HEMATOPOIETIC GROWTH FACTORS IN NEONATAL MEDICINE

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1 HEMATOPOIETIC GROWTH FACTORS IN NEONATAL MEDICINE Preface Robert D. Christensen xiii Evaluation and Treatment of Severe and Prolonged Thrombocytopenia in Neonates 1 Martha C. Sola Thrombocytopenia is one of the most common hematologic problems in the neonatal intensive care unit (NICU). Despite its prevalence, several basic pathophysiologic questions remain unanswered. For instance, there is a lack of evidence-based guidelines for treatment, and the kinetic mechanisms (decreased platelet production, increased platelet consumption, or sequestration) responsible for most varieties of neonatal thrombocytopenia are not well defined. Moreover, a clear correlation between degree of thrombocytopenia and the resulting bleeding risk has not been demonstrated, and no transfusion-trigger studies have been conducted in neonates. As a consequence of these deficiencies in knowledge, there is great variability in platelet transfusion practices among NICUs. This article presents an overview of the evaluation of a neonate with severe thrombocytopenia and a review of current and projected therapeutic options. Platelet Function in Term and Preterm Neonates 15 Matthew A. Saxonhouse and Martha C. Sola Platelet dysfunction likely contributes to the pathophysiology of catastrophic hemorrhages in preterm neonates. In vitro studies have demonstrated that platelets of both term and preterm neonates are hyporesponsive to a variety of agonists. In contrast, template bleeding times of term neonates are shorter than those from adults. Very little is known about this and other tests of primary hemostasis in premature and sick neonates in the neonatal VOLUME 31 NUMBER 1 MARCH 2004 v

2 intensive care unit (NICU). This article covers the current knowledge of platelet function in preterm and term neonates and reviews how new agents (such as recombinant thrombopoietin and recombinant factor VIIa) may enhance neonatal platelet function. Congenital Neutropenia 29 Robert D. Christensen and Darlene A. Calhoun The term congenital neutropenia signifies neutropenia that is present at birth. It includes a wide variety of disorders, some transient and others life long. Some varieties of congenital neutropenia are mild, with blood neutrophil concentrations below normal but not low enough to constitute a significant host defense deficiency. Other varieties of congenital neutropenia are characterized by low blood neutrophil concentrations and a predisposition to repeated infections. Neonatal Neutrophils: The Good, The Bad, and The Ugly 39 Joyce M. Koenig and Mervin C. Yoder Neonates are at considerable risk for bacterial and fungal infections, due in great part to a variety of age-related impairments in neutrophil function. In addition, evidence suggests that the tendency of the most immature neonates to develop chronic inflammatory disorders is also related to neutrophil dysfunction. This article provides an overview of specific functional deficiencies of neutrophils that have been reported in neonates. The Role of Molecular Genetics in the Pathogenesis and Diagnosis of Neonatal Sepsis 53 Antonio Del Vecchio, Nicola Laforgia, Mario Capasso, Achille Iolascon, and Giuseppe Latini Polymorphisms within genes encoding endogenous mediators of inflammation are good candidates for the individual differences in systemic inflammatory responses of neonates to infection. In a similar manner, polymorphisms in the genes encoding drugmetabolizing enzymes, drug transporters, and drug receptors can influence a neonate s risk of an adverse drug reaction or can alter the efficacy of drug treatment. Additionally, molecular tools are proving valuable in the diagnosis of neonatal infection. This article gives an overview of the genetic susceptibility to sepsis, discusses the use of molecular genetics in diagnostic tests for infection, and reviews the potential for more effective and specific therapies for sepsis based on genetic variability. vi

3 Immunoenhancement to Prevent Nosocomial Coagulase- Negative Staphylococcal Sepsis in Very Low-Birth- Weight Infants 69 Lori A. Devlin and Herbert A. Lassiter Extremely low-birth-weight infants are susceptible to invasion by coagulase-negative staphylococci (CONS). This article reviews the epidemiology, immunology, and microbiology of CONS and describes recent clinical trials of immunoenhancing agents such as intravenous immunoglobulin, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and mouse humanized chimeric anti-lipoteichoic acid antibody. Potential avenues of research to reduce the incidence of nosocomial CONS sepsis in premature neonates are presented. Long-Acting Erythropoietin: Clinical Studies and Potential Uses in Neonates 77 Robin K. Ohls and Aihua Dai Aranesp (darbepoietin alfa) is a biologically modified form of recombinant human erythropoietin (rhuepo). Two additional carbohydrate-binding sites give Aranesp a half-life about three times that of rhuepo. Extensive studies in adults and early studies in children indicate that Aranesp can be administered far less frequently than rhuepo with an equivalent erythropoietic effect. This article reviews these studies and reports on the in vitro effects of Aranesp on human fetal and neonatal erythroid progenitors. Nuclear Mechanisms of Hypoxic Cerebral Injury in the Newborn 91 Maria Delivoria-Papadopoulos and Om Prakash Mishra In early studies, we demonstrated that cerebral tissue hypoxia leads to N-methyl-D-aspartate receptor modification and results in increased intracellular Ca 2+. Our subsequent studies have demonstrated an alteration in nuclear Ca 2+ influx mechanisms and an increase in the nuclear Ca 2+ influx after hypoxia. The hypoxiainduced nuclear Ca 2+ influx increase correlated in a curvilinear function with the increase in the degree of cerebral tissue hypoxia. The activity of nuclear membrane high-affinity Ca 2+ -ATPase also increased with the increase in cerebral hypoxia. The expression of the proapototic protein Bax increased as an inverse function with cerebral tissue ATP and phosphocreatine concentrations. However, the expression of the antiapoptotic protein Bcl-2 did not increase after hypoxia. Cerebral tissue hypoxia also led to the activation of caspases 3, 8, and 9. Furthermore, our studies demonstrated that the fragmentation of neuronal genomic DNA increased with increase in degree of cerebral tissue hypoxia. Studies presented in this article elucidate nuclear Ca 2+ influx and nuclear Ca 2+ -mediated vii

