Thrombocytopenia in neonates is defined as a platelet count of less than 150 × 109/L. The prevalence of thrombocytopenia in healthy term infants is 1%–2%, whereas up to 35% of neonates admitted to intensive care units may have low platelet counts.1 There are developmental differences in megakaryopoiesis between neonates and older children. Neonatal megakaryocytes are less capable of upregulating platelet production or mounting as high a level of thrombopoietin (Tpo) when compared to adults with the same degree of thrombocytopenia.2 These developmental differences account for the vulnerability of sick neonates to thrombocytopenia.
The major causes of neonatal thrombocytopenia are increased platelet consumption or decreased platelet production. However, both mechanisms can contribute to thrombocytopenia in any given patient, particularly in sick or premature neonates.
Clinical Findings: History and Physical
A detailed medical history and physical examination will guide the diagnostic approach to thrombocytopenia. Medical history and complications during pregnancy are important because many maternal factors can cause neonatal thrombocytopenia. Maternal drugs and antibodies that cross the placenta can affect an infant’s platelet count. Complications during pregnancy that result in chronic fetal hypoxia or intrauterine growth retardation (IUGR) are frequent causes of early-onset neonatal thrombocytopenia.3 Causes of chronic fetal hypoxia and IUGR include pregnancy-induced hypertension or diabetes, placental insufficiency, and placental infarction or malformation. Perinatal asphyxia is another common cause of early-onset thrombocytopenia. Family history of chronic thrombocytopenia suggests a hereditary thrombocytopenia or a genetic syndrome associated with low platelet counts; a family history of previous neonatal thrombocytopenia suggests maternal immune-mediated thrombocytopenia.
Physical findings of thrombocytopenia vary with the platelet count and the primary cause of thrombocytopenia. Many neonates are asymptomatic. However, in those who have bleeding manifestations, bruising and petechiae are the most common presenting symptoms, often noted on the face and head secondary to birth trauma. Thrombocytopenia commonly is associated with mucocutaneous bleeding. Bleeding also can occur with trauma following phlebotomy, after intramuscular injections (prophylactic vitamin K or hepatitis vaccine), umbilical stump bleeding, or associated with circumcision. Intra-abdominal bleeding and intracranial hemorrhage (ICH) generally occur only in severe thrombocytopenia (platelet count less than 50 × 109/L). A bulging fontanel, seizures, or other neurologic signs in a thrombocytopenic neonate warrant urgent radiographic evaluation for an intracranial bleed. Sick infants in the intensive care unit also may have bleeding from intravenous sites, surgical sites, or endotracheal tubes.
When a low platelet count is suspected, a complete blood cell count (CBC) with a review of the peripheral blood smear should be done. The diagnostic approach to multilineage cytopenias is different from that for isolated thrombocytopenia. The morphology of platelets as well as red and white blood cells (WBCs) may provide clues to diagnosis. For example, the presence of WBC inclusions and large platelets suggests a hereditary macrothrombocytopenia, and the presence of microangiopathic red blood cell changes will lead to further investigation for disseminated intravascular coagulation (DIC) or other microangiopathic hemolytic processes. Thrombocytopenia is often an incidental finding when a CBC is obtained for assessing other hematologic parameters. In these cases, the primary reason for a CBC may explain the thrombocytopenia (eg, an elevated WBC count in an infant born to mother who has a fever most likely has thrombocytopenia secondary to sepsis). If the clinical picture is not consistent with the degree of thrombocytopenia, the platelet count should be repeated. Spurious thrombocytopenia can be seen with platelet agglutination or platelet satellitism.4 Both are often associated with ethylenediaminetetraacetic acid (EDTA), the anticoagulant in sample collection tubes. If spurious thrombocytopenia is suspected, review of the peripheral blood smear should provide the accurate count.
Differential Diagnosis/Diagnostic Algorithm
The differential diagnosis for neonatal thrombocytopenia is broad (see Figure 92-1 for a diagnostic algorithm). A most useful approach in sorting out the cause is based on the neonate’s clinical status. Thrombocytopenic neonates roughly fall into three different groups based on their clinical features (Table 92-1).
