Fetal and neonatal alloimmune thrombocytopenia (ORPHA:853)
A rare hematological disease characterized by maternal alloimmunisation against fetal platelet antigens that are inherited from the father and different from those present in the mother, and usually presents as a severe isolated thrombocytopenia in otherwise healthy newborns.
Epidemiology
The incidence of fetal/neonatal alloimmune thrombocytopaenia (FNAIT) has been estimated between 1/800 to 1/2 000 live births.
Clinical description
FNAIT has been considered to be the platelet counterpart of Rh Hemolytic Disease of the Newborn (RHD). Unlike RHD, FNAIT can occur during a first pregnancy. The spectrum of the disease may range from sub-clinical moderate thrombocytopenia to life-threatening bleeding in the neonatal period. Mildly affected infants may be asymptomatic. In those with severe thrombocytopenia, the most common presentations are petechiae, purpura or cephalohematoma at birth, associated with a major risk of intracranial hemorrhage (up to 20% of reported cases), which leads to death or neurological sequelae.
Etiology
FNAIT results from the transplacental passage of maternal alloantibodies (which are IgG) against fetal platelet antigens which are inherited from the father. In Caucasians, the most frequent platelet antigen (HPA) involved in FNAIT is HPA-1a (anti-HPA-1a alloantibodies), which is located on glycoprotein IIIa (GPIIIa), accounting for 75-80% of cases. The other main antigens involved are HPA-2, HPA-3, HPA-5, and HPA-15. The mechanisms of maternal immunization are only partly understood. Fetal syncytiotrophoblasts express GPIIIa on their cell surface and the spread of their extracellular vesicles in the maternal circulating blood system may possibly be at the origin of immunization, beginning with the first pregnancy.
Diagnostic methods
Alloimmune thrombocytopenia is more often unexpected and is usually diagnosed after birth. Once suspected, the diagnosis is confirmed by demonstration of maternal antiplatelet alloantibodies directed against a paternal antigen inherited by the fetus/neonate.
Differential diagnosis
Differential diagnosis includes sepsis/ infection, perinatal hypoxia, intrauterine growth restriction, prematurity, necrotizing enterocolitis, disseminated intravascular coagulation (DIC), other congenital conditions associated with thrombocytopenia, fetal intracranial hemorrhage without abnormal platelet count.
Antenatal diagnosis
To enable appropriate counseling for subsequent pregnancies, the father's HPA genotype should be determined wherever possible. If he is homozygous and particularly if the mother still has the relevant antiplatelet antibodies, the subsequent fetus is at risk. In the case of paternal heterozygosity for the offending antigen, or when paternity is uncertain, fetal HPA genotyping can be done on chorionic villi or amniotic cells. A noninvasive procedure of HPA genotyping from maternal serum is now available for some HPA.
Genetic counseling
Inheritance of the paternal HPA is autosomal dominant; genetic counselling should be offered to allo-immunized women, informing them that there is a 50% risk of having an HPA-incompatible fetus when the father is heterozygous for the offending antigen. All fetuses are HPA-incompatible if the father is homozygous for the offending antigen.
Management and treatment
Post-natal management involves transfusion of platelets devoid of this antigen, and should not be delayed by biological confirmation of the diagnosis (once the diagnosis is suspected), especially in case of severe thrombocytopenia. Prompt diagnosis and treatment are essential to reduce the chances of death and disability due to hemorrhage. Due to the high rate of recurrence and increased severity of the fetal thrombocytopenia in successive pregnancies, antenatal therapy should be offered. Fetal blood sampling by cordocentesis remains possible in situations of intermediate risk if there is a question about the indication of medical treatment and where vaginal delivery is requested.
Prognosis
The most feared complication of FNAIT is the occurrence of intracranial hemorrhage, leading to death or neurological sequelae. In addition, miscarriage has also been observed.

                            Last update: 
                            March 2022


                            - Expert reviewer(s): 
                            Dr Gérald BERTRAND  - Pr Norbert WINER