Platelets in neonates: Central mediators in haemostasis, antimicrobial defence and inflammation

Oliver Andres; Harald Schulze; Christian P. Speer

doi:10.1160/TH14-05-0476

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(01): 3-12
DOI: 10.1160/TH14-05-0476

Review Article

Schattauer GmbH

Platelets in neonates: Central mediators in haemostasis, antimicrobial defence and inflammation

Oliver Andres

¹University Children’s Hospital, University of Würzburg, Würzburg, Germany

,

Harald Schulze^*

²University of Würzburg, Department of Experimental Biomedicine, Würzburg, Germany

,

Christian P. Speer^*

¹University Children’s Hospital, University of Würzburg, Würzburg, Germany

› Author Affiliations

Abstract

Summary

Platelets are not only centrally involved in haemostasis, but also in antimicrobial defence and inflammation. Since evaluation of platelet physiology in the particular patient group of preterm and term neonatal infants is highly restricted for ethical reasons, there are hardly any data available in healthy and much less in extremely immature or ill neonates. By summarising current knowledge and addressing both platelet researchers and neonatologists, we describe neonatal platelet count and morphology, report on previous analyses of neonatal platelet function in primary haemostasis and provide insights into recent advances in platelet immunology that considerably impacts our clinical view on the critically ill neonatal infant. We conclude that neonatal platelets, originating from liver megakaryocytes, substantially differ from adult platelets and may play a pivotal role in the pathophysiology of neonatal sepsis or intraventricular haemorrhage, both complications which seriously augment perinatal morbidity and mortality.

Keywords

Platelet function - platelet immunology - neonatal sepsis - intraventricular haemorrhage - preterm infant

