Neonatal thrombocytopenia: Etiology

INTRODUCTION — Thrombocytopenia, defined as a platelet count <150,000/microL [1], occurs more often during the neonatal period than in older populations. In particular, the risk and severity of thrombocytopenia increases for newborns admitted to neonatal intensive care units (NICUs). Thrombocytopenia is associated with increased risk of bleeding, and severe thrombocytopenia (platelet count <50,000/microL) is associated with significant morbidity. As a result, it is important to identify at-risk infants, and if needed, to initiate therapy to prevent complications.

The etiology of neonatal thrombocytopenia in the newborn is reviewed here. The evaluation and general management of neonatal thrombocytopenia are discussed separately. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management".)

DEFINITIONS — Neonatal thrombocytopenia is defined as a platelet count <150,000/microL. This is the same definition used in adults, which corresponds to the 5^th percentile for a normal adult population (ie, approximately 5 percent of adults have platelet counts below this level). However, it is important to note that a considerably higher percentage of newborns, particularly preterm neonates, will present with thrombocytopenia [2-4]. (See 'Epidemiology' below.)

Thrombocytopenia is classified by severity depending on the platelet count:

●Mild – Platelet count 100,000 to <150,000/microL.

●Moderate – Platelet count 50,000 to 99,000/microL.

●Severe – Platelet count <50,000/microL. Severe thrombocytopenia is associated with an increased risk of bleeding resulting in morbidity or death [5].

EPIDEMIOLOGY — Healthy preterm and term newborns are more likely to be thrombocytopenic with platelet counts below <150,000/microL than adults and older children [3,4,6]. The risk of thrombocytopenia increases with decreasing gestational age (GA). One study of 34,146 neonates (GA from 22 to 42 weeks) reported the 5^th percentile for neonates was lower than the standard adult value of 150,000/microL and decreased with decreasing GA [4]. For example, the 5^th percentile was 104,200/microL for infants below 32 weeks gestational age (GA) and was 123,100/microL for late preterm (34 to 36 weeks GA) and term (GA greater than 37 weeks) infants. Platelet counts increased with advancing postnatal age.

Reported predisposing factors for neonatal thrombocytopenia include chronic fetal hypoxia related to pregnancy-related maternal hypertension, maternal diabetes, preterm birth, sepsis, asphyxia, intrauterine growth restriction (birth weight [BW] <10^th percentile for GA), and necrotizing enterocolitis (NEC) [1,7,8].

Severe thrombocytopenia — Severe neonatal thrombocytopenia is uncommon in the general healthy newborn population, with a reported incidence between 0.14 and 0.24 percent [2,9]. However, infants admitted to the neonatal intensive care unit (NICU) have a higher risk of severe thrombocytopenia, with a reported risk between 2.4 and 5 percent [10,11]. Data from NICUs in the United Kingdom demonstrated that 5 percent of infants admitted to NICUs had a platelet count <60,000/microL and 60 percent of these patients received platelet transfusions [12].

The risk of severe thrombocytopenia (platelet count <50,000/microL) increases with decreasing GA [4,13,14]. The risk is greatest in the most preterm infants (GA <28 weeks) as illustrated in a retrospective study of 284 extremely low birth weight (ELBW) infants (BW <1000 g) born between 2003 and 2004 that reported 28 percent of patients had severe thrombocytopenia, 56 percent had platelet counts of <100,000/microL, and 73 percent of patients had platelet counts of <150,000/microL within the first three days of life [7].

CLASSIFICATION OF ETIOLOGY — Causes of thrombocytopenia can be classified by several different methods including:

●Platelet size (large, normal, and small)

●Mode of acquisition (congenital or acquired)

●Timing of presentation – Early (<72 hours of age) or late (≥72 hours of age) onset

●Gestational age (GA)

●Mechanisms:

•Increased destruction (including sequestration/pooling and activation/consumption of platelets)

•Decreased production of platelets

These classifications are useful in the diagnostic evaluation of neonatal thrombocytopenia as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Diagnostic evaluation to identify underlying cause'.)