Table 92-1Differential Diagnosis of the Thrombocytopenic Newborn ||Download (.pdf) Table 92-1Differential Diagnosis of the Thrombocytopenic Newborn
Differential diagnosis of neonates with thrombocytopenia who are ill appearing, born prematurely, born to a mother with pregnancy complications and with other signs of medical illness considers the following:
Chronic hypoxia from placental insufficiency
Intrauterine growth retardation
Labor and delivery complications:
Hypoxia or acidosis after birth trauma
Bacterial infections (sepsis)
Congenital viral infections (cytomegalovirus, rubella)
Disseminated intravascular coagulation (DIC)
Necrotizing enterocolitis (NEC)
Thrombosis (DIC, indwelling vascular catheters, extracorporeal membrane oxygenation [ECMO])
Bone marrow disorders (leukemia, neuroblastoma or other solid tumors, storage diseases)
Neonates with thrombocytopenia and physical abnormalities or dysmorphic features:
Thrombocytopenia with absent radius (TAR) syndrome
Amegakaryocytic thrombocytopenia and radioulnar synostosis (ATRUS)
Chromosomal disorders caused by trisomy 13, 18, or 21 and Turner syndrome
Neonates with thrombocytopenia but who are otherwise healthy appearing with no physical abnormalities or other medical conditions:
Secondary to maternal autoimmune thrombocytopenia (ITP)
Neonatal alloimmune thrombocytopenia (NAIT)
Wiskott-Aldrich syndrome (WAS)
Diagnostic algorithm. IUGR, intrauterine growth retardation; KMS, Kasabach-Merritt syndrome.
ILL-APPEARING PREMATURE INFANTS BORN TO MOTHERS WITH SIGNS OF MEDICAL ILLNESS
Within the group of premature neonates with thrombocytopenia who are ill appearing and born to mothers with pregnancy complications or with other signs of medical illness, the time of onset of thrombocytopenia is useful to further guide the inquiry.
Mild-to-moderate thrombocytopenia (50,000–100,000) developing within the first 72 hours is most likely secondary to maternal/pregnancy-related factors.3,5 Fetuses exposed to chronic intrauterine hypoxia from a variety of complications as well as fetuses with IUGR are often thrombocytopenic at birth. The pathophysiology for the low platelet count is thought to be related to decreased platelet production, a consequence of reduced megakaryocyte progenitors and inadequate upregulation of Tpo.2 Often, these neonates also will have neutropenia, nucleated red blood cells (nRBCs), and sometimes polycythemia. These hematologic abnormalities generally are not severe and resolve within the first 2 weeks of life. This group of patients can safely be monitored without additional workup until thrombocytopenia has resolved. However, if thrombocytopenia persists beyond 10 days or becomes severe (less than 50,000), further workup is warranted.
Infections, a frequent cause of thrombocytopenia in both term and preterm infants, should be ruled out in any ill-appearing newborn with low platelet count. Congenital, perinatal, or acquired postnatal infections all are associated with thrombocytopenia.
Bacterial sepsis is the most common cause of late onset of thrombocytopenia, occurring at greater than 72 hours of life.1,3 Thrombocytopenia secondary to bacterial infection usually develops rapidly and is often severe, particularly in preterm infants. Gram-negative sepsis leads to a most severe thrombocytopenia. DIC frequently complicates neonatal sepsis and is a major mechanism for the low platelet count observed in infections.
Congenital and perinatal viral infections also cause neonatal thrombocytopenia. Cytomegalovirus (CMV) and herpes simplex virus infections are the ones most commonly associated with low platelet counts. Neonates with congenital infections may not be ill appearing but often will have other suggestive clinical features (ie, microcephaly, seizures, hepatosplenomegaly, intracerebral calcification, or hearing loss).
Many other medical complications seen in the neonatal intensive care unit (NICU) are associated with thrombocytopenia. For example, thrombocytopenia is found in 50% of infants with necrotizing enterocolitis (NEC). In the early stage of NEC, the degree of thrombocytopenia correlates with the severity of bowel necrosis.6 Increasing platelet counts suggest improvement of the disease process. Thrombosis causes thrombocytopenia by increased platelet consumption. NICU patients are at high risk for thrombosis because of increased susceptibility to DIC, the use of indwelling vascular catheters, and the use of extracorporeal membrane oxygenation (ECMO). Exchange transfusions also can cause thrombocytopenia by dilution.
