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Fetal and Neonatal Alloimmune Thrombocytopenia
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is characterized by the presence of transient isolated neonatal thrombocytopenia secondary to maternal antibodies against paternally inherited antigens expressed on the fetal platelets. FNAIT is the most common cause of severe thrombocytopenia (<50,000/μL) in term neonates as well as the most common cause of intracranial hemorrhage (ICH). While the incidence varies depending on the definition of thrombocytopenia and in particular how it is identified (clinically vs. by screening), it is estimated that approximately 1 in 1000 to 1 in 5000 live births are affected.
Estimates of the incidence, severity, and other features of cases of FNAIT are highly dependent on how cases are accrued ( Table 94.1 ). One way is the summation of clinically detected neonates, with cases identified because the neonate is sufficiently affected to merit a blood count secondary to bleeding and bruising prompting diagnosis. Additional cases can be identified by a platelet count done for other reasons (i.e., sepsis investigation). Cases can also be identified by screening of either all mothers (for antigen status, e.g., human platelet antigen 1 [HPA-1]) or of all neonates (by platelet count). Cases accrued by maternal platelet antigen screening are substantially more frequent but clinically milder than those accrued by clinical detection of the neonate ( Table 94.1 ).
Table 94.1
FNAIT Identified by Screening Versus Clinical Diagnosis
| Screening | Clinical Diagnosis | |
|---|---|---|
| Incidence | 1:500–1:1000 | 1:3000–1:10,000 |
| Thrombocytopenia (platelet count/μL) | 50–100,000 | 90% < 50,000; 50% < 20,000 |
| ICH | 2:100,000 | 10%–20% of cases (10% of 1:5000 = 2:100,000) |
| Development | Not studied | Mildly abnormal even without ICH |
| Findings associated with FNAIT | Not studied | 1/3 but mainly minor |
| Antenatal treatment of next pregnancy | C/S at 37 weeks | IVIG ± steroids |
| Maternal disease associated | Not studied | High incidence of autoimmunity (RA and DM) |
| Prediction of severity | Antibody titers | Previous fetus had an ICH |
| Worsening of next pregnancy | Sometimes | 99 + % at least as severe |
| Timing of sensitization | 75% at birth | 60% prior to birth of 1st neonate |
FNAIT with severe thrombocytopenia has a substantial risk for in utero and perinatal ICH with resulting long-term neurological disability or death. Prompt investigation and management of neonatal (or rarely fetal) thrombocytopenia is critical for the neonate, future pregnancies, and possibly pregnancies in female siblings of the mother. Usually, results of parental platelet antigen and antibody testing are not immediately available. Therefore, treatment needs to be instituted empirically pending these results, while recognizing that diagnostic testing to explore the possibility of FNAIT is important. Significant improvement in subsequent fetal/neonatal outcomes have occurred with maternal treatment with intravenous immune globulin and/or steroids in the next pregnancy.
FNAIT is usually characterized by the presence of transient isolated thrombocytopenia secondary to the production and transplacental passage of maternal antibodies directed against paternally inherited antigens expressed on the fetal/neonatal platelet. FNAIT is the platelet equivalent of hemolytic disease of the fetus and newborn (HDFN) in which the same type of incompatibility occurs, only in the case of FNAIT involving platelet instead of red cell antigens ( Table 94.2 ).
Table 94.2
Differences and Similarities Between NAIT and Hemolytic Disease of the Fetus and Newborn (HDFN)
| Differences with HDFN | Similarities With HDFN |
|---|---|
| Primiparous pregnancy can be affected in NAIT No routine screening exists for NAIT No preventative treatment is available for NAIT IVIG is relatively effective for in utero disease in NAIT |
Pathophysiology is similar: antigen incompatibility of the parents and maternal antibody production of which the IgG crosses the placenta and affects the fetus by destroying fetal cells EPO and TPO receptors are in the fetal brain Neonatal cytopenias are transient until the maternal antibodies disappear from neonatal circulation No evidence for or against a role for breast feeding in perpetuating neonatal disease exists Severe cytopenia is associated with significant clinical consequences |
Pathophysiology
HPAs are platelet-specific antigens that reside on platelet surface membrane glycoproteins (see Chapter 31 ). HPAs are expressed on fetal platelets from the 16th week of gestation and are the antigenic source for alloimmunization in NAIT.
