Mechanisms underlying thrombocytopenia in the neonatal intensive care unit.

UNLABELLED: Thrombocytopenia is one of the most common hematological problems among neonates in the neonatal intensive care unit (NICU), but in the majority of cases the kinetic mechanism responsible is unclear. This review focuses on both traditional and innovative methods used to evaluate the mechanisms responsible for thrombocytopenia in neonates, and analyzes the data generated from those methods. CONCLUSION: Results of studies using new methods for evaluating thrombocytopenia, coupled with recent descriptions of marrow megakaryocyte mass, suggest that decreased platelet production complicates most cases of thrombocytopenia among neonates in the NICU.

The relationship between hematocrit and bleeding time in very low birth weight infants during the first week of life.

OBJECTIVES: The bleeding time is a measurement of platelet and capillary interaction following a small standardized cutaneous incision. In adults, anemia causes a prolongation of the bleeding time, and we hypothesized that the same would be true in very low birth weight (VLBW) infants during their first week of life. STUDY DESIGN: Template bleeding times, using the Surgicutt Newborn device, were performed on 20 VLBW weight infants 0.28 l/l had no significant reduction in bleeding time following transfusion. CONCLUSIONS: In VLBW infants, during their first week of life (the time when their risk of intraventricular hemorrhage is greatest), a low hematocrit is associated with a significant prolongation in the bleeding time.

Platelet transfusions in the neonatal intensive care unit:factors predicting which patients will require multiple transfusions.

BACKGROUND: Previous studies suggest that recombinant thrombopoietin (rTPO) will increase platelet production in thrombocytopenic neonates. However, the target populations of neonates most likely to benefit should be defined. Studies suggest that rTPO will not elevate the platelet count until 5 days after the start of treatment. Therefore, the neonates who might benefit from rTPO are those who will require multiple platelet transfusions for more than 5 days. This study was designed to find means of prospectively identifying these patients. STUDY DESIGN AND METHODS: A historic cohort study of all patients in the neonatal intensive care unit (NICU) at the University of Florida who received platelet transfusions from January 1, 1997, through December 31, 1998, was conducted. RESULTS: Of the 1389 patients admitted to the NICU during the study period, 131 (9.4%) received platelet transfusions. Seventeen were treated with extracorporeal membrane oxygenation and were excluded from further analysis. Of the remaining 114 patients, 55 (48%) received one transfusion and 59 (52%) received more than one transfusion (21 had >4). None of the demographic factors examined predicted multiple platelet transfusions. However, two clinical conditions did; liver disease and renal insufficiency. Neonates who received one platelet transfusion had a relative risk of death 10.4 times that in neonates who received none (p = 0.0001). Neonates who received >4 platelet transfusions had a risk of death 29.9 times that in those who received no transfusions (p = 0.0001). CONCLUSION: NICU patients with liver disease or renal insufficiency who receive one platelet transfusion are likely to receive additional transfusions. Therefore, these patients constitute a possible study population for a Phase I/II rTPO trial.

Epidemiologic and outcome studies of patients who received platelet transfusions in the neonatal intensive care unit.

STUDY DESIGN: We conducted a historic cohort study of neonates who received platelet transfusions at the National Institute of Perinatology, Mexico City, from January 1997 to May 2000. We obtained descriptive and outcome data, and assessed demographic and laboratory means of predicting "good candidates" for a future recombinant thrombopoietin (rTpo) trial. RESULTS: A minority of the transfused patients (11.4%) received only one transfusion; the majority (88.6%) received multiple transfusions. Neonates who received one or more platelet transfusions were more likely to die (24.5% mortality) than neonates who received no platelet transfusions (3.7% mortality). Regression analyses indicated that the presence of liver disease was the best predictor of a "good candidate" for rTpo administration. CONCLUSION: The majority of neonates in our institution who receive platelet transfusions receive multiple, not single, transfusions. Receiving any platelet transfusion is a marker for high risk of death. Neonates with liver disease who receive platelet transfusions might be a reasonable group for a phase I rTpo trial.

Dose-response relationship of megakaryocyte progenitors from the bone marrow of thrombocytopenic and non-thrombocytopenic neonates to recombinant thrombopoietin.

