139: Thrombocytopenia and Platelet Dysfunction

Thrombocytopenia is defined as a platelet count <150,000/μL and is classified as mild (100–149,000/μL), moderate (50–99,000/μL), or severe (<50,000/μL). One percent of normal neonates may have mild thrombocytopenia.

Thrombocytopenia is the most common hematologic abnormality among sick newborn infants (when admitted to the neonatal intensive care unit [NICU], incidence is as high as 35%). Its incidence reaches 70% in newborn infants with birthweight <1000 g.

1. Normal platelets. Similar to older children and adults, the platelet life span in neonates is 7–10 days, and the mean platelet count is >200,000/μL.

2. Etiology of thrombocytopenia. See Figure 139–1.

   1. Maternal disorders causing thrombocytopenia in infant

      1. Chronic intrauterine hypoxia is the most frequent cause of thrombocytopenia in preterm neonates in the first 72 hours of life. This is seen in cases of placenta insufficiency such as diabetes and pregnancy-induced hypertension.

      2. Preeclampsia (in particular with HELLP syndrome [hemolysis, elevated liver enzymes, low platelet count]). Thrombocytopenia is present at birth, is usually associated with neutropenia, and should recover by the second week of life.

      3. Drug use (eg, heparin, quinine, hydralazine, tolbutamide, and thiazide diuretics).

      4. Infections (eg, TORCH [toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus] infections, bacterial or viral infections).Disseminated intravascular coagulation (DIC).

      5. Antiplatelet antibodies

         1. Antibodies against maternal and fetal platelets (autoimmune thrombocytopenia)

            • (a) Idiopathic thrombocytopenic purpura (ITP)

            • (b) Drug-induced thrombocytopenia

            • (c) Systemic lupus erythematosus

         2. Antibodies against fetal platelets (isoimmune thrombocytopenia)

            • (a) Neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia, seen mostly in term infants <72 hours of age. It is due to an incompatibility in human platelet antigen (HPA) between the newborn infant and its HPA-negative mother. HPA-1a is the most common incompatibility in Caucasians, while HPA-4b incompatibility is mostly seen in Asians. Only 10% of HPA-1a–negative women become sensitized after being exposed to HPA-1a because this immunological response occurs in the presence of specific human leukocyte antigens (HLAs) such as HLA-B8, HLA-DR3, and HLA-DR52a. HLA antibodies, though common, do not cause significant thrombocytopenia.

            • (b) Immune thrombocytopenia can be found in some cases of hemolytic disease of the newborn.

   2. Placental disorders causing thrombocytopenia in infant (rare)

      1. Chorioangioma

      2. Vascular thrombi

      3. Placental abruption

   3. Neonatal disorders causing thrombocytopenia

      1. Decreased platelet production

         1. Isolated.

         2. Thrombocytopenia and absent radius syndrome (TAR syndrome) is characterized by normal neutrophil and red blood cell counts; absent radii, usually bilateral; and the presence of a normal thumb.

         3. Fanconi anemia is characterized by pancytopenia and the presence of abnormal (hypoplastic or aplastic) thumb.

         4. Rubella syndrome.

         5. Congenital leukemia.

         6. Trisomies 13, 18, or 21 or Turner syndrome.

         7. Inherited metabolic disorders include methylmalonic, propionic, and isovaleric acidemia; ketotic glycinemia.

         8. Congenital amegakaryocytic thrombocytopenia.

      2. Increased platelet destruction

         1. Many “sick” newborns develop thrombocytopenia that is not associated with any specific pathologic state. About 20% of newborns admitted to the NICU have thrombocytopenia, and 20% of those counts are <50,000/μL. This form of thrombocytopenia generally improves after the primary sickness (respiratory distress syndrome [RDS], persistent pulmonary hypertension of the newborn [PPHN], etc.) resolves.

         2. Pathologic states associated with thrombocytopenia

            • (a) Sepsis. Bacterial and Candida sp.

            • (b) Congenital infections. TORCH infections, especially cytomegalovirus (CMV). Neonates with human immunodeficiency virus (HIV) and Enterovirus frequently have thrombocytopenia.

