INTERNATIONAL JOURNAL OF IMMUNOLOGY AND IMMUNOBIOLOGY (ISSN:2631-6706)

Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is one of the leading causes of isolated severe thrombocytopenia in term infants. Neonatologists and gynecologists should be alert to early recognize such cases. Increased suspicion would help to early determinate diagnosis, initiate appropriate therapy and protect present and subsequent pregnancies. The purpose of the study has been the presentation of the clinical diversity of illness along to the necessary investigation to establish the diagnosis.

Patient’s methods

We have included nine neonates and one fetus with early-onset thrombocytopenia of unknown cause. We have identified platelet alloantibodies in the serum of 5/8 infants, in 1 fetus, and in 8/8 mothers. We have used polymerase sequence reaction in restricted fractioned length portions (PCR-RFLP) for genotyping of specific platelet antigens in neonates and their parents.

Results 

We have established the diagnosis of neonatal alloimmune thrombocytopenia in eight patients. We present the clinical heterogeneity of the disease through analysis of these cases

Neonatal alloimmune thrombocytopenia is amongst the most frequent causes of severe thrombocytopenia in neonates. It is encountered in approximately 1:1000 live births [1]. Alloimmune thrombocytopenia is due to maternal alloantibodies that associate to fetal platelet antigens (HPA-type) that the fetus has inherited from his father. Alloantibodies are transferred through placentas to the fetus and destroy fetal platelets. Complications of the disease may present in the prenatal, antenatal or postnatal period. The severity of the disease may vary among patients, and clinical heterogeneity may handicap diagnosis. 

We have included nine neonates admitted in a University Neonatal Intensive Care Unit due to early-onset thrombocytopenia of unknown cause during the interval September 2007-June 2009. Infants of mothers with pre-eclampsia, sepsis or drugs abuse, as long as neonates with asphyxia, intrauterine or perinatal infection have been excluded from the study. We have recorded a detailed obstetric and perinatal history along with clinical examination and complications in each patient. We have eliminated microbial or viral infection through thorough laboratory investigation.

We have performed further analysis and identified antiplatelet antibodies (HPA-type) in the serum of 5/8 neonates, in 1/8 fetus and 8/8 mothers. We conducted examination for anti-HLA-I antibodies in all neonate-mother pairs. HPA genotyping has been used to define specific HPA incompatibilities between mother and child.

We have used polymerase sequence reaction in restricted fractioned fragments length polymorphism (PCR-RFLP) method for genotyping of specific platelet alloantigens (HPAtype) (Figure 1). We have identified Polymorphism of three systems of specific antigens of platelets (HPA-1, HPA-5, and HPA-3) to be responsible for alloimmunization of the fetuses. After DNA secretion, the sequence-specific primers’ pair is selected for each HPA-system so that final product of polymerization will include the whole region of the genome with polymorphism for each system. We recognize this area from restricted endonucleases. This enzyme acts while it develops specific detectable fragments of DNA which are different for each allele and we further discriminate them in an agarose gel.

During the study period, we have examined nine neonates, and we have established the diagnosis of alloimmune thrombocytopenia in 8 out of 9 newborns. The neonates were of Greek nationality, four were full-term (gestation week 37-40 weeks and birth weight 2740- 3310gr) and three preterms (gestation week 30-36 weeks and birth weight 1300-2370gr), four boys and four girls.

In all cases, pregnancy was uncomplicated. In one instance pregnancy occurred after HLA immunotherapy and multiple abortions have preceded this gestation. Four of the mothers had previous deliveries (IV^th delivery for the 2nd mother, III^rd delivery for the 3rd mother, II^nd delivery for the 4^th and 8^th mother). We established enumeration according to the sequence of appearance of each patient. Apgar score in all neonates has been >8 in 5’.

According to criteria to enroll in the study, obstetric and perinatal histories were free for mother’s thrombocytopenia, autoimmune diseases, infections, and hypertension, drug abuse during pregnancy. All mothers’ platelet counts were normal. An extensive laboratory investigation was negative for congenital either viral infection. None of the neonates had any malformations and evaluation of coagulation was reasonable.

Four diagnosed patients suffered minor complications of the disease. Two of the full-term neonates developed petechiae on the trunk, the face, on the axillaries and genitival areas whereas the rest of the infants were asymptomatic. We analyze characteristics of the newborns included in the study in (Table 1) (neonates with minor complications of the disease) and (Table 2) (infants with severe complications of the disease). We diagnosed thrombocytopenia in 1st day of life in 7/8 neonates. In 1/3 asymptomatic newborns, diagnosis of thrombocytopenia has been set in 1st day of life and 2/3 in the 4th day of life due to the investigation of respiratory distress and hyperbilirubinemia, respectively.