Less-frequent causes of thrombocytopenia among this group of neonates include bone marrow infiltration diseases such as congenital malignancies (leukemia, neuroblastoma, or other solid tumors) and storage diseases. In these conditions, there usually are other physical findings (hepatomegaly, splenomegaly, and other masses).
THROMBOCYTOPENIA AND PHYSICAL ABNORMALITIES OR DYSMORPHIC FEATURES
Careful examination for congenital anomalies can provide important clues to the diagnosis in neonates with thrombocytopenia. Many chromosomal abnormalities (trisomy 13, 18, or 21 and Turner syndrome) are associated with low platelet counts. Most neonates with Jacobsen syndrome are thrombocytopenic or pancytopenic at birth.7 Jacobsen syndrome is caused by partial deletion of the long arm of chromosome 11; in addition to thrombocytopenia, there is a high incidence of platelet dysfunction. These patients therefore might have more bleeding manifestation.
Thrombocytopenia with absent radius (TAR) syndrome is a rare autosomal recessive disorder characterized by severe thrombocytopenia present at birth with skeletal abnormalities of the radius.8 Patients with TAR have radial aplasia, usually bilateral, but thumbs are always present. However, these thumbs are often abnormal (hypoplastic or held in an abnormal position), and there occasionally is also hypoplasia of the humerus and ulnar bones. In addition, cardiac defects, brain anomalies, and dysmorphic facial features are common in patients with TAR. Most infants with TAR present with profound thrombocytopenia (platelet counts often less 10 × 109/L) in the first week after birth. Risks for serious bleeding complications are greatest in the first months after birth. Platelet counts gradually improve over their first year of life and are usually normal after several years.
Amegakaryocytic thrombocytopenia and radioulnar synostosis (ATRUS) is another rare autosomal recessive syndrome with upper limb anomalies and thrombocytopenia. This syndrome is caused by mutations in the HOXA11 gene, and in contrast to TAR, the thrombocytopenia does not improve.8
Children with Fanconi anemia (FA), a congenital bone marrow failure syndrome, can have radial anomalies similar to patients with TAR but those individual’s thumbs are always affected. Median age of thrombocytopenia in patients with FA is 7 years old, so it is unlikely to be an issue in the neonatal period.1
Kasabach-Merritt syndrome (KMS) is characterized by consumptive coagulopathy (thrombocytopenia, hypofibrinogenemia, elevated fibrin degradation products) with vascular malformations. It was first described in a child with a large capillary hemangioma; however, recent studies have shown that KMS is mainly associated with aggressive vascular tumors such as Kaposiform hemagnioendotheliomas and tufted angioma, not infantile hemangiomas.9 Local platelet sequestration and activation of coagulation proteins within these vascular tumors lead to shortened platelet survival. Significant thrombocytopenia (below 50 × 109/L) and bleeding complications are common. In 50% of patients, the vascular lesions are notable at birth. These generally are single large lesions in the subcutaneous or deep-tissue compartment, and they are locally invasive. The subcutaneous lesions often are notable on physical examination, but visceral malformations may not be apparent and their presentation may be abdominal distention, organ dysfunction, or high-output cardiac failure.
THROMBOCYTOPENIA IN OTHERWISE HEALTHY-APPEARING NEONATES WITH NO PHYSICAL ABNORMALITIES OR OTHER MEDICAL CONDITIONS
Thrombocytopenia in otherwise-healthy infants is primarily caused by immune-mediated platelet destruction because maternal antibodies have crossed the placenta into the fetal circulation. However, neonates with occult infection may also be well appearing; therefore, infection should always be considered in this clinical setting. Less-common causes of thrombocytopenia in healthy-appearing infants include hereditary thrombocytopenias without dysmorphic features. These include amegakaryocytic thrombocytopenia, hereditary macrothrombocytic disorders, Wiskott-Aldrich syndrome (WAS), and Bernard-Soulier syndrome.