Full Text

References

References
1 Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Arch Mikrosc Anat 1865; 01: 1-42.
2 Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006; 133: 251-258.
3 Bizzozero J. Ueber einen neuen Formbestandtheil des Blutes und dessen Rolle bei der Thrombose und der Blutgerinnung. Arch Pathol Anat Physiol Klin Med 1882; 90: 261-332.
4 Mazzarello P. et al. Giulio Bizzozero: a pioneer of cell biology. Nat Rev Mol Cell Biol 2001; 02: 776-781.
5 Wright JH. The Origin and Nature of the Blood Plates. Boston Med Surg J 1906; 154: 643-645.
6 Wright JH. Die Entstehung der Blutplättchen. Virchows Archiv 1906; 186: 55-63.
7 Coller BS. Historical perspective and future directions in platelet research. J Thromb Haemost 2011; 09 (Suppl. 01) 374-395.
8 Roberts IAG, Chakravorti S. Thrombocytopenia in the Newborn. In: Platelets. 3 ed.. Academic Press; 2013. pp. 929-951.
9 Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect 2014; 68 (Suppl. 01) S24-32.
10 Stoll BJ. et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 2011; 127: 817-826.
11 Stoll BJ. et al. Changes in pathogens causing early-onset sepsis in very-lowbirth-weight infants. N Engl J Med 2002; 347: 240-247.
12 Stoll BJ. et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110: 285-291.
13 Bersani I, Speer CP. Nosocomial sepsis in neonatal intensive care: inevitable or preventable?. Z Geburtshilfe Neonatol 2012; 216: 186-190.
14 Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology 2009; 95: 353-361.
15 Speer CP. Neonatal respiratory distress syndrome: an inflammatory disease?. Neonatology 2011; 99: 316-319.
16 Perlman JM. et al. Fluctuating cerebral blood-flow velocity in respiratory-distress syndrome. Relation to the development of intraventricular hemorrhage. N Engl J Med 1983; 309: 204-209.
17 Gould SJ, Howard S. An immunohistochemical study of the germinal layer in the late gestation human fetal brain. Neuropathol Appl Neurobiol 1987; 13: 421-437.
18 Nakamura Y. et al. Germinal matrix hemorrhage of venous origin in preterm neonates. Hum Pathol 1990; 21: 1059-1062.
19 Stanworth SJ. et al. Prospective, observational study of outcomes in neonates with severe thrombocytopenia. Pediatrics 2009; 124: e826-834.
20 von Lindern JS. et al. Thrombocytopenia in neonates and the risk of intraven-tricular hemorrhage: a retrospective cohort study. BMC Pediatr 2011; 11: 16.
21 Muthukumar P. et al. Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions. Transfus Med 2012; 22: 338-343.
22 Pahal GS. et al. Normal development of human fetal hematopoiesis between eight and seventeen weeks’ gestation. Am J Obstet Gynecol 2000; 183: 1029-1034.
23 Forestier F. et al. Hematological values of 163 normal fetuses between 18 and 30 weeks of gestation. Pediatr Res 1986; 20: 342-346.
24 Van den Hof MC, Nicolaides KH. Platelet count in normal, small, and anemic fetuses. Am J Obstet Gynecol 1990; 162: 735-739.
25 Forestier F. et al. Developmental hematopoiesis in normal human fetal blood. Blood 1991; 77: 2360-2363.
26 Hohlfeld P. et al. Fetal thrombocytopenia: a retrospective survey of 5,194 fetal blood samplings. Blood 1994; 84: 1851-1856.
27 Burrows RF, Kelton JG. Incidentally detected thrombocytopenia in healthy mothers and their infants. N Engl J Med 1988; 319: 142-145.
28 Sainio S. et al. Thrombocytopenia in term infants: a population-based study. Obstet Gynecol 2000; 95: 441-446.
29 de Moerloose P. et al. Neonatal thrombocytopenia: incidence and characterization of maternal antiplatelet antibodies by MAIPA assay. Br J Haematol 1998; 100: 735-740.
30 Wiedmeier SE. et al. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol 2009; 29: 130-136.
31 Castle V. et al. Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 1986; 108: 749-755.
32 Haque KN, Bahakim HM. Percentile curves for various hematologic measurements at birth in Arab preterm babies of different gestational ages. Am J Dis Child 1991; 145: 645-649.
33 Obladen M. et al. Venous and arterial hematologic profiles of very low birth weight infants. European Multicenter rhEPO Study Group. Pediatrics 2000; 106: 707-711.
34 Sitaru A-G. et al. Neonatal platelets from cord blood and peripheral blood. Platelets 2005; 16: 203-210.
35 Gerday E. et al. Testing platelet mass versus platelet count to guide platelet transfusions in the neonatal intensive care unit. Transfusion 2009; 49: 2034-2039.
36 Zisk JL. et al. Transfusing neonates based on platelet count vs. platelet mass: A randomized feasibility-pilot study. Platelets. 2013 Epub ahead of print.
