|Year : 2014 | Volume
| Issue : 3 | Page : 137-139
Neonatal alloimmune thrombocytopenia
Rajesh Singh Laishram
Department of Pathology, Regional Institute of Medical Sciences, Lamphelpat, Imphal, Manipur, India
|Date of Web Publication||5-Jan-2015|
Rajesh Singh Laishram
Department of Pathology, Regional Institute of Medical Sciences, Lamphelpat, Imphal, Manipur
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Laishram RS. Neonatal alloimmune thrombocytopenia. J Med Soc 2014;28:137-9
NAIT is caused by maternal antibodies raised against alloantigens carried on fetal platelets. It occurs when a woman becomes alloimmunized against fetal platelet antigens inherited from the fetus's father leading to fetal thrombocytopenia (<150000 platelets/μL). The formal first report describing the condition now designated as NAIT was given by Harrington et al. in 1953 where he described two infants born with severe thrombocytopenia to mothers with normal platelet counts. In 1962 Shulman et al. first described a maternal antibody raised against a defined platelet alloantigen designated Pl AI which was the cause of platelet destruction in the newborn. Pl AI was later found to be identical to an antigen designated ZW a by Dutch workers (vanLoghem et al.)  in 1959 and is now known as HPA-1a(Human platelet antigen 1a). Subsequently, numerous other platelet specific antigens were described to be capable of inducing maternal immunization during pregnancy thereby causing fetal platelet destruction. NAIT is now recognized as an important complication of pregnancy. Unlike erythrocyte alloimmunization, NAIT may appear during first pregnancies and often with progressively more severe manifestations in subsequent pregnancies. ,, NAIT is one of the leading cause of severe thrombocytopenia in the new born , and should not be confused with autoimmune thrombocytopenia, in which both the mother and fetus are affected due to maternal autoantibodies. Most cases are mild with widespread petechiae and other skin lesions. However, severe cases can cause intracranial hemorrrhage resulting in death or long-term disability.  At present, there are no national screening programs for NAIT and a history of an affected sibling is currently the best indicator of risk to a current pregnancy. 
Several studies showed the incidence of NAIT to be between one in 1000 and one in 2000 HPA-1a positive infants. ,[ , The incidence of the HPA-1a negative (HPA-1bb) phenotype in Caucasian population is about 2.5%. One third of these patients are positive for the HLA-DR antigen B3*0101. 
NAIT is believed to be produced by platelet transfer of natural immunoglobin IgG antibodies against fetal platelet antigens inherited from the father. So far 24 human platelet-specific alloantigens (HPAs have been described many of them being grouped in biallelic systems). ,, Antibodies against the antigens are designated anti-HPA. In white populations, the most common antibody is anti HPA-1a (75-80%) which targets the polymorphic Leu/Pro reisdue of glycoprotein IIIa(GPIIIa) on the platelet membrane. , The timing and mechanism of immunization is not known but Kumpel and colleagues  have proposed the expression of HPA-1a not only on fetal platelets but also on other fetal cells. GPIIIa, the platelet glycoprotein carrying the HPA-1a/1b polymorphism has been noticed on the surface of villous syncytiotrophoblast in both first trimester and term placenta  and its interaction with the maternal immune system could be one plausible explanation.
Antigens capable of triggering NAIT are carried on platelet membrane glycoproteins (GPs) GPIb-V-IX (von Willebrand receptor), GPIIb/IIIa (αIIb/β3 integrin, fibrinogen receptor), GPIa/IIa (a collagen receptor) and CD109.  Antigen HPA nomenclature was developed by international consensus under which antigens system are designated HPA-1, HPA-2, etc, more or less in the order of their discovery. , In each system the more common and less common alleles are designated 'a' and 'b', respectively.
IT has been known that platelets normally express small quantities of A and B antigens on their surface.  Curtis et al.  showed that in a subset of individuals (type 2 high expressers), platelet A1& B antigens levels are extremely high and raised the possibility that some infants possessing this trait could be at risk for thrombocytopenia if born to an ABO incompatible mother. NAIT thus can be caused by maternal IgG anti-B (and presumably anti-A) antibodies under some circumstances.
Glycoprotein IV (CD 36) is a member of the class B scavenger receptor family of proteins expressed on platelets, red cells, endothelial cells and other tissues.  NAIT associated with maternal immunization against CD36 is similar to that seen in infants affected by HPA-specific antibodies. 
There are many studies with different role in relating between HLA and NAIT. King et al.  reported that woman sensitized to class I HLA antigens routinely give birth to infants with normal platelet counts negating the relation between HLA and NAIT. However, there are other literatures containing many anecdotal reports of infants born with apparent NAIT possibly caused by maternal anti-HLA. ,,
The clinical presentation depends on the time of onset and severity of the thrombocytopenia. The most common ones include bleeding into skin and may be the only sign in 47% of cases.  The bleeding may be mild or widespread petechiaes or ecchymoses within a few hours after birth or in some cases with hematoma formation at injection sites.  Typically, no other explanation for the thrombocytopenia is found after evaluation for bacterial or viral infection, disseminated intravascular coagulation or other congenital conditions associated with thrombocytopenia. The most serious complication of NAIT is intracranial hemorrhage seen in 10-20% of symptomatic infants. 
Routine test include a complete blood count which will document the platelet count and determine whether it is an isolated thrombocytopenia or a part of pancytopenia syndrome. Low platelet with increased IT (immature-total) ratio will guide for septicemia. A maternal blood sample should be examined to exclude low platelets in the mother (suggestive of autoimmune thrombocytopenia). All the other common causes of thrombocytopenia should not be ignored before subjecting the case to special tests.
As sensitization to fetal platelet antigens can occur during first pregnancy, investigators typed women pregnant for the first time for HPA-1a in an attempt to identify infants at risk for NAIT.  But cost is a concern for performing this screening test routinely. It should be performed in those cases with appropriate clinical setting and a positive family history. Proper lab diagnosis of NAIT requires sophisticated testing.
Flow cytometry using secondary probes specific for IgG and IgM immunoglobulin isotypes  provides a rapid and a sensitive method of detecting platelet reactive antibodies. Modified antigen capture enzyme-linked immunosorbent assay (MACE) is used to detect maternal antibodies reactive with HPA antigens carried on GP IIb/GPIIIa and GPIa/IIa using paternal platelets.  Monoclonal antibody immobilization of platelet antigens (MAIPA) is another slightly different approach widely used in Europe. 
With the advent of DNA based methods, it has made serological typing for HPA antigens obsolete. The nucleotide changes that encode individual antigens can be rapidly and accurately identified.  Other PCR-based techniques like PCR-sequence specific primer amplification , followed by electrophoresis and visualization of DNA bands are also being used by some laboratories. The idea is to type the paternal and maternal DNA.
All the causes of neonatal thrombocytopenia are to be considered. The main causes other than NAIT are septicemia, autoimmune thrombocytopenia, drug-related destruction of platelets, DIC, necrotizing enterocolitis, hypersplenism, Kasabach-Merritt syndrome and thrombosis.  Less common causes include genetic abnormalities (e.g., Congenital amegakaryocytic thrombocytopenia, congenital platelet disorder), bone marrow infiltrative disease (e.g., Bone marrow metastasis, neonatal leukemia) or toxic megakryocyte injury. 
NAIT is a relatively uncommon disease but a leading cause of severe thrombocytopenia in new born and subsequent intra cranial hemorrhage. The diagnosis should be suspected if a neonate presents with unexplained hemorrhage or if there is a family history of NAIT. At present there is no simple, safe, precise and validated test for NAIT.
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