Neonatal thrombocytopenia secondary to maternal idiopathic thrombocytopenia purpura (ITP) is primarily a maternal disorder that secondarily affects the fetus and infant. ITP is a common cause of immune thrombocytopenia during pregnancy and is seen in association with other maternal autoimmune diseases, including systemic lupus erythematosus (SLE), lymphoproliferative disorders, and Graves disease. Maternal antibodies in these disorders are directed against “public” platelet antigens, usually glycoproteins IIb/IIIa and Ib/IX. The immunoglobulin (Ig) G antibody-coated platelets are cleared by the reticuloendothelial system, causing maternal thrombocytopenia. The fetus is secondarily affected because maternal antibodies cross the placenta and bind to the same public antigens on fetal platelets.
Maternal ITP is the most likely cause of moderate-to-severe thrombocytopenia (platelet counts less than 70 × 109/L) occurring in otherwise-healthy pregnant women. This is to be distinguished from “gestational benign thrombocytopenia,” a common cause of mildly decreased platelet counts (greater than 70 × 109/L) in otherwise-healthy pregnancies. This gestational thrombocytopenia occurs in asymptomatic women with no history of low platelet counts prior to pregnancy, appears in late gestation, and generally resolves spontaneously after delivery. This is a maternal condition and does not cause thrombocytopenia in neonates.
In mothers with ITP, 10%–15% of their neonates will have transient mild neonatal thrombocytopenia (platelet count less than 100,000) with minimal-to-no bleeding symptoms. The incidence of severe neonatal thrombocytopenia (platelet counts below 50 × 109/L) and bleeding complications is 3%–5%. In pregnant women with ITP, there is no reliable predictor of the expected degree of neonatal thrombocytopenia except for the magnitude of thrombocytopenia in a previous pregnancy.10 The diagnosis of secondary autoimmune thrombocytopenia in infants is based on maternal history of ITP and the clinical course of the neonate once other causes of a low platelet count are excluded.
Neonatal alloimmune thrombocytopenia (NAIT) is the platelet equivalent of hemolytic disease of the newborn caused by Rh D incompatibility. It occurs when maternal platelets lack an antigen that the fetus has inherited from the father. Maternal IgG antibodies form against the “foreign” antigen on fetal platelets, cross the placenta, and destroy fetal platelets. In contrast to neonatal autoimmune thrombocytopenia, NAIT can result in very low platelet counts, and affected fetuses and neonates are at high risk for serious bleeding complications. There are no maternal consequences. Unlike Rh hemolytic disease, 50% of NAIT cases occur in the first pregnancy of an at-risk couple.
Neonatal alloimmune thrombocytopenia has been associated with sensitization to several different platelet-specific alloantigens. The most commonly identified antibody in sensitized Caucasian women is anti-human platelet antigen 1a (HPA-1a), accounting for 80%–90% of NAIT cases. Homozygosity for HPA-1b antigen (ie, HPA-1a negative) is seen in about 2% of pregnant women, but not all HPA-1a-negative women become alloimmunized. Sensitization in this population is related to human leukocyte antigen (HLA) type and is more common in women with HLA-B8, HLA-DR3, and HLA-DR52a. In Asians, NAIT occurs with sensitization to HPA-4. NAIT also occurs with maternal HLA antibodies alone or in combination with HPA antibodies. HLA antibodies, though common, usually do not cause significant thrombocytopenia because other tissues bearing HLA antigens also can absorb these antibodies, thus sparing platelets.
Clinical manifestations of NAIT vary from mild to moderate thrombocytopenia in a healthy-appearing infant to severe thrombocytopenia with bleeding complications. The platelet count commonly falls further during the first week after birth. The most serious complication of NAIT is ICH. It is estimated that ICH occurs in about 10%–20% of affected newborns. Of most importance, more than 25% of these ICH events occur in utero prior to delivery. One should suspect NAIT in any healthy newborn with unexplained severe thrombocytopenia and whose mother has a normal platelet count with no history of ITP or of having had a prior splenectomy for ITP. The workup should include antiplatelet antibody testing of maternal serum; however, sometimes no antibodies are found in presumed NAIT cases. It is for this reason that platelet antigen testing of both parents also is critical in the diagnostic workup. The recurrence rate of NAIT is greater than 75% in subsequent pregnancies, and generally the thrombocytopenic course is more severe in subsequently affected children.