This review will describe the most common causes of neonatal thrombocytopenia based on the underlying mechanism of thrombocytopenia (table 1) [5,15]. Case series report that a cause of thrombocytopenia is identified in approximately 50 to 75 percent of infants admitted to neonatal intensive care units (NICUs) [7,8].

INCREASED DESTRUCTION — Increased platelet destruction is the most common mechanism for neonatal thrombocytopenia and is seen in a number of neonatal conditions. In particular, thrombocytopenia due to an underlying destructive immunologic mechanism is a common cause of early-onset neonatal thrombocytopenia, especially in otherwise healthy term newborns. This is caused by the placental crossing of maternal antibodies, which destroy neonatal platelets. In a French prospective study, the incidence of immune thrombocytopenia, (defined as a platelet count <150,000/microL) in the general newborn population was estimated at 0.3 percent [16].

Immune-mediated thrombocytopenia — Immune-mediated processes are among the most common causes of neonatal thrombocytopenia. Autoantibodies, drug-dependent antibodies, or alloantibodies mediate platelet destruction through interaction with platelet membrane antigens or by forming immune complexes, which can bind to reticuloendothelial cell Fc receptors leading to platelet clearance from the circulation.

In neonates, causes of immune-mediated thrombocytopenia include (see "Neonatal immune-mediated thrombocytopenia"):

●Neonatal alloimmune thrombocytopenia (NAIT)

●Neonatal autoimmune thrombocytopenia

●Drug-induced thrombocytopenia due to drug-dependent antibodies

Neonatal alloimmune thrombocytopenia — Neonatal alloimmune thrombocytopenia (NAIT), also referred to as fetal and neonatal alloimmune thrombocytopenia (FNAIT), occurs when fetal platelets contain an antigen inherited from the father that the mother lacks. During pregnancy, the mother forms immunoglobulin G (IgG)-class antiplatelet antibodies against the "foreign" antigen, which cross the placenta and destroy fetal (FNAIT) and neonatal (NAIT) platelets that express the paternal antigen. The clinical manifestations, diagnosis, and management of NAIT are discussed in detail separately. (See "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal alloimmune thrombocytopenia'.)

Neonatal autoimmune thrombocytopenia — Neonatal autoimmune thrombocytopenia is mediated by maternal antibodies that react with both maternal and fetal platelets. This occurs in maternal autoimmune disorders, including immune thrombocytopenia and systemic lupus erythematosus (SLE). The diagnosis usually is apparent from the mother's medical history and the presence of maternal thrombocytopenia. However, the platelet count of affected mothers may be normal after a splenectomy or if there is sufficient compensatory thrombopoiesis. Mothers of infants with unexplained neonatal thrombocytopenia should be investigated for the presence of an autoimmune disorder, as neonatal thrombocytopenia can be the initial presenting sign [17]. (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)

Healthy women without a history of an autoimmune disorder sometimes develop gestational thrombocytopenia that usually is mild [2,18]. This condition may be a mild and transient form of ITP and is considered benign. Neonatal thrombocytopenia is rare. (See "Thrombocytopenia in pregnancy", section on 'Gestational thrombocytopenia (GT)'.)

The clinical manifestations, diagnosis, and management of neonatal autoimmune thrombocytopenia are discussed in detail separately. (See "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal autoimmune thrombocytopenia'.)

Sequestration and trapping — Causes of thrombocytopenia due to sequestration and trapping in the neonate are uncommon and include:

●Hypersplenism – Thrombocytopenia may be associated with an enlarged spleen. Underlying disorders resulting in splenomegaly include hemolytic anemia, congenital hepatitis due to viral infection, and portal vein thrombosis [19]. The clinical features depend upon the associated condition. Management includes identification and treatment of the underlying cause. Platelet transfusions are given as needed. Splenectomy, often considered in the older child or adult, is rarely needed in the neonatal period. (See "Approach to the child with an enlarged spleen".)

