Pathophysiology, classification, and complications of common asymptomatic thrombocytosis in newborn infants

1. Megakaryopoiesis and thrombopoiesis

Little is known about the pathophysiology underlying thrombocytosis in neonates. Platelets are nonnucleated fragments arising from megakaryocytes. Hematopoiesis transitions from the yolk sac to the liver and then to the bone marrow. Megakaryocytes are found in the yolk sac at a gestational age of 5 weeks and in the liver by a gestational age of 10 weeks, while platelets are first found in the circulation at a gestational age of 8–9 weeks [6]. Bone marrow megakaryopoiesis starts at a gestational age of 11 weeks and then dominates at a gestational age of 20 weeks. Thus, bone marrow is the primary site for megakaryopoiesis in newborn infants.

Megakaryopoiesis and platelet production (thrombopoiesis) are mainly regulated by TPO and other cytokines and hematopoietic growth factors such as interleukin-3 (IL-3), IL-6, and IL-11 [7]. The increased production of these factors during infection or inflammation can stimulate megakaryocyte production, resulting in elevated platelet counts. Ishiguro et al. [8] reported that elevated serum TPO and IL-6 concentrations precede thrombocytosis during acute infection. Platelets are activated by endothelial injury, infection, acute/chronic inflammation, and anemia. Following infection, platelets are activated to interact with leukocytes, monocytes, bacteria, and others through multiple receptors. Activated platelets can interact with bacteria through various receptors such as Tall-like receptor (TLR)-4, a low-affinity receptor for the constant fragment (Fc) of immunoglobulin G (FcγRIIa) and glycoprotein (Gp) IIb/IIIa [9]. As a result, platelets assist in clearing bacteria by presenting them to neutrophils, thus enhancing phagocytosis during infection [7].

2. Thrombopoietin

The regulation of platelet counts relies on the negative feedback mechanism of TPO, which binds to the TPO receptor on platelets and megakaryocytes, reducing plasma-free TPO levels and decreasing thrombopoiesis. A reduction in platelet counts leads to elevated plasma-free TPO, resulting in increased thrombopoiesis [7]. Platelets are mainly removed from the blood in the spleen and liver.

It is well established that TPO concentrations in newborn infants are higher than those in adults [10]. Levels increase after birth, peak on the 2nd day of life, and start decreasing at 1 month of age [11], and they are inversely correlated with platelet counts. Nakayama et al. [12] reported similar results that serum TPO levels soon after birth to 1 month of age are significantly higher than those at 2–6 months after birth. Thereafter, TPO levels decrease with age (Fig.1) [13]. The low expression of TPO receptor on the platelets of newborn infants until 1 month of age decreases TPO clearance, leading to elevated plasma-free TPO levels and increased thrombopoiesis [12]. Megakaryocyte precursor cells of newborn infants are more sensitive to TPO than those of adults [2]. Platelet counts are typically low in small-for-gestational-age (SGA) newborns at birth [14]. However, TPO concentrations in SGA newborns remain controversial. TPO concentrations were significantly elevated in SGA newborns compared to appropriate-for-gestational-age newborns (135 pg/mL vs. 94 pg/mL, respectively) [15] and healthy term newborns (86 pg/mL vs. 72 pg/mL, respectively) [16]. On the other hand, TPO concentrations were not elevated in SGA newborns, especially those with liver problems [14].

3. Anemia and erythropoietin

Erythropoietin (EPO), a regulator of erythrocyte production, is structurally similar to TPO with an amino terminal domain containing a sequence homologous to that of EPO [17,18]. Preterm infants with thrombocytosis show decreased red blood cell counts and elevated endogenous EPO levels due to anemia, which probably results in elevated platelet counts [4]. Increased production of thrombopoietic factors, cytokines, and other hematopoietic growth factors due to anemia might be related to elevated platelet counts as well [2]. Yadav et al. [19] and Özcan et al. [5] reported that anemia was present in 29% and 9% of pediatric patients with thrombocytosis, respectively. It was also reported that 34% of newborn infants with anemia have thrombocytosis [20]. These findings support a negative feedback mechanism of endogenous EPO in thrombocytosis, which has functional as well as structural similarities to TPO. Recombinant human EPO, a potent thrombopoietic factor, also affects thrombopoiesis and erythropoiesis [21,22].