4 mechanisms, including signal transduction, apoptotic gene transcription, caspase activation, and nuclear DNA fragmentation, that result in hypoxic neuronal injury in the newborn brain. Biomarkers of Hypoxic Brain Injury in the Neonate 107 Giuseppe Buonocore and Serafina Perrone The specific pathologic processes preceding the onset of irreversible cerebral injury seem to be a combination of several complex mechanisms due to the severity and duration of the insult to the biochemical modifications in the brain. An early diagnosis of the newborn at high risk for brain damage is relevant for preventive programs. Neuroprotective strategies will benefit from the detection of biochemical markers with high reliability and predictability for brain injury. The Role of Complement in Neonatal Hypoxic-Ischemic Cerebral Injury 117 Herbert A. Lassiter Complement activation participates in tissue injury after temporary loss of blood flow (ischemia-reperfusion injury). Recently reported evidence indicates that complement activation is a pathologic mechanism of injury in the post-hypoxic-ischemic neonatal brain. Therefore, recently developed complement inhibitors may find a role in the amelioration of neonatal hypoxic-ischemic cerebral injury. Further research is needed to better define the role of complement in human neonatal cerebral injury and to determine the neuroprotective effect and safety of pharmacologic agents designed to inhibit complement. Recombinant Erythropoietin as a Neuroprotective Treatment: In Vitro and In Vivo Models 129 Sandra Juul The biologic effects of erythropoietin in the central and peripheral nervous system involve the activation of its specific cell surface receptor and corresponding signal transduction pathways. This article reviews the neuroprotective effects of erythropoietin in brain, emphasizing the progress made using in vitro and in vivo research models. Role of Cytokines in Human Intestinal Villous Development 143 Akhil Maheshwari Villous development of the intestine is beginning to be understood in terms of the underlying molecular mechanisms. There is increasing information on the role of cytokines as extrinsic regulators in this process. This article summarizes information available on various cytokines that have been studied in this context. viii

5 Necrotizing Enterocolitis: Preventative Strategies 157 Kristina M. Reber and Craig A. Nankervis Necrotizing enterocolitis (NEC) remains a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC is unclear, prevention strategies have been developed based on clinical observations and epidemiologic and experimental data. Most current strategies have centered on feeding practices (eg, institution of feeds, advancement of feeds, composition of feeds, and standardization of feeding practices). Emerging strategies include amino acid supplementation, the use of platelet-activating factor (PAF) antagonists or PAF-acetylhydrolase administration, polyunsaturated fatty acid administration, epidermal growth factor administration, and the use of pre- and probiotics. Hematopoietic Growth Factors in Neonatal Medicine: The Use of Enterally Administered Hematopoietic Growth Factors in the Neonatal Intensive Care Unit 169 Darlene A. Calhoun and Robert D. Christensen The practice of complete bowel rest in prematurely delivered neonates and those who have undergone surgery for congenital anomalies of the gastrointestinal (GI) tract is common in neonatal intensive care units (NICU). However, increased recognition of the critical role of growth factors in GI development suggests that this practice might be modified to include the administration of synthetic amniotic fluid-like solutions designed to bridge the neonate between their intra-uterine environment and that of the NICU. This article reviews advances in administering synthetic amniotic fluid-like solutions in the NICU. Epidermal Growth Factor and Necrotizing Enterocolitis 183 Bohuslav Dvorak As the number of extremely low-birth-weight infants increases, necrotizing enterocolitis remains a critical eminent problem. Supplementation of enteral feeds with biologically active substances normally present in breast milk, such as epidermal growth factor, seems to be a logical and safe way to reduce the incidence of intestinal inflammation and necrotizing enterocolitis. Continuing basic research and clinical studies are essential before epidermal growth factor can be introduced as an efficient therapeutic approach in the treatment of neonatal necrotizing enterocolitis. Index 193 ix