-235
- 67 Young G, Loechelt B J, Rakusan T A, Nichol J L, Luban N L. Thrombopoietin levels in HIV-associated thrombocytopenia in children. J Pediatr . 1998; 133 765-769
- 68 Ballmaier M, Schulze H, Strauss G. 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
- 69 Chessells J M, Wigglesworth J S. Haemostatic failure in babies with rhesus isoimmunization. Arch Dis Child . 1971; 46 38-45
- 70 Koenig J M, Christensen R D. Neutropenia and thrombocytopenia in infants with Rh hemolytic disease. J Pediatr . 1989; 114 625-631
- 71 Saade G R, Moise Jr J K, Copel J A, Belfort M A, Carpenter Jr J R. Fetal platelet counts correlate with the severity of the anemia in red-cell alloimmunization. Obstet Gynecol . 1993; 82 987-991
- 72 Nicolini U, Nicolaidis P, Tannirandorn Y. Fetal liver dysfunction in Rh alloimmunization. Br J Obstet Gynaecol . 1991; 98 287-293
- 73 Colarizi P, Fiorucci P, Roggini M, Papoff P. Circulating thrombopoietin levels in a neonate with osteopetrosis. Pediatrics . 1999; 103 700-701
- 74 Warwick R M, Vaughan J, Murray N, Lubenko A, Roberts I. In vitro culture of colony forming unit-megakaryocyte (CFU-MK) in fetal alloimmune thrombocytopenia. Br J Haematol . 1994; 88 874-877
- 75 Colarizi P, Fiorucci P, Caradonna A. Circulating thrombopoietin levels in neonates with infection. Acta Paediatr . 1999; 88 332-337
- 76 Schwab M, Niemeyer C, Schwarzer U. Down syndrome, transient myeloproliferative disorder, and infantile liver fibrosis. Med Pediatr Oncol . 1998; 31 159-165
- 77 Ruchelli E D, Uri A, Dimmick J E. Severe perinatal liver disease and Down syndrome: an apparent relationship. Hum Pathol . 1991; 22 1274-1280
- 78 Ganick D J. Hematological changes in Down's syndrome. Crit Rev Oncol Hematol . 1986; 6 55-69
- 79 Bonno M, Azuma E, Kawasaki H. Thrombopoietin level is inversely related to blast count, not platelet number, in Down syndrome neonates with transient myeloproliferative disorder. Am J Hematol . 1998; 58 267-272
- 80 Sekine I, Hagiwara T, Miyazaki H. Thrombocytopenia with absent radii syndrome: studies on serum thrombopoietin levels and megakaryopoiesis in vitro. J Pediatr Hematol Oncol . 1998; 20 74-78
- 81 al-Jefri A H, Dror Y, Bussel J B, Freedman M H. 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
- 82 Letestu R, Vitrat N, Masse A. 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
- 83 Strippoli P, Savoia A, Iolascon A. Mutational screening of thrombopoietin receptor gene (c-mpl) in patients with congenital thrombocytopenia and absent radii (TAR). Br J Haematol . 1998; 103 311-314
- 84 Hedberg V A, Lipton J M. Thrombocytopenia with absent radii. A review of 100 cases. Am J Pediatr Hematol Oncol . 1988; 10 51-64
- 85 Freedman M H, Estrov Z. Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect. Am J Pediatr Hematol Oncol . 1990; 12 225-230
- 86 Muraoka K, Ishii E, Tsuji K. 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
- 87 Ballmaier M, Germeshausen M, Schulze H. C-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood . 2001; 97 139-146
- 88 Van Den Oudenrijn S, Bruin M, Folman C C. Mutations in the thrombopoietin receptor, mpl, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol . 2000; 110 441-448
- 89 Ihara K, Ishii E, Eguchi M. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA . 1999; 96 3132-3136
- 90 D'Andrea A D, Grompe M. Molecular biology of Fanconi anemia: implications for diagnosis and therapy. Blood . 1997; 90 1725-1736
- 91 Cremer M, Schulze H, Linthorst G. Serum levels of thrombopoietin, IL-11, and IL-6 in pediatric thrombocytopenias. Ann Hematol . 1999; 78 401-407
- 92 Kuefer M U, Wang W C, Head D R. Thrombopoietin level in young patients is related to megakaryocyte frequency and platelet count. J Pediatr Hematol Oncol . 1998; 20 36-43
- 93 Dror Y, Freedman M H. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood . 1999; 94 3048-3054
