Neonatal Alloimmune Thrombocytopenia

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) results from the destruction of fetal platelets by maternal antibodies that cross the placenta and bind to fetal platelet antigens inherited from the father. FNAIT is one of the most common causes of severe isolated thrombocytopenia in newborns and occurs in approximately one in 1000 births.

This syndrome can be thought of as the platelet counterpart of hemolytic disease of the fetus and newborn (HDFN). Unlike HDFN, FNAIT frequently occurs during first pregnancies. Placental transfer of maternal IgG begins around week 12 of gestation and continues throughout the pregnancy. Fetal IgG levels can be higher than the maternal IgG level.

Approximately 40 to 60% of cases are unexpectedly discovered during the third trimester of the first pregnancy when intracranial hemorrhage (ICH) is detected by sonography. A major advance is the use of fetal blood sampling for accurate diagnosis and for assessment of the severity of fetal thrombocytopenia. Options for management include maternal treatment with IVIG and/or corticosteroids. For cases considered to be at high risk of ICH, fetal platelet transfusions may be required.

After birth, FNAIT is suspected when a full-term, otherwise healthy, newborn, begins to bleed shortly after birth and is found to be thrombocytopenic. Maternal platelet count is within the reference range. Diagnosis is confirmed by detection of a maternal platelet alloantibody against the father's platelets.

After birth, the platelet count may continue to fall, and the infant's platelet count should be measured daily. If there is a perceived risk of bleeding, a platelet transfusion should be given when the platelet count falls below 30,000/uL. Compatible donor platelets or maternal platelets are preferred. Procurement of antigen negative platelets can be logistically difficult because only 2.5% of donors lack HPA-1a antigens. Maternal platelets can be collected but need to be plasma-reduced or washed with saline, to remove maternal anti-platelet antibody. Ideally, they should be tested for transfusion transmitted diseases and irradiated prior to transfusion. Neither antigen negative platelets nor maternal platelets may be available soon enough in an emergency situation. In this case, random donor platelets can be combined with or without an infusion of intravenous immunoglobulin. Most patients transfused with antigen positive platelets from random donors achieve a significant increase in platelet count.

Subsequent pregnancies involving incompatible fetuses are at very high risk of FNAIT and usually have more severe thrombocytopenia. Antenatal management of these cases is critical. The goal of therapy is to increase fetal platelet count to greater than 50,000/uL and prevent ICH.

In Caucasians, approximately 80% of severe cases are caused by HPA-1a antibody. These maternal alloantibodies not only destroy and inhibit production of fetal platelets; they also impair vascular integrity and angiogenesis, resulting in an increased risk of bleeding. Antibodies to a number of other platelet antigens or, possibly, HLA antibodies are responsible for the other 20% of cases. The role of anti-HLA class I antibodies in FNAIT is not fully understood.

Currently 33 human platelet antigens (HPA) have been identified. The majority of HPAs are expressed on the GPIIb and GPIIIa glycoprotien complex on the platelet membrane. Twelve of the HPA are clustered into six biallelic groups called HPA-1, HPA-2, HPA-3, HPA-4, HPA-5 and HPA-15. The antigens are numbered in order of discovery with the higher frequency antigen labeled "a" and the lower frequency antigen labeled "b".

HPA System Glycoprotein CD
HPA-1 a & b GP IIIa CD61
HPA-2 a & b GPIb alpha CD42b
HPA-3 a & b GPIIb CD41
HPA-4 a & b GPIIIa CD61
HPA-5 a & b GPIa CD49b
HPA-15 a & b CD 109 CD 109

 

Identification of the maternal antibody is accomplished by incubating maternal serum with paternal platelets and a panel of genotyped group O donor platelets. The monoclonal antibody specific immobilization of platelet antigens (MAIPA) assay is considered to be the gold standard reference method for detection of platelet antibodies. 

HPA compatibility can be confirmed by genotyping for paternal platelet antigens. High throughput genotyping methods are now available in reference laboratories. 

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