37 Baer VL. et al. Severe Thrombocytopenia in the NICU. Pediatrics 2009; 124: e1095-1100.
38 Christensen RD. et al. Thrombocytosis and thrombocytopenia in the NICU: incidence, mechanisms and treatments. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 04) 15-17.
39 Brown RE. et al. Effects of sepsis on neonatal thrombopoiesis. Pediatr Res 2008; 64: 399-404.
40 Liu Z-J. et al. Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood. 2014 Epub ahead of print.
41 White JG. Platelet Structure. In: Platelets. 3 ed.. Academic Press; 2013. pp. 117-144.
42 Ts’ao CH. et al. Function and ultrastructure of platelets of neonates: enhanced ristocetin aggregation of neonatal platelets. Br J Haematol 1976; 32: 225-233.
43 Suarez CR. et al. Neonatal and maternal platelets: activation at time of birth. Am J Hematol 1988; 29: 18-21.
44 Saving KL. et al. Platelet ultrastructure of high-risk premature infants. Thromb Res 1994; 73: 371-384.
45 Mielke Jr., CH. et al. The standardized normal Ivy bleeding time and its prolongation by aspirin. Blood 1969; 34: 204-215.
46 Andrew M. et al. Modified bleeding time in the infant. Am J Hematol 1989; 30: 190-191.
47 Andrew M. et al. Evaluation of an automated bleeding time device in the newborn. Am J Hematol 1990; 35: 275-277.
48 Mull MM, Hathaway WE. Altered platelet function in newborns. Pediatr Res 1970; 04: 229-237.
49 Feusner JH. Normal and abnormal bleeding times in neonates and young children utilizing a fully standardized template technic. Am J Clin Pathol 1980; 74: 73-77.
50 Setzer ES. et al. Platelet dysfunction and coagulopathy in intraventricular hemorrhage in the premature infant. J Pediatr 1982; 100: 599-605.
51 Del Vecchio A. et al. Template bleeding times of 240 neonates born at 24 to 41 weeks gestation. J Perinatol 2008; 28: 427-431.
52 Harrison P, Lordkipanidzé M. Clinical Tests of Platelet Function. In: Platelets. 3 ed.. Academic Press; 2013. pp. 519-545.
53 Carcao MD. 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.
54 Israels SJ. et al. Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyzer. J Pediatr 2001; 138: 116-119.
55 Roschitz B. et al. 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.
56 Boudewijns M. 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.
57 Saxonhouse MA. et al. Closure times measured by the platelet function analyzer PFA-100 are longer in neonatal blood compared to cord blood samples. Neon-atology 2010; 97: 242-249.
58 Cvirn G. et al. Collagen/endogenous thrombin-induced platelet aggregation in cord versus adult whole blood. Neonatology 2009; 95: 187-192.
59 Strauss T. et al. Clot formation of neonates tested by thromboelastography correlates with gestational age. Thromb Haemost 2010; 103: 344-350.
60 Sheffield MJ. et al. Effect of ampicillin on the bleeding time of neonatal intensive care unit patients. J Perinatol 2010; 30: 527-530.
61 Sheffield MJ. et al. Effect of ampicillin on bleeding time in very low birth-weight neonates during the first week after birth. J Perinatol 2011; 31: 477-480.
62 Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost 2012; 38: 865-883.
63 Israels SJ. Platelet Function in the Newborn. In: Platelets. 3 ed.. Academic Press; 2013. pp. 503-516.
64 Corby DG, Zuck TF. Newborn platelet dysfunction: a storage pool and release defect. Thromb Haemost 1976; 36: 200-207.
65 Corby DG, O’Barr TP. Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine. Dev Pharmacol Ther 1981; 02: 215-225.
66 Corby DG, O’Barr TP. Neonatal platelet function: a membrane-related phenomenon?. Haemostasis 1981; 10: 177-185.
67 Israels SJ. et al. Deficient collagen-induced activation in the newborn platelet. Pediatr Res 1990; 27: 337-343.
68 Israels SJ. et al. Deficient thromboxane synthesis and response in platelets from premature infants. Pediatr Res 1997; 41: 218-223.
69 Tanindi S. et al. The normalization period of platelet aggregation in newborns. Thromb Res 1995; 80: 57-62.
70 Ucar T. et al. Platelet aggregation in term and preterm newborns. Pediatr Hematol Oncol 2005; 22: 139-145.
71 Jones CR. et al. Maternal and fetal platelet responses and adrenoceptor binding characteristics. Thromb Haemost 1985; 53: 95-98.
72 Andrews NP. et al. Blood platelet behaviour in mothers and neonates. Thromb Haemost 1985; 53: 428-432.
73 Gader AMA. et al. Dose-response aggregometry in maternal/neonatal platelets. Thromb Haemost 1988; 60: 314-318.