4. Infection and inflammation

Platelets have proinflammatory activity in addition to procoagulant activity. Infectious pathogens and immune complexes formed by them can activate platelets, which then secrete molecules to activate immune reactions [23]. Thom et al. [24] suggested that rebound vigorous multilineage hematopoiesis following myelosuppression due to critical illnesses such as infection, inflammation, or iron deficiency can lead to hyperactive bone marrow and result in thrombocytosis.

1. Classification by platelet count (Table 1)

Table 1.

Classification by platelet count

Thrombocytosis in newborn infants has variably been defined as a platelet count of >400,000/µL, >600,000/µL, or >900,000/µL. Thrombocytosis as defined and classified by Sutor [25] is widely used. Thrombocytosis has been defined as a platelet count ≥500,000/µL and classified as mild (500,000–699,000/µL), moderate (700,000–899,000/µL), severe (900,000–999,000/µL), or extreme (≥1,000,000/µL) according to peak platelet count [26].

2. Classification by etiology (Table 2)

Table 2.

Classification by etiology

Neonatal thrombocytosis is also classified as essential (primary) or reactive (secondary). In most cases, this is a reactive process. Essential thrombocytosis, a myeloproliferative neoplasm with an estimated annual incidence rate of approximately 1.00 per 100,000 adults, is extremely rare in newborns [1]. The incidence of essential thrombocytosis in newborn infants is not well known. Essential thrombocytosis is represented by megakaryocytic hyperplasia in the bone marrow with thrombocytosis, which is mainly caused by mutations in Janus kinase 2 (JAK2) or myeloproliferative leukemia (MPL, a TPO receptor gene) [27]. It is known to increase the risk of vascular events such as hemorrhage and thrombosis due to thrombocytosis. Antiplatelet or cytoreductive treatments are needed to reduce these complications. The differential diagnosis of essential thrombocytosis includes reactive (secondary) thrombocytosis, spurious thrombocytosis, or other forms of myeloproliferative neoplasms such as polycythemia vera or primary myelofibrosis. On the other hand, reactive thrombocytosis is considered a benign condition that is more common in newborns than in adults. Increased platelet production as a result of megakaryopoiesis occurs due to several conditions, such as infections, inflammation, tissue injury, and anemia, resulting in reactive thrombocytosis. Iron deficiency, hemorrhage, stress, exposure to epinephrine, vitamin E deficiency, and rebound from thrombocytopenia can also cause thrombocytosis [20]. Denton and Davis [28] reported that all pediatric cases of extreme thrombocytosis (platelet count, ≥1,000,000/µL) are reactive, requiring no treatment. Wiedmeier et al. [26] reported that all cases of extreme thrombocytosis (platelet count, ≥1,000,000/µL) in newborns and young infants are reactive. All resolved without any hemorrhagic or thromboembolic compliations. They also reported that infection (mostly respiratory tract infections), postoperative status, and anemia could cause thrombocytosis, generally a benign and self-limiting condition [26]. Reactive thrombocytosis rarely increases the risk of hemorrhagic and thromboembolic complications in newborn infants, and it usually does not require antiplatelet or cytoreductive treatment [29]. Elevated platelet counts have also been reported in infants with severe osteogenesis imperfecta, notably those younger than 2 years of age. The authors suggested that elevated platelet counts in infants with severe osteogenesis imperfecta can serve as a marker of inflammation [30]. Asplenia [2] and sickle cell disease [31] can also cause thrombocytosis, especially cases of extreme thrombocytosis (platelet count, ≥1,000,000/µL) due to reduced platelet storage and removal.