Martha Sola-Visner

Thrombocytopenia among extremely low birth weight neonates: data from a multihospital healthcare system

Objectives:Thrombocytopenia is common in neonatal intensive care units (NICU), with 18 to 35% of patients developing this problem before hospital discharge. It might be even more common among extremely low birth weight neonates (ELBW, ⩽1000 g birth weight). However, little is known about thrombocytopenia in the ELBW population. We sought to determine the incidence, timing, causes, platelet transfusions given, and outcomes of thrombocytopenia among ELBW neonates.Study design:We performed a cohort analysis of all 284 ELBW neonates born during 2003 and 2004 cared for in any of the Intermountain Healthcare level III NICUs.Results:Multiple platelet counts were obtained in all 284 (range, 4 to 441 platelet counts/patient). Of the 284, 208 (73%) had one or more platelet counts ⩽150 000/μl. Most were detected during the first days of life; 80% were detected during the first week and only 20% were detected thereafter. Thrombcytopenia was more common among the smallest patients; 85% incidence among those ⩽800 g, 60% among those 801 to 900 g, and 53% among those 901 to 1000 g. Platelet transfusions were given to 129 of the 208 thrombocytopenic neonates. More than 90% were given prophylactically (the patient was not bleeding). The mortality rate among those that received platelet transfusions was twice that of those that received no platelet transfusions (P<0.01). In 48% of cases, the cause of the thrombocytopenia went undiagnosed. The most common explanations were being small for gestational age or delivered to a hypertensive mother, DIC, bacterial infection, fungal infection, and necrotizing enterocolitis, respectively.Conclusions:We observed thrombocytopenia among ELBW neonates at a rate more than twice that reported among the general NICU population. Much remains to be discovered about the etiology and best treatments of thrombocytopenia among ELBW neonates.

Platelet reference ranges for neonates, defined using data from over 47 000 patients in a multihospital healthcare system

Objective:Identifying a platelet count as abnormal (thrombocytopenia or thrombocytosis) can facilitate recognizing various disease states. However, the published reference ranges for platelet counts in neonates may be imprecise, as they were generated from relatively small sample sizes and compiled before modern platelet enumeration methods.Study design:We derived new neonatal reference ranges for platelet counts and mean platelet volume (MPV) measurements using electronic data accumulated during a recent 6-year period from a multihospital healthcare system.Result:Platelet counts were obtained between the first and the 90th day after birth, from 47 291 neonates delivered at 22 to 42 weeks gestation. The first platelet counts obtained in the first 3 days of life, increased over the range of 22 to 42 weeks gestation. In those born ⩽32 weeks gestation, the lower reference range (5th percentile) was 104 200 μl−1, but it was 123 100 μl−1 in late-preterm and -term neonates. Advancing postnatal age had a significant effect on platelet counts; during the first 9 weeks, the counts fit a sinusoidal pattern with two peaks; one at 2 to 3 weeks and a second at 6 to 7 weeks. The upper limit of expected counts (95th percentile) during these peaks were as high as 750 000 μl−1.Conclusion:The figures herein describe reference ranges for platelet counts and MPV determinations of neonates at various gestational ages during their first 90 days. Expected values differ substantially from the 150 000 μl−1 to 450 000 μl−1 range previously used to define neonatal thrombocytopenia and thrombocytosis. The new definitions will render the diagnoses of neonatal thrombocytopenia and thrombocytosis less commonly than when the old definitions were used, because the new ranges are wider than 150 000 μl−1 to 450 000 μl−1.

Neonatal thrombocytopenia: What we do and don't know

The evaluation and management of thrombocytopenia is a frequent challenge for neonatologists, as it affects 22-35% of infants admitted to the neonatal intensive care unit. Multiple disease processes can cause neonatal thrombocytopenia, and these can be classified as those inducing early thrombocytopenia (< or =72 h of life) and those inducing late-onset thrombocytopenia (>72 h). Most cases of neonatal thrombocytopenia are mild to moderate, and do not warrant intervention. In approximately 25% of affected neonates, however, the platelets count is <50 x 10(9)/L, and therapy with platelet transfusions is considered to decrease the risk of hemorrhage. The existing evidence to establish platelet transfusion triggers in neonates is very limited, but it suggests that transfusing platelets to non-bleeding neonates with platelet counts >50 x 10(9)/L does not decrease the risk of intraventricular hemorrhage (IVH), and that 30 x 10(9)/L might be an adequate threshold for stable non-bleeding neonates. However, adequately powered multi-center studies are needed to conclusively establish the safety of any given set of neonatal transfusion guidelines.

Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes

Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low-ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome.

Testing platelet mass versus platelet count to guide platelet transfusions in the neonatal intensive care unit

BACKGROUND: Platelet (PLT) transfusions can bestow significant benefits but they also carry risks. This study sought a safe means of reducing PLT transfusions to neonatal intensive care unit (NICU) patients with thrombocytopenia by comparing two transfusion guidelines, one based on PLT count and the other on PLT mass (PLT count times mean PLT volume).

Current Approaches to the Evaluation and Management of the Fetus and Neonate with Immune Thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia is not a well-known disease, except among specialists in maternal-fetal medicine, neonatologists, and certain pediatricians (ie, hematologists). However, this is by far the most common cause of early severe thrombocytopenia in neonates and of intracranial hemorrhage in term neonates. In addition, if a newborn is affected with alloimmune thrombocytopenia, the next child in the family will likely be more severely affected. Thus, the accurate diagnosis and appropriate management of this disorder are of extreme importance in perinatal medicine and will constitute the focus of this review.

Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system

Objective:Several studies have indicated a correlation between the number of platelet transfusions received by newborn intensive care unit (NICU) patients and the mortality rate. The number of platelet transfusions might be a marker for level of illness, and thus predictive of mortality. However, an alternative hypothesis is that multiple platelet transfusions themselves are harmful in this population.Study Design:We evaluated data from all thrombocytopenic neonates cared for in the Intermountain Healthcare NICUs in the past 4 years, seeking associations between the lowest platelet count recorded, number of platelet transfusions received and mortality rate. We also conducted a sensitivity analysis to examine the hypothesis that platelet transfusions were responsible for some fraction of the mortality rate.Result:Transfusion and outcome data were examined from 1600 thrombocytopenic NICU patients. At any level of platelet count, some patients received platelet transfusions but others did not. However, at all levels of platelet count, those that received platelet transfusions had a higher mortality rate. Neonates not given any platelet transfusions had a mortality rate of 2%, those with 1 or 2 transfusions had a mortality rate of 11% (P<0.001); those with >10 had a mortality rate of 35% (P<0.001); and those with ⩾20 had a mortality rate of 50% (P<0.001). A sensitivity analysis suggested that the platelet transfusions themselves were very likely responsible for some fraction of the increasing mortality rate.Conclusion:The number of platelet transfusions administered in the NICU predicts the mortality rate. Some of this correlation is ascribable to unknown and unmeasured factors such as level of illness. However, the present data and the sensitivity analysis both suggest that some of this correlation is due to harmful effects of multiple platelet transfusions in this group of patients.

Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies

Thrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Frequently, platelet transfusions are given to thrombocytopenic infants in an attempt to decrease the incidence or severity of hemorrhage, which is often intracranial. Whereas there is very limited evidence to guide platelet transfusion practices in this population, preterm infants in the first week of life (the highest risk period for bleeding) are nearly universally transfused at higher platelet counts than older infants or children. To a large extent, this practice has been influenced by the observation that neonatal platelets are hyporeactive in response to multiple agonists in vitro, although full-term infants exhibit normal to increased primary hemostasis. This apparently paradoxical finding is due to factors in the neonatal blood that enhance the platelet-vessel wall interaction and counteract the platelet hyporeactivity. Relatively few studies have evaluated the platelet function and primary hemostasis of preterm infants, the subset of neonates at highest risk of bleeding and those most frequently transfused. Current understanding of platelet production and function in preterm and full-term neonates, how these factors affect their response to thrombocytopenia and their primary hemostasis, and the implications of these developmental differences to transfusion medicine are reviewed herein.

Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates.

Thrombocytopenia is frequent among sick neonates, but little is known about its underlying mechanisms. It is known, however, that neonatal megakaryocytes are smaller and of lower ploidy than their adult counterparts and that smaller megakaryocytes produce fewer platelets than larger, more polyploid, megakaryocytes. We hypothesized that neonatal megakaryocytes would not increase their size in response to thrombocytopenia, thus limiting the ability of neonates to mount a response. To test this, we obtained marrow specimens from thrombocytopenic and nonthrombocytopenic neonates and adults. Megakaryocytes were immunohistochemically stained, quantified using an eyepiece reticle, and measured using an image analysis system with incorporated electronic micrometer. We found that, after adjusting for differences in cellularity, neonates and adults had similar megakaryocyte concentrations. When samples from the same sources were compared (tibial clot and vertebral body sections in neonates, iliac crest biopsies in adults), there were also no differences in megakaryocyte concentration between thrombocytopenic and nonthrombocytopenic subjects. The megakaryocyte diameter, however, was greater in adults than in neonates (19.4 ± 3.0 versus 15.3 ± 1.7 μm, p < 0.0001). Thrombocytopenic adults also had a higher proportion of large megakaryocytes than nonthrombocytopenic adults (p < 0.001). This was not observed among thrombocytopenic neonates, suggesting a developmental limitation in their ability to increase megakaryocyte size.

Distinct differences in platelet production and function between neonates and adults: implications for platelet transfusion practice

Thrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Among neonates, preterm infants are the subgroup at highest risk for thrombocytopenia and hemorrhage, which is frequently intracranial. Although there is no evidence of a relationship between platelet (PLT) count and occurrence of major hemorrhage, preterm infants are commonly transfused prophylactically when PLT counts fall below an arbitrary limit, and this threshold is usually higher than for older infants or adults. This liberal practice has been influenced by the observation that, in vitro, neonatal PLTs are hyporeactive in response to multiple agonists. However, full‐term infants exhibit normal to increased primary hemostasis due to factors in neonatal blood that enhance the PLT–vessel wall interaction. Additionally, cardiorespiratory problems are considered the main etiologic factors in the development of neonatal intraventricular hemorrhage. In this review, we will discuss the developmental differences that exist in regard to PLT production and function, as well as in primary hemostasis in preterm and term neonates, and the implications of these developmental differences to transfusion medicine. PLT transfusions are not exempt of risk, and a better understanding of the PLT function and the hemostatic profile of premature infants and their changes over time and in response to illness is the starting point to design randomized controlled trials to define optimal use of PLT transfusions in premature neonates. Without these future trials, the marked disparities in PLT transfusion practice in neonates between hospitals and countries will remain over time.