Megakaryocyte (MK) progenitors from the marrow of adults undergo dose-dependent clonogenic proliferation in response to recombinant thrombopoietin (rTpo). It is unknown whether progenitors from the marrow of thrombocytopenic neonates display rTpo dose-dependent proliferation and whether they are more or less sensitive to rTpo than progenitors from non-thrombocytopenic neonates or adults. To assess this, we cultured marrow from four thrombocytopenic and four non-thrombocytopenic neonates, and from six healthy adults, in a serum-free system in the presence of increasing concentrations of rTpo (0-100 ng/ml). Marrow from the thrombocytopenic and non-thrombocytopenic neonates generated three times more MK colonies/105 light density cells (129 +/- 39 and 167 +/- 30 respectively) than marrow from adults (54 +/- 30, P < 0.0001) at a rTpo concentration of 50 ng/ml. Neonatal and adult samples had a rTpo dose-dependent increase in MK colonies. However, neonates reached a maximal number of colonies at a rTpo concentration of 10 ng/ml, compared with 50 ng/ml in adults, resulting in a larger area under the rTpo dose-response curve for neonatal progenitors (P = 0. 0047). Neonates also generated more large MK colonies than the adults (24% vs. 2% at 100 ng/ml).

Performing and interpreting the bleeding time in the neonatal intensive care unit.

In summary, the bleeding time is a helpful clinical tool to detect and investigate certain hemostatic defects in neonates and to evaluate the adequacy of treatments. A prolonged bleeding time alone is sometimes not sufficient to diagnose specific conditions requiring further investigations. Platelet hyporeactivity in the first days of life, gestational age, platelet dysfunction secondary to various neonatal or maternal pathologic conditions, neonatal or maternal drug administration, and hematocrit must be considered for the correct interpretation of the bleeding time test in neonates. In addition, reliable test results can be ensured only by the scrupulous execution of the procedure.

Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit.

Thrombocytopenia is a very frequent problem among sick neonates, affecting up to 35% of all infants admitted to the NICU. Although multiple clinical conditions have been causally associated with neonatal thrombocytopenia, the cause of the thrombocytopenia is unclear in up to 60% of affected neonates. This article provides neonatologists with a practical approach to the thrombocytopenic neonate, with an emphasis on conditions that could be life-threatening or could have significant implications for further pregnancies. An overview of the current therapeutic modalities is also presented, including a discussion of the possible use of recombinant thrombopoietic cytokines to treat certain groups of thrombocytopenic neonates.

Pharmacokinetics, pharmacodynamics, and safety of administering pegylated recombinant megakaryocyte growth and development factor to newborn rhesus monkeys.

Thrombocytopenia is common among sick neonates. Certain groups of thrombocytopenic adults respond favorably to the administration of recombinant thrombopoietin or to pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a recombinant human polypeptide that contains the receptor-binding N-terminal domain of thrombopoietin. The effectiveness and safety of such treatment in neonates, however, have not been reported. The purpose of the present study was to determine the biologic activity and safety of PEG-rHuMGDF administration to newborn rhesus monkeys. Eight monkeys were divided into four groups and treated subcutaneously with 0.00, 0.25, 1.00, or 2.50 microg/kg once daily for 7 d. Complete blood counts, serum chemistries, clotting panels, and MGDF levels were followed serially, and hematopoietic progenitor cell assays were performed on bone marrow aspirates before the first dose and again on d 8. Pharmacokinetic evaluations were performed on the animals that received the highest dose of PEG-rHuMGDF. All monkeys had normal growth during the study period, and all chemistries, clotting studies, and blood pressure measurements were normal. The peak serum MGDF concentration occurred at 3 h, and the half-life was 8.4 to 13.0 h. As in adult rhesus monkeys, platelet counts in the treated neonates began to rise on d 6, peaked on d 11, and returned to baseline by d 23. The two highest doses generated an 8- to 12-fold increase in platelets, whereas those treated with 0.25 microg/kg had a 6-fold increase. Other hematologic parameters measured were unaffected. Thus, newborn monkeys responded to doses of PEG-rHuMGDF that were similar to or smaller than (per kilogram body weight) those that are effective in adult animals and did so without obvious short-term toxicity.

A bone marrow biopsy technique suitable for use in neonates.

Thrombocytopenia and neutropenia are common among neonates in intensive care units. Bone marrow aspirations are sometimes performed as part of their evaluation. However, marrow biopsies have not been reported from living neonates. Since architecture and cellularity cannot generally be accurately assessed from marrow aspirates, we devised a biopsy technique which we successfully applied to five cytopenic neonates (three with severe persistent thrombocytopenia and two with idiopathic neutropenia). This technique used a 19 gauge, half-inch Osgood needle to obtain bone marrow clots from the tibias of small preterm neonates which enabled the assessment of marrow cellularity and architecture. On the basis of our initial experience we have ceased using the traditional bone marrow aspiration technique in neonates and now use this technique exclusively.

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.