Several genetic disorders are associated with thrombocytopenia at birth, and these conditions may not have other clinical features notable at birth. These genetic conditions include WAS, congenital amegakaryocytic thrombocytopenia (CAMT), hereditary macrothrombocytopenia, and Bernard-Soulier syndrome.
Wiskott-Aldrich syndrome is a rare X-linked disorder characterized by immunodeficiency, eczema, and thrombocytopenia. A unique hematologic feature of this disorder is that platelets are much smaller than normal. This syndrome is caused by mutation of the WAS gene on the short arm of chromosome X. Children with WAS have thrombocytopenia, small platelet size at birth, and impaired platelet function. Gastrointestinal (GI) bleeding commonly is seen and may be the presenting sign. Symptoms associated with immune dysregulation (frequent infections, eczema, autoimmune phenomena) generally become more apparent later. The diagnosis is confirmed by determining WAS protein expression by flow cytometry. Bone marrow transplantation is the only curative treatment.
Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disorder associated with severe thrombocytopenia. This disorder often presents in infancy with bleeding symptoms (petechiae, mucosal and GI bleeding). Subgroups of children with CAMT also have congenital anomalies (cardiac defects, abnormal facies, microcephaly). Bone marrow examination reveals a paucity of megakaryocytes but is otherwise normal. Thrombocytopenia progresses to pancytopenia in later childhood, and progression to leukemia sometimes occur. Stem cell transplantation is the only curative treatment.
Hereditary macrothrombocytopenias are a group of autosomal dominant disorders caused by mutations in the MYH9 gene. Collectively, these disorders include May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. They are characterized by mild-to-moderate thrombocytopenia with giant platelets. Neutrophil inclusions (Dohle bodies), nephritis, and deafness are seen in some cases. Usually, these macrothrombocytopenic disorders are not associated with a significant bleeding tendency.
Like hereditary macrothrombocytopenia, mild thrombocytopenia and giant platelets also are seen in Bernard-Soulier syndrome. This is a rare autosomal recessive disorder caused by mutations in components of the GP1b/IX/V platelet receptor.11 Bernard-Soulier patients’ platelets are unable to adhere to vascular subendothelium. Because of platelet dysfunction, patients with Bernard-Soulier syndrome will experience bleeding symptoms in excess of their degree of thrombocytopenia.
Treatment of thrombocytopenic neonates should be guided by the degree of thrombocytopenia and bleeding symptoms. Also important is discovering the most likely diagnosis and the likelihood of bleeding associated with that diagnosis.
Neonates with mild bleeding symptoms and platelet counts greater than 50,000 can be safely monitored without treatment. However, if the infant is experiencing significant bleeding or needs to undergo an invasive procedure or surgery, treatment to increase the platelet count is necessary. In most circumstances, thrombocytopenia can be corrected rapidly by platelet transfusions. Administration of 10–15 mL/kg of platelets can be both a therapeutic and a diagnostic intervention. A more than 50,000 rise in platelet count obtained 30–45 minutes posttransfusion suggests decreased production as the primary cause of the thrombocytopenia, and a lack of an appropriate increase suggests increased platelet destruction.
Since the mid-1990s, there have been no randomized controlled trials addressing the appropriate platelet transfusion threshold in neonates. There are some published guidelines; however, there is no agreed-on threshold.3,5,12,13 Most guidelines take into account the platelet count and the neonates’ clinical condition.
For stable term infants with only mild bleeding symptoms, many consider keeping the platelet count greater than 20,000. For preterm or clinically unstable term infants, it is reasonable to keep the platelet count greater than 30,000 given their increased risk of bleeding. Any neonate with major hemorrhage should be transfused to maintain the platelet count greater than 50,000. In general, infants with platelet counts over 100,000 do not experience increased bleeding. If significant bleeding is noted at this level of thrombocytopenia, other causes of hemorrhage, such as platelet dysfunction or coagulation defects, should be investigated. Platelet transfusions in this group of patients are unlikely to improve the hemorrhagic condition.