The most frequently involved alloantigen in NAIT is HPA-1a in the Caucasian population, where incompatibility at the HPA-1 polymorphism accounts for ∼70%–80% of severe NAIT. Ethnic variation in allele distribution is important to consider, in particular that HPA-4 incompatibility accounts for 80% of FNAIT in the Asian population in whom the HPA-1a/1b polymorphism is extremely rare.
Additionally, incompatibilities at HPA-5b, HPA-3a and 3b, and HPA-9b have been identified. HPA-5b incompatibility is the second most common cause of FNAIT but is usually associated with a less severe phenotype. One possible explanation is the high density of GPIIIa molecules on the platelet surface (∼26,000 potential targets for anti-HPA-1a). In contrast, HPA-5 is expressed on the platelet surface at much lower density (∼1000 potential targets of anti-HPA5b). HPA-3 incompatibility represents only 1% of cases although 10% of pregnancies have an incompatibility of HPA-3a or 3b, and most cases are severe, similar to HPA-1a incompatibility. In addition, anti-HPA3a or 3b may be hard to detect. HPA-9b is more recently described and is now reported to be the second most common cause of severe cases of FNAIT in Caucasians. HPA-9b is found only in 1:500–1:1000 people, and antibodies against it are extremely difficult to measure. Therefore, if the father has HPA-9b in a thrombocytopenic fetus who clinically appears to have FNAIT and in whom the rest of the workup does not reveal an alternative etiology, the diagnosis of FNAIT secondary to HPA-9b incompatibility is made even in the absence of detectable anti-HPA-9b antibody.
In the Caucasian population, 97%–98% of individuals express HPA-1a on their platelets (75% HPA-1a/1a homozygous or 25% 1a/1b heterozygous); the remaining 2%–2.5% are HPA-1a negative. It is these HPA-1b/1b homozygous mothers who are at risk of the development of NAIT in each pregnancy, including the first, if their partner is HPA-1a heterozygous or homozygous.
In addition to HPA alloantigen incompatibilities and the presumptive role of antigen exposure to the mother, in the development of NAIT, additional genetic modifiers are involved in the development of alloantibodies. Only approximately 12% of mothers who are HPA-1a-negative produce antibodies; the additional presence of HLA DRB3∗0101 in the mother confers a 10–20-fold increased relative risk of antibody production.
It is believed that the exposure of incompatible fetal platelets to the maternal circulation results in the production of maternal IgG anti-HPA antibodies. However, it has been proposed that these antibodies could arise from expression of GPIIIa and thus HPA-1a on the surface of the syncytiotrophoblast from the maternal side of the placenta. The standard explanation of pathophysiology is that these IgG antibodies are transported across the placenta and bind to fetal platelets. These antibody-coated platelets are removed from fetal circulation by the reticuloendothelial system with resultant fetal thrombocytopenia. Recent work has suggested that these alloantibodies also damage fetal megakaryocytes and thus contribute to fetal thrombocytopenia. Furthermore, because GPIIIa is expressed on vascular endothelial cells, it may also contribute to fetal ICH via an alternative mechanism in addition to the creation of severe fetal thrombocytopenia.
Clinical Presentation
FNAIT can occur in any pregnancy with most cases evident in full-term neonates. NAIT should be suspected when a neonate presents with a platelet count <50,000/μL, with or without bleeding symptoms in the perinatal period. Bleeding symptoms in the neonate with NAIT can include petechiae, hematoma, melena, hematuria, hematemesis, hemoptysis or, most significantly, ICH. Additional cases of NAIT can be identified in neonates without bleeding symptoms who have thrombocytopenia detected incidentally on blood counts obtained for sepsis or other nonhemorrhagic evaluations.
As we incorporate additional information from screening programs for FNAIT, it has been identified that 75% of sensitization occurs after the birth of the first child, similar to Rh disease, attributed to delivery-related transplacental hemorrhage. However, in more than 60% of clinically severe cases the first affected pregnancy is caused by prior sensitization. In those cases, sensitization must occur antenatally ( Table 94.1 ).
Thrombocytopenia with FNAIT can occur as early as the 13th week of gestation, with up to 75% of clinical ICHs occurring prenatally. In untreated cases, ICH occurs in 10%–20% of affected fetuses/neonates with a 15% fatality rate, and may present with fetal distress, encephalomalacia, intracranial cysts, and focal neurological exam including a full fontanelle, anemia, or poor feeding. The presentation can include fetal anemia or porencephaly; the most common time of hemorrhage seems to be approximately 32 weeks of gestation.
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