74 Gelman B. et al. Impaired mobilization of intracellular calcium in neonatal platelets. Pediatr Res 1996; 39: 692-696.
75 Israels SJ. et al. Impaired signal transduction in neonatal platelets. Pediatr Res 1999; 45: 687-691.
76 Ahlsten G. et al. Arachidonic acid-induced aggregation of platelets from human cord blood compared with platelets from adults. Biol Neonate 1985; 47: 199-204.
77 Shenkman B. et al. Increased neonatal platelet deposition on subendothelium under flow conditions: the role of plasma von Willebrand factor. Pediatr Res 1999; 45: 270-275.
78 Ferrer-Marin F. et al. Effects of in vitro adult platelet transfusions on neonatal hemostasis. J Thromb Haemost 2011; 09: 1020-1028.
79 Katz JA. et al. Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma. Blood 1989; 73: 1851-1858.
80 Weinstein MJ. et al. Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocyto-penic purpura. Br J Haematol 1989; 72: 68-72.
81 Linder N. et al. Deposition of whole blood platelets on extracellular matrix under flow conditions in preterm infants. Arch Dis Child Fetal Neonatal Ed 2002; 86: F127-130.
82 Levy-Shraga Y. et al. Platelet Function of Newborns as Tested by Cone and Plate(let) Analyzer Correlates with Gestational Age. Acta Haematol 2006; 115: 152-156.
83 Strauss T. et al. Impaired platelet function in neonates born to mothers with diabetes or hypertension during pregnancy. Klin Padiatr 2010; 222: 154-157.
84 Finkelstein Y. et al. Whole blood platelet deposition on extracellular matrix under flow conditions in preterm neonatal sepsis. Eur J Pediatr 2002; 161: 270-274.
85 Rajasekhar D. et al. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72: 957-963.
86 Gatti L. et al. Platelet activation in newborns detected by flow-cytometry. Biol Neonate 1996; 70: 322-327.
87 Grosshaupt B. et al. Hyporeactivity of neonatal platelets is not caused by preacti-vation during birth. Eur J Pediatr 1997; 156: 944-948.
88 Rajasekhar D. et al. Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997; 77: 1002-1007.
89 Simak J. et al. Surface expression of major membrane glycoproteins on resting and TRAP-activated neonatal platelets. Pediatr Res 1999; 46: 445-449.
90 Pietrucha T. et al. Differentiated reactivity of whole blood neonatal platelets to various agonists. Platelets 2001; 12: 99-107.
91 Hézard N. et al. 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.
92 Schmugge M. et al. The relationship of von Willebrand factor binding to activated platelets from healthy neonates and adults. Pediatr Res 2003; 54: 474-479.
93 Bednarek FJ. et al. The platelet hyporeactivity of extremely low birth weight neonates is age-dependent. Thromb Res 2009; 124: 42-45.
94 Irken G. et al. Platelet activation during the early neonatal period. Biol Neonate 1998; 73: 166-171.
95 Keh D. et al. Response of neonatal platelets to nitric oxide in vitro. Intensive Care Med 2001; 27: 283-286.
96 Haiden N. et al. Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity. Thromb Haemost 2005; 93: 118-123.
97 Mankin P. et al. Imparied platelet--dense granule release in neonates. J Pediatr Hematol Oncol 2000; 22: 143-147.
98 Ichinose F. et al. Platelet hyporeactivity in young infants during cardiopulmon-ary bypass. Anesth Analg 1999; 88: 258-262.
99 Semple JW. et al. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
100 Yeaman MR, Bayer AS. Antimicrobial Host Defense. In: Platelets. 3 ed.. Academic Press; 2013. pp. 767-801.
101 Vieira-de-Abreu A. et al. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 2012; 34: 5-30.
102 Brass LF. et al Signal Transduction During Platelet Plug Formation. In: Platelets. 3 ed.. Academic Press; 2013. pp. 367-398.
103 Worth RG. et al. Platelet FcgammaRIIA binds and internalizes IgG-containing complexes. Exp Hematol 2006; 34: 1490-1495.
104 Movat HZ. et al. Platelet phagocytosis and aggregation. J Cell Biol 1965; 27: 531-543.
105 Meseguer J. et al. Are thrombocytes and platelets true phagocytes?. Microsc Res Tech 2002; 57: 491-497.
106 Jaff MS. et al. Platelet phagocytosis: a probable mechanism of thrombocytope-nia in Plasmodium falciparum infection. J Clin Pathol 1985; 38: 1318-1319.
107 Andonegui G. et al. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417-2423.
108 Cognasse F. et al. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol 2005; 83: 196-198.
109 Aslam R. et al. Platelet Toll-like receptor expression modulates lipopolysac-charide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006; 107: 637-641.