For immune-mediated thrombocytopenia (neonatal autoimmune and NAIT), platelet transfusions sometimes do not result in a rise in platelet count because of the presence of maternal antibodies. For neonatal thrombocytopenia secondary to maternal ITP, intravenous immune globulin (IVIG) should be given to those with a platelet count less than 30,000 or who have any bleeding manifestations. A dose of 1 g/kg is safe and effective, with a response rate of 80%–90%. For infants with suspected or known NAIT but no evidence of hemorrhage, IVIG and prophylactic platelet transfusion should be given to term infants with platelet counts less than 30,000 and preterm infants with platelet counts less than 50,000. If HPA antigen mismatch is known, HPA-compatible platelets can be used. However, given that most cases of NAIT are unsuspected and there is a high incidence of bleeding associated with the diagnosis, platelet transfusions should not be delayed while waiting workup or availability of compatible platelets. Random donor platelet transfusions have been shown to produce a significant elevation of the platelet count in most cases of NAIT.14,15 For infants with ICH or other bleeding symptoms, platelet transfusions should be first-line treatment, with the goal to keep the platelet count greater than 50,000–100,000. Some recommend complementing random platelet transfusions with IVIG (1 g/kg/d for up to 3 days) and intravenous methylprednisolone (1 mg every 8 hours with IVIG).16 For both of these immune thrombocytopenia conditions, platelet counts fall during the first week of life and therefore needs to be monitored closely until there is consistent recovery to a safe platelet level.
Severe thrombocytopenia seen in consumptive processes such as infection and KMS should improve when the underlying conditions improve with treatment. Because these disease processes often have other coagulopathies, such as low fibrinogen or other factor levels, coagulation studies should be performed and replacement of specific factors given if they are low and the patient is experiencing bleeding.
Thrombocytopenia secondary to medical conditions that cause decreased platelet production, such as genetic syndromes and a marrow infiltrative process, may require regular transfusions to treat or prevent bleeding complications, particularly in those with associated platelet dysfunction such as WAS. In neonates with thrombocytopenia caused by impaired production, platelet transfusions should result in an improvement of platelet count that gradually falls over the next 5–7 days. Lack of an appropriate platelet response to transfusion suggests development of an alloantibody against an antigen on the transfused platelets. This complication is usually not seen in the neonatal period.
For immune-mediated neonatal thrombocytopenia (NAIT and neonatal thrombocytopenia secondary to maternal ITP), parents need to be counseled regarding the risks and management of future pregnancies. They should be referred to obstetricians specialized in managing high-risk pregnancies. For both conditions, the best predictor for the degree of fetal thrombocytopenia in the future is the disease severity of a previously affected infant in the same family. There are no reliable noninvasive methods for monitoring and managing affected pregnancies. No data support that antenatal treatment of maternal ITP alters the neonatal outcome. On the other hand, for pregnancies with a known history of NAIT and particularly with a history of neonatal ICH, antenatal treatment is critical to prevent serious in utero bleeding. Treatment generally involves weekly IVIG and daily prednisone. The timing and intensity of the treatment are guided by outcome of previously affected fetuses. If there was ICH in utero, treatment is started earlier than when bleeding previously was minimal. In the past, fetal platelet measurements by percutaneous umbilical cord sampling were recommended. However, significant bleeding complications were seen with this procedure. Fetal blood sampling is used much less currently.16 For fetuses with suspected NAIT, delivery by cesarean section is recommended.
Long-term outcome of neonates with thrombocytopenia depends on the cause of thrombocytopenia and the associated bleeding complications. Neurocognitive defects and death are seen in children with serious ICH. Infants who have chronic thrombocytopenia caused by genetic syndromes associated with defective thrombopoiesis might be transfusion dependent for life, but in general, platelet transfusions in this group are reserved for major hemorrhage or in preparation for invasive procedures.
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