- 94 Grottum K A, Hovig T, Holmsen H. Wiskott-Aldrich syndrome: qualitative platelet defects and short platelet survival. Br J Haematol . 1969; 17 373-388
- 95 Mullen C A, Anderson K D, Blaese R M. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood . 1993; 82 2961-2966
- 96 Srivastava R N. Wiskott-Aldrich syndrome. Arch Dis Child . 1967; 42 604-607
- 97 Kajiwara M, Nonoyama S, Eguchi M. WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro. Br J Haematol . 1999; 107 254-262
- 98 Tomer A, Scharf R E, McMillan R, Ruggeri Z M, Harker L A. Bernard-Soulier syndrome: quantitative characterization of megakaryocytes and platelets by flow cytometric and platelet kinetic measurements. Eur J Haematol . 1994; 52 193-200
- 99 Hirayama Y, Sakamaki S, Matsunaga T. Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells. Blood . 1998; 92 46-52
- 100 Kojima S, Matsuyama T, Kodera Y, Tahara T, Kato T. Measurement of endogenous plasma thrombopoietin in patients with acquired aplastic anaemia by a sensitive enzyme-linked immunosorbent assay. Br J Haematol . 1997; 97 538-543
- 101 Hou M, Andersson P O, Stockelberg D. Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes. Br J Haematol . 1998; 101 420-424
- 102 Kocak U, Gursel T, Ozturk G. The effect of steroid and intravenous immunoglobulin on thrombopoietin levels in pediatric patients with immune thrombocytopenic purpura. Blood Coagul Fibrinolysis . 2000; 11 121-125
- 103 Emmons R V, Reid D M, Cohen R L. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood . 1996; 87 4068-4071
- 104 Sakane Y, Wada H, Kazuyo H. Increased thrombopoietin levels in idiopathic thrombocytopenic purpura patients with a poor response to steroid therapy. Blood Coagul Fibrinolysis . 1998; 9 315-321
- 105 Cole J L, Marzec U M, Gunthel C J. Ineffective platelet production in thrombocytopenic human immunodeficiency virus-infected patients. Blood . 1998; 91 3239-3246
- 106 Wolber E M, Ganschow R, Burdelski M, Jelkmann W. Hepatic thrombopoietin mRNA levels in acute and chronic liver failure of childhood. Hepatology . 1999; 29 1739-1742
- 107 Komura E, Matsumura T, Kato T. Thrombopoietin in patients with hepatoblastoma. Stem Cells . 1998; 16 329-333
- 108 Miura N, Terai M, Meng Y G, Sato T, Niimi H. Serum thrombopoietin levels in Kawasaki disease. Br J Haematol . 1998; 100 387-388
- 109 Ishiguro A, Ishikita T, Shimbo T. Elevation of serum thrombopoietin precedes thrombocytosis in Kawasaki disease. Thromb Haemost . 1998; 79 1096-1100
- 110 Taksin A L, Couedic J PL, Dusanter-Fourt I. Autonomous megakaryocyte growth in essential thrombocythemia and idiopathic myelofibrosis is not related to a c-mpl mutation or to an autocrine stimulation by Mpl-L. Blood . 1999; 93 125-139
- 111 Yoshida N, Ishii E, Koga N, Kamimura T, Miyazaki S. Analysis of thrombopoietin and c-mpl expression in a child with essential thrombocythemia. Pediatr Hematol Oncol . 1998; 15 359-363
- 112 Kaushansky K. Thrombopoietin. N Engl J Med . 1998; 339 746-754
- 113 Vadhan-Raj S, Verschraegen C F, Bueso-Ramos C. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med . 2000; 132 364-368
- 114 Kuter D J. Future directions with platelet growth factors. Semin Hematol . 2000; 37 41-49
- 115 Li J, Xia Y, Bertino A, Coburn J, Kuter D J. Characterization of an anti-thrombopoietin antibody that developed in a cancer patient following the injection of PEG-rHuMGDF. Blood (Abst). 1999; 94 51a
- 116 Yang C, Xia Y, Li J J K D. The appearance of anti-thrombopoietin antibody and circulating thrombopoietin-IgG complexes in a patient developing thrombocytopenia after injection of PEG-rHuMGDF. Blood (Abst). 1999; 94 681a
- 117 Sola M C, Christensen R D, Hutson A D, Tarantal A F. Pharmacokinetics, pharmacodynamics, and safety of administering pegylated recombinant megakaryocyte growth and development factor to newborn rhesus monkeys. Pediatr Res . 2000; 47 208-214
- 118 Yagi M, Ritchie K A, Sitnicka E. Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc Natl Acad Sci USA . 1999; 96 8126-8131