Severe neonatal thrombocytopenia is a rare but fatal disease in NICU, however, it is rarely reported and examined in detail, particularly in the Chinese population. This study was conducted at a large tertiary pediatric hospital in China. Our data indicated that the overall incidence rate of severe neonatal thrombocytopenia was 3.3% in our NICU over the last 5 years, which was comparable to the rates reported in the literature. We discovered that lower birth weight was correlated with lower platelet counts in this cohort. Furthermore, severe thrombocytopenia at anytime during the NICU stay was more common in the smallest patients, with the prevalence in ELBW neonates more than twice as high as in patients weighing over 1,000 g at birth. Biological differences observed between fetal, neonatal, and adult megakaryocytes are likely involved in the marked susceptibility of ELBW neonates to develop thrombocytopenia [5].
Our data showed sepsis, especially early-onset sepsis, predominated among the etiologies of severe neonatal thrombocytopenia, which was consistent with the findings of Ree et al. [6]. The increased incidence of severe thrombocytopenia may be attributable to a partial response in terms of platelet and thrombopoietin production during sepsis with diminished energy reserves in the host [7]. Furthermore, we explore the pathogenic organisms in culture-positive cases, indicating that gram-negative bacteria was the most common pathogen isolated from blood culture samples and was shown to be associated with a lower nadir platelet count. Arabdin et al. [8] reported that neonatal thrombocytopenia was independently associated with gram-negative sepsis. In animal models, the likely mechanisms of thrombocytopenia associated with gram-negative sepsis include cell-free extracts comprising lipopolysaccharide and a constituent of gram-negative bacteria’s cell wall [9]. Furthermore, it was discovered that an elevated CRP level, an infective marker, was associated with decreased platelet counts. This finding was also supported by Rabindran et al. [10] and Arabdin et al. [8].
Genetic defect was the second most common etiology in our series. Trio-WES was performed for neonates with a suspected genetic disease or an unknown cause of severe thrombocytopenia, resulting in the diagnosis of 28 patients, including seven cases caused by WAS gene mutation, which has been highlighted in previous studies. We analyzed the records of these patients to look for any commonality of features among this group and found that congenital thrombocytopenia needs to be considered when unexplained severe or very severe thrombocytopenia occurs in term or normal birth weight neonates within three days after birth, especially in those with congenital malformations or a family history of thrombocytopenia.
In our study, perinatal asphyxia, especially severe asphyxia, also played an important role in severe neonatal thrombocytopenia. The findings revealed that the incidence of early-onset severe thrombocytopenia was significantly higher in neonates following perinatal asphyxia in comparison to late-onset severe thrombocytopenia. The mechanism by which perinatal asphyxia causes early-onset thrombocytopenia remains unclear. Several studies have shown that acute severe hypoxia may play a role in the pathogenesis of neonatal thrombocytopenia: reducing platelet survival time and impairing platelet production by altering the structural and functional characteristics of megakaryocytes [11, 12]. The results in these studies also suggest a correlation between the severity of perinatal asphyxia and thrombocytopenia, and are thus in agreement with our study.
The prevalence of hemorrhage in thrombocytopenic neonates was approximately 20–30% according to the literature and thus markedly lower than our rate of 61.9% in severe thrombocytopenia [13]. The higher incidence of total hemorrhage in neonates with very severe thrombocytopenia discovered in our study was similar to that reported in the literature [4]. The risk of hemorrhage was found to be associated with definite causes of thrombocytopenia in this study. NEC and sepsis have been identified as the most common diagnoses in the hemorrhage and IVH group, respectively, as shown in our data. And a similar result was observed in Robert et al.’s study [14]. However, pathological hemorrhage in neonates is multifactorial and unlikely to be attributable solely to a lower platelet count. We recorded over half of the neonates who have developed IVH become thrombocytopenic during the subsequent course of bleeding, as opposed to thrombocytopenia being the cause of IVH, which was in line with several studies [13, 15, 16], and whether there was a causal link between severe thrombocytopenia and IVH requires a deeper inquiry.
In line with previous reports, platelet transfusions did not shorten the duration of thrombocytopenia, which may be explained, in part, by the fact that severely ill patients receive more platelet transfusions; but may also be explained by adverse effects of platelet transfusions [17]. We recorded a comparable overall mortality rate of 26.8%, which was positively correlated with the number of platelet transfusions, but not with the platelet nadir. This finding was in line with several studies [16, 18, 19]. Neonates with late-onset severe thrombocytopenia had a higher mortality rate than those with early-onset severe thrombocytopenia (26.1% vs. 11.2%), and the highest mortality rate was attributable to severe thrombocytopenia secondary to NEC. We speculate that this increase in mortality rate can be explained by the fact that severe thrombocytopenia secondary to NEC occurs more commonly after 72 h of life and has more serious and life-threatening conditions.
The great majority (62.3%) of deaths were ascribed to cardiopulmonary failure and 10 (5.2%) cases eventually progressed to mutiple organ dysfunction syndrome. DIC was recorded in 10 (5.2%) episodes of discharge diagnosis and coagulopathy in 56 (28.9%). The prolongation of both PT and APTT in deceased patients indicated a correlation between death from severe thrombocytopenia and coagulation disorders [20]. The production and accumulation of lactate in blood occur after asphyxia due to poor tissue perfusion following anaerobic metabolism [21]. Given the elevated lactate levels observed in deceased patients, it is plausible that perinatal asphyxia was more prevalent and severe in this cohort compared to those who survived.
A limitation of this study is that it was conducted at a single centre with a relatively small sample size due to the rarity of the disease and the diversity of its aetiologies. Multicentre studies are required to address the limitations of the sample size and the discrepancies in the results due to regional specificity. In addition, intrauterine growth restriction and antenatal steroid administration were not included in the analysis, as several patients were initially treated in the outer court and subsequently transferred to our specialized children’s hospital.