110 Garraud O, Cognasse F. Platelet Toll-like receptor expression: the link between “danger” ligands and inflammation. Inflamm Allergy Drug Targets 2010; 09: 322-333.
111 Panigrahi S. et al. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res 2013; 112: 103-112.
112 Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004; 430: 257-263.
113 Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature 2007; 449: 819-826.
114 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820.
115 Hoebe K. et al. CD36 is a sensor of diacylglycerides. Nature 2005; 433: 523-527.
116 Falker K. et al. The toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLCgamma2 signalling cascade. Cell Signal 2014; 26: 279-286.
117 Zhang G. et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol 2009; 182: 7997-8004.
118 Vincent JL. et al. Platelet function in sepsis. Crit Care Med 2002; 30 (Suppl. 05) S313-317.
119 Vieira-de-Abreu A. et al Inflammation. In: Platelets. 3 ed.. Academic Press; 2013. pp. 733-766.
120 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
121 Luck S. et al. Estimated early-onset group B streptococcal neonatal disease. Lancet 2003; 361: 1953-1954.
122 Siauw C. et al. Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades. Thromb Haemost 2006; 95: 836-849.
123 Jenne CN. et al. Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 2013; 35: 254-261.
124 Krijgsveld J. et al. Thrombocidins, microbicidal proteins from human blood platelets, are C-terminal deletion products of CXC chemokines. J Biol Chem 2000; 275: 20374-20381.
125 Kraemer BF. et al. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog 2011; 07: e1002355.
126 Miyabe K. et al. Effects of platelet release products on neutrophilic phagocytosis and complement receptors. Thromb Res 2004; 114: 29-36.
127 Bergmeier W, Wagner DD. Inflammation. In: Platelets. 2 ed.. Academic Press; 2007. pp. 713-726.
128 Michelson AD, Newburger PE. Platelets and leukocytes: aggregate knowledge. Blood 2007; 110: 794-795.
129 Haselmayer P. et al. TREM-1 ligand expression on platelets enhances neutro-phil activation. Blood 2007; 110: 1029-1035.
130 Klesney-Tait J. et al. The TREM receptor family and signal integration. Nat Immunol 2006; 07: 1266-1273.
131 Yost CC. et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood 2009; 113: 6419-6427.
132 Marcos V. et al. Delayed but functional neutrophil extracellular trap formation in neonates. Blood 2009; 114: 4908-4911 author reply 11-12.
133 Weyrich AS. et al. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 07: 241-246.
134 Assoian RK. et al. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 1983; 258: 7155-7160.
135 Kunzmann S. et al. Antenatal inflammation induced TGF-beta1 but suppressed CTGF in preterm lungs. Am J Physiol Lung Cell Mol Physiol 2007; 292: L223-231.
136 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
137 von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
138 Elzey BD. et al. Platelet-Mediated Modulation of Adaptive Immunity: A Communication Link between Innate and Adaptive Immune Compartments. Immunity 2003; 19: 9-19.
139 Elzey BD. et al. Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood 2008; 111: 3684-3691.
140 Sprague DL. et al. Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 2008; 111: 5028-5036.
141 Elzey BD. et al. Platelet CD40L at the interface of adaptive immunity. Thromb Res 2011; 127: 180-183.
142 Sitaru A-G. et al. Chorioamnionitis is associated with increased CD40L expression on cord blood platelets. Thromb Haemost 2005; 94: 1219-1223.
143 Italiano Jr., JE. et al. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010; 17: 578-584.
144 Boilard E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
145 Brown GT, McIntyre TM. Lipopolysaccharide signaling without a nucleus: ki-nase cascades stimulate platelet shedding of proinflammatory IL-1beta-rich microparticles. J Immunol 2011; 186: 5489-5496.
146 Risitano A. et al. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 2012; 119: 6288-6295.
147 Wasiluk A. et al. Platelet-derived microparticles and platelet count in preterm newborns. Fetal Diagn Ther 2008; 23: 149-152.
148 Michelson AD. et al. Platelet and platelet-derived microparticle surface factor V/Va binding in whole blood: differences between neonates and adults. Thromb Haemost 2000; 84: 689-694.
149 Goerge T. et al. Inflammation induces hemorrhage in thrombocytopenia. Blood 2008; 111: 4958-4964.
150 Crispino JD. GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol 2005; 16: 137-147.