Little is known about thrombopoietin (Tpo) production in human fetuses and neonates. As a step toward determining whether Tpo is relevant to platelet production in the fetus and neonate, we hypothesized that: (1) like other cytokines, Tpo is present in the cord blood in higher concentrations than in adult plasma; (2) Tpo and its receptor (c-mpl) are expressed in fetuses at, and following, 5-6 weeks post-conception (when platelet production begins); and (3) the sites of Tpo and c-mpl production in the fetus are similar to those of adults. We quantified Tpo, by ELISA, in the plasma of 50 adults, as well as in the umbilical cord plasma of 50 preterm and term infants. We also characterized, by RT-PCR, the organ distribution of Tpo and c-mpl during fetal development (at 8 and 16 weeks). Tpo concentrations were measurable (> or =41 pg/ml) in only two of the 50 adult samples (44 and 46 pg/ml), but in 24 of the 50 cord plasma samples (of the 24 samples, the median was 62 pg/ml; mean+/-SD, 80+/-39 pg/ml). Tpo levels did not correlate with either gestational age or platelet count at birth. Similarly to adults, in the fetal tissues, Tpo transcripts were found in all organs tested, but the most dense bands were from liver. C-mpl transcripts were also predominantly from liver. We conclude that: (1) Tpo is present in higher concentrations in cord plasma than in venous plasma of adults; (2) Tpo and c-mpl transcripts are detected in human fetuses as early as the onset of platelet appearance; and(3) Tpo and c-mpl have a similar organ distribution in fetuses and adults.

Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit.

Thrombocytopenia is a frequent occurrence in the neonatal intensive care unit (NICU), but the role of thrombopoietin (Tpo) in the pathophysiology is unknown. We obtained serial plasma Tpo concentrations in 20 thrombocytopenic neonates in our NICU, and performed bone marrow studies in 15. The initial Tpo levels ranged from undetectable (<41 pg/ml) to 1112 pg/ml and did not correlate with gestational age or platelet count. Neonates with decreased marrow megakaryocytes did not have plasma Tpo levels as high as those reported in adults, particularly in small for gestational age infants (Tpo < 300 pg/ml). In 14/15 neonates followed until resolution, the Tpo concentration decreased as the platelet count increased.

Production of granulocyte colony-stimulating factor by the human placenta at various stages of development.

The human placenta is capable of producing a variety of haematopoietic growth factors in vitro. It is not clear, however, whether the placenta produces such factors in vivo and if so, whether placental production of haematopoietic growth factors has a physiological role in fetal haematopoietic development. As a step toward making this determination, we assessed whether the onset of placental production of granulocyte colony-stimulating factor (G-CSF), in vivo, coincides with the onset of granulocytopoiesis in the developing fetus. To make this assessment, we obtained human placentae between 10 weeks of gestation and term and studied production of G-CSF in several ways. First, we sought to determine whether the onset of production of G-CSF mRNA in the placenta immediately precedes the appearance of neutrophil development in the fetus. Second, we assessed the effect of gestational age on the capacity of the placenta to generate G-CSF in vitro, by incubating cubes of placenta, with or without including interleukin-1 alpha (IL-1 alpha) in the culture media, and quantifying G-CSF in the cell culture supernatants 24 h later. Third, we assessed the rate of G-CSF production by the placenta, by perfusing two normal, term placentae using a membrane-oxygenator system, and quantifying G-CSF, at intervals, in the perfusates. We found: (1) no evidence that placental production of G-CSF is involved in regulating granulocytopoiesis in the fetus, (2) that the healthy placenta contains little or no G-CSF mRNA in vivo, (3) the placenta at term has a far greater capacity to produce G-CSF, when stimulated, than does the placenta before term, and (4) that although the placenta does not normally produce G-CSF in vivo, it has the capacity of generating very large quantities of G-CSF continuously over at least several days.

[Bacampicillin in dentistry. Clinical efficacy and tolerance]. / La bacampicillina in odontostomatologia. Efficacia clinica e tolleranza.

The efficacy and tolerability of the Bacampicillin was evaluated on 80 patients (40 males and 40 females) with infectious pathology. This antibiotic was delivered at different dosage, alone or in association with Fans. The Authors report the statistical results showing the good therapeutical activity, at full dosage, with minor side effects.

[Study on health status and oral hygiene of children at a primary school. Health status and oral hygiene in schoolchildren]. / Indagine sullo stato di salute e di igiene orale dei bambini di una scuola elementare. Stato di salute e di igiene orale in età scolare.

The Authors refer about a research made in a primary school after checking mouth sickness in school boys. The research concerns three periods: 1st. medicaL examination, 2 nd. instructions about a correct oral hygiene, 3 rd. anew inspection. The conclusions they made, are the following: now only the children know what they must do for their teeth in order to avoid mouth sickness and how to prevent then, but also their parents and often their teachers are not sensitive to this problem. So it is necessary that the prevention work begun by the dentist, will be carried on by parents and by teachers.