●Kasabach-Merritt phenomenon – Kasabach-Merritt is associated with kaposiform hemangioendothelioma, an aggressive form of giant hemangioma, and not true common hemangiomas of infancy. Thrombocytopenia results from shortened platelet survival caused by sequestration of platelets in the vascular malformation with platelet activation and consumption. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)", section on 'Kasabach-Merritt phenomenon'.)

Platelet activation and consumption

Disseminated intravascular coagulation — Disseminated intravascular coagulation (DIC) is a systemic process producing both thrombosis and hemorrhage. It is a secondary disorder caused by activation of the coagulation system by tissue damage from a variety of primary underlying diseases (eg, sepsis, asphyxia, meconium aspiration, necrotizing enterocolitis, or severe neonatal respiratory distress syndrome) [3,20]. The diagnosis is based on both clinical findings (eg, hemorrhage and thrombocytopenia in a patient with a predisposing medical condition) and abnormal coagulation studies. Confirming laboratory studies include prolonged prothrombin time, prolonged activated partial thromboplastin time, decreased plasma fibrinogen concentration, and increased fibrin degradation product or D-dimer levels. (See "Disseminated intravascular coagulation in infants and children", section on 'Diagnosis'.)

The causes, diagnosis and management of neonatal DIC are discussed in detail separately. (See "Disseminated intravascular coagulation in infants and children".)

Thrombosis — Thrombocytopenia often accompanies thrombosis in newborns. The risk of thrombosis is increased by the presence of an indwelling catheter, or by medical conditions predisposing to thrombosis, including prematurity and sepsis. Renal vein thrombosis is the most common form of neonatal thrombosis that is not associated with an indwelling catheter. Patients should be evaluated for a thromboembolic disorder if thrombocytopenia cannot be explained by other conditions. (See "Neonatal thrombosis: Clinical features and diagnosis".)

Type 2B von Willebrand disease — In type 2B von Willebrand disease (vWD), the structurally abnormal von Willebrand factor has increased affinity for its receptor (glycoprotein IB) on the platelet [21-23]. This may lead to formation of small platelet aggregates, which are cleared from the circulation resulting in a lower platelet count. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Abnormalities in the CBC and coagulation tests'.)

DECREASED PRODUCTION — Causes of neonatal thrombocytopenia due to decreased platelet production include genetic disorders and diseases associated with bone marrow infiltration or suppression. In addition, early thrombocytopenia associated with intrauterine growth restriction (IUGR) due to decreased platelet production is frequently seen in neonates born to mothers with preeclampsia or other causes of placental insufficiency, particularly preterm infants [24,25].

Preeclampsia — Thrombocytopenia due to decreased production is common in infants of mothers with preeclampsia and other hypertensive disorders of pregnancy [26]. The incidence of neonatal thrombocytopenia associated with this preeclampsia has been estimated at 1 per 100 live births, and it is more likely to occur in preterm infants [3,26]. (See "Preeclampsia: Clinical features and diagnosis".)

In affected infants, thrombocytopenia typically is noted at birth or in the first few days after delivery. The nadir is reached at two to four days of age, with resolution by day 7 to 10 [3].

Neutropenia is a common accompanying finding and is caused by decreased production mediated by an inhibitor of neutrophil production [27,28]. It is likely that the associated thrombocytopenia is caused by a similar mechanism [3].

Genetic disorders — Genetic disorders can result in isolated thrombocytopenia or thrombocytopenia associated with other clinical findings.

Congenital platelet disorders — Genetic disorders associated with thrombocytopenia due to decreased production are numerous but rare. These disorders as well as those associated with platelet dysfunction are discussed in greater detail separately. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders' and "Inherited platelet function disorders (IPFDs)" and "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

Chromosome abnormalities — Thrombocytopenia may occur in infants with chromosome abnormalities, including trisomies 21, 18, and 13 and Turner syndrome, although the incidence in most of these conditions is not known. In a case series of 226 neonates with Down syndrome, 66 percent had thrombocytopenia in the first week of life, and 6 percent had platelet counts <50,000/microL [29].