            • (c) Thrombosis (renal vein, intracardiac, vascular).

            • (d) DIC.

            • (e) Intrauterine growth restriction.

            • (f) Birth asphyxia.

            • (g) Necrotizing enterocolitis (NEC) or bowel ischemia.

            • (h) Platelet destruction associated with giant hemangioma (Kasabach-Merritt syndrome).

3. Platelet dysfunction

   1. Drug-induced platelet dysfunction

      1. Maternal use of aspirin

      2. Indomethacin

   2. Metabolic disorders

      1. Phototherapy-induced metabolic abnormalities

      2. Acidosis

      3. Fatty acid deficiency

      4. Maternal diabetes

   3. Inherited thrombasthenia (Glanzmann disease)

Low birthweight; low gestational age; small for gestational age; hypoxia at birth (Apgar score <5 at 5 minutes); umbilical line placement; respiratory assistance; hyperbilirubinemia; phototherapy; respiratory distress syndrome; sepsis, especially by Candida infection; meconium aspiration; NEC; mother with ITP; preterm infants of hypertensive mothers

1. Symptoms and signs. It is important to assess the general condition of the infant carefully. A “sick”-appearing newborn implies a very different approach for the investigation and treatment of thrombocytopenia (such as sepsis) than the infant who otherwise appears healthy (such as with most cases of alloimmune thrombocytopenia).

   1. Generalized superficial petechiae are often present, particularly in response to minor trauma or pressure, or increased venous pressure. Platelet counts are usually <60,000/μL. Note: Petechiae in normal infants tend to be clustered on the head and upper chest, do not recur, and are associated with normal platelet counts. They are a result of a transient increase in venous pressure during birth.

   2. Gastrointestinal bleeding, mucosal bleeding, or spontaneous hemorrhage in other sites may be occurring with platelet counts <20,000/μL.

   3. Intracranial hemorrhage may occur with severe thrombocytopenia.

   4. Large ecchymoses and muscle hemorrhages are more likely to be due to coagulation disturbances than to platelet disturbances.

2. History

   1. There may be a family history of thrombocytopenia or a history of intracranial hemorrhage in a sibling.

   2. Maternal drug ingestion may be a factor.

   3. A history of infection should be noted.

   4. Previous episodes of bleeding may have occurred.

3. Placental examination. The placenta should be carefully examined for evidence of chorioangioma, thrombi, or abruptio placentae.

4. Physical examination

   1. Petechiae and bleeding sites should be noted.

   2. Physical malformations may be present. TAR syndrome, rubella syndrome, giant hemangioma, or trisomy syndromes.

   3. Hepatosplenomegaly may be caused by viral or bacterial infection or congenital leukemia

1. Laboratory studies

   1. For all newborns

      1. Neonatal platelet count. Thrombocytopenia diagnosed from a capillary sample should be confirmed by a repeated count from a sample obtained from a venous sample and by careful examination of peripheral blood smear.

      2. Complete blood count (CBC) and differential.

      3. Blood typing.

   2. For healthy newborns without congenital anomalies

      1. Coombs test.

      2. Maternal serum and whole blood sample for rapid HPA-1a (PlA1) phenotyping plus screen for anti-HPA alloantibodies. These antibodies are not detected in 10% of sensitized mothers.

      3. Maternal, paternal, and infant genotyping of HPA 1–5 and 15 are required for diagnosis and for matching platelet donors.

      4. TORCH evaluation and rapid HIV test.

      5. Test for maternal thrombocytopenia. A low maternal count suggests autoimmune thrombocytopenia or inherited thrombocytopenia (X-linked recessive thrombocytopenia or autosomal dominant thrombocytopenia).

      6. In cases of unexplained and severe thrombocytopenia, a bone marrow study is indicated. However, because of its technical difficulties in neonates, new blood tests are being developed to evaluate platelet production. Many have shown promising results (serum thrombopoietin [Tpo] concentrations, megakaryocyte progenitors, reticulated platelet percentages [RP%], and glycocalicin concentrations). An immature platelet fraction (IPF) test is similar to RP%, is already available, and is being used in some institutions. Bone marrow studies are still indicated in selected patients (marrow cellularity or megakaryocyte morphology).

