Acquired Neonatal Thrombocytopenia

Pathophysiology

The mechanisms responsible for neonatal thrombocytopenia can be broadly categorized as follows:

• 1.

  increased platelet consumption,

• 2.

  decreased platelet production, and

• 3.

  hypersplenism.

In practice, determining the precise mechanisms leading to thrombocytopenia in a critically ill neonate may be difficult due to overlapping clinical presentations and especially the limited ability to perform any testing including bone marrow aspiration and biopsy, which remain the diagnostic gold standard.

Increased platelet consumption can be further categorized into immune- and nonimmune-mediated etiologies. Immune thrombocytopenia reflects an increased rate of immunoglobulin or complement-mediated platelet clearance, which may be alloimmune or autoimmune. Alloimmune neonatal thrombocytopenia, as discussed in Chapter 94 , is secondary to transplacental transfer of maternal antibody to a nonshared platelet antigen. Alternatively, maternal immune thrombocytopenia (ITP) can result in neonatal thrombocytopenia from transplacental passage of a maternal auto-anti-platelet antibody reactive with all platelets including fetal and neonatal ones. Rarely, neonates can develop an autoimmune-mediated ITP from systemic lupus erythematosus (SLE) (see Chapter 100, Chapter 101, Chapter 102, Chapter 103 ). Nonimmune-mediated pathology that contributes to platelet consumption includes viral, bacterial, or fungal sepsis, necrotizing enterocolitis (NEC), disseminated intravascular coagulation (DIC), vascular malformations with Kasabach–Merritt syndrome (KMS), congenital thrombotic thrombocytopenia purpura (TTP), type 2B von Willebrand disease, and thrombosis.

Decrease in platelet production can be seen in the perinatal period with chronic fetal hypoxia, congenital infections, and bone marrow infiltration. Chronic fetal hypoxia is secondary to placental insufficiency from pregnancy-induced hypertension, preeclampsia, HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet count) or intrauterine growth restriction (IUGR) may have a depressive effect on megakaryocytic platelet production. Congenital infections, which can decrease bone marrow platelet production, include typical TORCH infections which include Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus), Rubella, Cytomegalovirus (CMV) and Herpes Infections ( Herpes Simplex Virus (HSV) and Human Herpesvirus 6 (HHV-6)), and HIV. Bone marrow infiltration may result from congenital leukemia, neuroblastoma, histiocytosis, transient myeloproliferative disease in Down syndrome, or osteopetrosis. Especially, the latter may have accompanying hepatosplenomegaly. Fetal and neonatal megakaryocytes are smaller with lower ploidy producing less platelets per megakaryocyte. This means a newborn may have limited response to increased demand for platelets. This inability to respond to thrombocytopenia may be more pronounced in the preterm neonate, where the relatively low level of thrombopoietin also limits platelet production.

Lastly, the sequestration with increased entrapment of platelets in the spleen may occur with hemolytic anemia, congenital hepatitis, congenital viral infections, portal vein thrombosis, or virtually any cause of substantial splenomegaly.

Clinical Presentation

The clinical presentation of thrombocytopenia ranges from asymptomatic (detected on a routine laboratory test) to life-threatening bleeding. Symptomatic presentations may include petechiae, ecchymoses, melena, cephalohematoma, hematuria, endotracheal bleeding, umbilical stump bleeding and oozing from venipuncture/heelstick sites, or most seriously focal neurological symptoms.

Clinical history should include the age of neonate, gestational age at birth, birth weight, Apgar scores, timing of onset of thrombocytopenia, and details of prenatal care/delivery including fetal monitoring records. It is important to incorporate the maternal history in clinical decision-making, specifically any history of hypertension, HELLP, preeclampsia, ITP, and maternal infectious serologies and cultures (TORCH infections, and Group B streptococcus status). Additionally, it is important to note any familial history of previous thrombocytopenia, especially neonatal, with attention to severity, duration, and clinical manifestations.

Physical examination should include signs of bleeding, presence of hepatosplenomegaly, survey for dysmorphic features, e.g., abnormalities of thumbs, radius, inability to rotate the forearm and the presence of any features suggestive of trisomies 21, 18, 13, Turner syndrome, or Jacobsen syndrome. Laboratory evaluation should include complete blood count with review of the peripheral smear with special attention to platelet agglutination and confirmation of maternal platelet count. Additional testing and monitoring for signs of bleeding (head sonogram and also urine, stool, and gastric aspirate) will be dictated by the clinical situation.

Differential Diagnosis

The approach to thrombocytopenia in this neonatal period can be categorized based on the timing of presentation into early (<72 hours) and late onset (>72 hours), with additional focus on the severity of presentation and the prenatal/postnatal age of the infant.

Early-onset thrombocytopenia is most often associated with pregnancy/placental complications, infection, sepsis, DIC (see Chapter 120 ), or Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) (see Chapter 91 ). With a marked, <50K platelet count on day 1 of life, early-onset thrombocytopenia, an immediate diagnostic evaluation is indicated and intervention with consideration of infection and FNAIT for appropriate therapeutic management. In less severe presentations of early-onset thrombocytopenia, maternal placental insufficiency, IUGR, preeclampsia, HELLP, maternal diabetes, and fetal hypoxia are the relevant etiologies for consideration. Overlapping an early and late timeframe of identification the TORCH infections, thrombosis, vascular consumption from KMS or autoimmune thrombocytopenia (ITP/SLE) should be included in the differential diagnosis.

In late-onset thrombocytopenia, the vast majority are secondary to postnatal bacterial or fungal sepsis, liver disease, and/or NEC. In a premature infant, subsequent hypogammaglobulinemia may contribute to infections. If one of the foregoing is not definite, differential diagnosis for late-onset thrombocytopenia should also include inborn errors of metabolism and drug-induced thrombocytopenia. Finally, it is important to consider genetic thrombocytopenia in the etiology of neonatal presentation, including thrombocytopenia-absent radii syndrome, congenital amegakaryocytic thrombocytopenia, Wiskott–Aldrich syndrome, Fanconi anemia, MYH-9-related thrombocytopenia, Chediak–Higashi syndrome, Bernard–Soulier syndrome, Jacobsen syndrome, trisomies 21, 18, and 13, congenital TTP, and von Willebrand type 2B (see Chapter 93 ).

Diagnosis of Acquired Thrombocytopenia