Chromosomal abnormalities also contribute to a significant proportion of mild thrombocytopenia detected in utero. In a report of 247 cases of platelet counts <150,000/microL detected by consecutive fetal blood sampling, chromosomal abnormality was the etiology in 43 fetuses (17 percent) [30].

Infiltrative disorders — Rarely, bone marrow infiltrative disorders (neonatal leukemia or neuroblastoma) can cause decreased platelet production. However, these are rare in the neonatal period. (See "Treatment and prognosis of neuroblastoma", section on 'Newborns'.)

MISCELLANEOUS CAUSES — Thrombocytopenia is associated with a variety of conditions that cannot be classified easily or are associated with more than one pathologic mechanism. In some conditions categorized as miscellaneous (eg, bacterial sepsis and asphyxia), both increased destruction and suppressed bone marrow production may contribute to thrombocytopenia [15].

Infection — Thrombocytopenia caused by bacteria, viral, and fungal infections may be the result of more than one pathogenetic mechanism. In most cases of bacterial sepsis, thrombocytopenia is caused by increased platelet destruction. However, in infants with severe infections, thrombocytopenia is caused by platelet destruction and consumption due to disseminated intravascular coagulation (DIC) combined with inadequate upregulation of platelet production in the bone marrow [31].

●Bacterial infection:

•Destructive mechanisms for thrombocytopenia induced by bacterial sepsis include DIC, endothelial damage, antibody-mediated injury, platelet apoptosis induced by gram-negative bacteria, loss of sialic acid from the platelet membrane caused by neuraminidase-producing bacteria, and platelet aggregation caused by adherence of bacterial products to platelet membranes [3,19]. (See "Disseminated intravascular coagulation in infants and children", section on 'Sepsis'.)

•Decreased platelet production due to injury to the megakaryocytes in bone marrow or suppression of megakaryopoiesis by bacterial products.

●Viral infection – Thrombocytopenia may occur with congenital viral infections, including herpes simplex virus (HSV), human immunodeficiency virus (HIV), rubella, and cytomegalovirus (CMV) [32,33].

•Destructive mechanisms include platelet aggregation, loss of sialic acid from the platelet membrane caused by viral neuraminidase, splenomegaly, and reticuloendothelial hyperactivity [3].

•Decreased production may be caused by viral effects on the megakaryocytes [19].

●Fungal infection – Platelet consumption can be seen in fungal infections, sometimes associated with catheter-related thrombosis or DIC. (See "Candida infections in neonates: Epidemiology, clinical manifestations, and diagnosis".)

Asphyxia — Thrombocytopenia is more common in infants with birth asphyxia than in those without birth asphyxia [8,34-36]. The underlying mechanism is uncertain, although there are data that suggest hypoxia contributes to a decrease in platelet production. However, asphyxia is also associated with DIC, which may cause platelet activation and consumption [3,34,37].

Based on retrospective case series, one-third to one-half of neonates with perinatal asphyxia developed thrombocytopenia (platelet count <150,000/microL) that presented within the first 48 hours of life, with a nadir occurring on the third day of life [34,37]. Thrombocytopenia is generally mild and transient, and most patients will not require platelet transfusions.

Therapeutic hypothermia started within the first six hours after delivery is the only proven neuroprotective intervention for hypoxic-ischemic encephalopathy. Hypothermia increases the risk of thrombocytopenia as well as coagulopathy [38]. (See "Perinatal asphyxia in term and late preterm infants", section on 'Therapeutic hypothermia'.)

Drug-related thrombocytopenia — Neonatal drug-related thrombocytopenia is a result of the following:

●Platelet destruction caused by maternal drug-dependent antibodies – Neonatal thrombocytopenia is mediated by maternal IgG antibodies, which cross the placenta and affect fetal platelets. Drugs associated with maternal immune-mediated platelet destruction include quinidine and antiepileptic agents (eg, carbamazepine, phenytoin and valproic acid) [19]. (See "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal autoimmune thrombocytopenia' and "Thrombocytopenia in pregnancy", section on 'Other causes of thrombocytopenia'.)