   3. For healthy newborns with congenital anomalies

      1. Chromosome analysis for trisomies and Turner syndrome

      2. “DEB/MMC” (diepoxybutane/mitomycin C) stress test to establish DNA breakage in peripheral blood lymphocytes

   4. For “sick” newborns

      1. Differential of white blood count, serum C-reactive protein, bacterial and fungal blood cultures

      2. Coagulation studies. Prothrombin time, activated partial thromboplastin time, fibrinogen, and d-dimer level

      3. TORCH titers Culture of cytomegalovirus from urine samples, and other viruses if indicated (coxsackie, echovirus)

1. Obstetric management of maternal autoimmune thrombocytopenia

   1. The occurrence of fetal hemorrhage (in utero) is very rare compared with the risk of such hemorrhage in alloimmune thrombocytopenia (10%).

   2. Treatment is aimed at prevention of an intracranial hemorrhage during vaginal delivery.

   3. There is an increased risk of severe neonatal thrombocytopenia and intracranial hemorrhage if antibody is present in the maternal plasma or if fetal scalp platelet counts are <50,000/μL.

   4. Cesarean delivery may be indicated.

2. Management of maternal alloimmune thrombocytopenia

   1. After a pregnancy has been affected by alloimmune thrombocytopenia, the proportion of subsequent pregnancies affected mostly depends on the father's genotype. If the father is heterozygous (HPA-1a/HPA-1b), the risk is 50%, and the risk is close to 100% if he is homozygous (HPA-1a/HPA-1a). The history of intracranial hemorrhage in a previous sibling is predictive of the presence of severe thrombocytopenia for the next fetus. In subsequent pregnancies, administering corticosteroids and intravenous immune globulin (IVIG) during the third trimester coupled with transfusions of platelets to the fetus using ultrasound-guided intraumbilical cord infusion has been described.

   2. Instrumental vaginal delivery, fetal scalp electrodes, and fetal scalp blood sampling should be avoided. Vaginal delivery is allowed when fetal platelet count is known to be >50,000/μL and presentation and labor are normal. Otherwise cesarean delivery is indicated.

3. Treatment of infants with thrombocytopenia

   1. Treat the underlying cause (eg, sepsis). If drugs are the cause, stop their administration.

   2. Platelet transfusions

      1. Platelet transfusions are indicated if active bleeding is occurring with any degree of thrombocytopenia or if there is no active bleeding but platelet counts are <20,000/μL. It may be desirable to transfuse premature infants with a greater risk of hemorrhage “those that are sick or in the first week of life” if the platelet count is <50,000/μL. Leukocyte-reduced, irradiated, random donor platelets are given in a dosage of 10–20 mL/kg of standard platelet concentrates. The plasma in platelets should be ABO and Rh compatible with the infant's red blood cells. The platelet count should increase to >100,000/μL. Platelet count should be repeated 1 hour posttransfusion. Failure to achieve or sustain a rise in platelet count suggests a destructive process. Washed and irradiated maternal platelets or platelets from an HPA-compatible donor (in general HPA-1a–negative platelets) need to be used for infants with alloimmune thrombocytopenia. When not available, a random donor platelet transfusion combined with IVIG may achieve a transient rise.Harmful effects related to platelet transfusions have been raised, such as an increased incidence of bacterial infection and an exacerbation of inflammatory injury. In addition, mortality rate in thrombocytopenic NICU patients who received platelet transfusions increased dramatically with the increase in the number of platelet transfusions.

   3. IVIG. 400 mg/kg/d for 3–5 consecutive days, or a single dose of 1000 mg/kg on 2 consecutive days is given for immune thrombocytopenia.

   4. Prednisone. 2 mg/kg/d may also be beneficial in immune thrombocytopenia.

Etiology of the thrombocytopenia dictates the outcome and prognosis.