●Platelet destruction caused by neonatal drug-dependent antibodies – For example, thrombocytopenia due to heparin-associated antiplatelet antibodies is a rare side effect of heparin therapy in newborns. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

●Bone marrow suppression ‒ Bone marrow suppression results in decreased platelet production. This may occur following administration of chemotherapeutic agents to the mother or newborn infant for a malignancy. (See "Drug-induced immune thrombocytopenia".)

If drug-associated thrombocytopenia is suspected, the offending agent should be withdrawn. Transfusions should be given for low platelet counts (<20,000/microL) or for bleeding. If an immune-mediated condition is suspected, intravenous immune globulin (IVIG) can be used while awaiting confirmation.

Dilution — Thrombocytopenia can occur after an exchange transfusion because the relatively large volume of platelet-poor transfused blood can dilute the concentration of circulating platelets. However, the condition for which the exchange transfusion was performed (eg, erythroblastosis fetalis) also can result in thrombocytopenia.

SUMMARY

●Definitions ‒ Although neonatal thrombocytopenia is defined as a platelet count <150,000/microL, healthy preterm and term newborns frequently have platelet counts below this defined normal value. (See 'Definitions' above and 'Epidemiology' above.)

●Risk factors ‒ Predisposing risk factors for neonatal thrombocytopenia include preterm birth, sepsis, asphyxia, intrauterine growth restriction (birth weight [BW] <10^th percentile for gestational age [GA]), and necrotizing enterocolitis. Both the risk and severity of thrombocytopenia increases with decreasing GA and for infants admitted to the neonatal intensive care unit (NICU). (See 'Epidemiology' above.)

●Severe thrombocytopenia ‒ Severe neonatal thrombocytopenia (defined as a platelet count <50,000/microL) is uncommon in the general healthy newborn population. However, the risk increases for infants admitted to the NICU especially for the most preterm infants (BW <1000 g). (See 'Definitions' above and 'Epidemiology' above.)

●Etiology classification ‒ Causes of thrombocytopenia can be classified according to mechanism of thrombocytopenia (due to increased destruction [including sequestration and pooling of platelets] or due to decreased production) (table 1). Other classification schema use platelet size (large, normal, and small), mode of acquisition (congenital or acquired), timing with early (<72 hours of age) or late (≥72 hours of age) onset, and GA (preterm versus term). (See 'Classification of etiology' above.)

●Etiology

•Causes of increased platelet destruction in neonates include:

-Neonatal alloimmune thrombocytopenia (see "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal alloimmune thrombocytopenia')

-Neonatal autoimmune thrombocytopenia (see 'Neonatal autoimmune thrombocytopenia' above and "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal autoimmune thrombocytopenia')

-Sequestration and trapping – Hypersplenism and Kasabach-Merritt phenomenon (see 'Sequestration and trapping' above)

-Platelet activation and consumption – Disseminated intravascular coagulation and thrombosis (see 'Platelet activation and consumption' above and "Disseminated intravascular coagulation in infants and children", section on 'Other etiologies in neonates')

•Causes of decreased platelet production in neonates include:

-Preeclampsia (see 'Preeclampsia' above)

-Genetic disorders with defects in megakaryocyte development and differentiation (table 2) (see 'Genetic disorders' above)

-Bone marrow infiltrative diseases – Neonatal leukemia or neuroblastoma (see 'Infiltrative disorders' above)

•Other causes that include both mechanisms (increased destruction and decreased production) or cannot be classified based on these two mechanisms include:

-Serious bacterial, viral, or fungal infection (see 'Infection' above)

-Perinatal asphyxia (see 'Asphyxia' above)

-Drug-related thrombocytopenia (see 'Drug-related thrombocytopenia' above)

-Dilution (see 'Dilution' above)