Minimum platelet count was 19000k/µl and maximum platelet count was 65000k/µl on the day of diagnosis of thrombocytopenia in asymptomatic neonates. In 2 infants, thrombocytopenia resolved in a ten days interval without therapy. No platelet transfusion was initiated, as platelet count was not less than 30000 k/µl. On the contrary, in three full-term neonates (Tables 1 and 2), thrombocytopenia resolved upon the 2^nd and the 7^th day; after intravenous initiation of immunoglobulin at a dose 1g/kg/d for one day in the two patients and two days in the third (8^th) recorded patient [2]. Furthermore, we initiated a platelet transfusion to one neonate (2^nd patient) due to a decrease in platelet count till 19000k/µl.

Four of the infants suffered severe complications of the disease; thus they are further analyzed. The first recorded patient has been a prematurely delivered neonate on the 30^th week of gestation. For this patient, the diagnosis of alloimmune thrombocytopenia was established prenatally. The previous pregnancy ceased due to severe intracranial hemorrhage- hydrocephalus of the fetus developed between 28 and 32 weeks of gestation. Due to dismal obstetric history, examination for fetal alloimmune thrombocytopenia has been performed eight months after termination of the first pregnancy. Fetal platelet count was 4000 k/µl. Platelet genotyping and platelet antibody screening were performed showing platelet HPA system mismatch between mother and father. Mother’s platelet blood group was HPA-1b1b and father’s platelet blood group HPA-1a1a. There was a complete mismatch of platelet blood groups between parents. The fetus had alleles from both parents. It was HPA-1a positive, and it sensitized the mother during her first pregnancy. Anti-HPA-1a antibodies were identified in mother’s serum which confirmed the diagnosis of fetal alloimmune thrombocytopenia. We concluded that the first baby developed met hemorrhagic hydrocephalus by fetal alloimmune thrombocytopenia.

In the second pregnancy (after natural conception) chorionic villi were withdrawn, to perform fetus genotyping. Fetus genotyping revealed that the fetus was 1a1b heterozygous and it could also develop hemorrhagic complications due to NAIT. Antenatal treatment of the fetus was of paramount importance in order not to produce hemorrhage.

During the second pregnancy, the healthy 31-year-old mother started prophylactic treatment with intravenous immunoglobulin intravenously 1g/kg in weekly intervals from 16^th to 22^nd week of gestation. On 22^nd gestation week, evaluation of platelets’ count through the umbilical artery revealed that the platelet count was 13000k/µl. After platelet transfusion, platelet count increased to 384000k/µl. Fetal platelet count has been evaluated weekly, and transfusion of platelets to the fetus has been performed through cordocentesis every week. Last intrauterine platelet transfusion was performed one week before delivery in gestation age of 29w+^3d. Fetal platelet count was 55000k/µl and increased to 526000k/µl after the transfusion.

Steroids were also initiated given the imminent launch of labor for two days. Unfortunately, three days after the last platelet transfusion the baby was delivered prematurely (on 30^th gestation week) with cesarean section due to breech presentation and labor  onset. The newborn infant boy needed resuscitation with bag and mask. The infant had spontaneous breaths, lovely color and tone in 5 minutes after delivery. Apgar score was 5 in the first minute and 8 in five minutes after birth. Birth weight was 1300gr. As the delivery happened at a local hospital, the newborn was then transmitted to a central universal Neonatal Intensive Care Unit (NICU) department. After its admission in NICU, blood cultures were taken, and combined antibiotic therapy with ampicillin and gentamycin were initiated along with parenteral therapy. Mother’s platelets were irradiated after delivery to be available for transfusion to the neonate if the platelet count in the newborn was less than 35 x109 k/µl.

Newborn’s platelet count was 224 x 109 k/µl immediately after delivery. We initiated treatment with intravenous immunoglobulin (IVIG) (1g/kg) in the first and second day of life. Platelet count continued to decline till 87 x109 k/µl on the fourth day of life. Intravenous immunoglobulin was re-initiated on the fourth day for two days. We discontinued therapy on the 5^th day of life due to the increase of platelets till 100000k/µl. Platelet count rose to 246 x109 k/µl on the 8^th day of life. Head ultrasound on the fourth day revealed increased echogenicity on the right parietal lobe. We initiated total parenteral nutrition for five days. Enteral feeding was started on the 4^th day and gradually increased to reach full enteral feeding on the 12^th day 

Despite the good clinical condition, the platelet count was not stable, and a de novo decrease of platelets to 105 x109 k/µl occurred on the 12^th day. We drew blood cultures, and we initiated combined antibiotic therapy. Platelet count continued to decline till 63 x109 k/µl on the 13^th day. We re-initiated IVIG treatment (0,5g/kg/day) for four days. Blood cultures and systemic infection indices were negative; thus antibiotic therapy was discontinued two days after its initiation. There were no clinical signs of microbial or viral infection during all episodes of thrombocytopenia. Platelet count reached to normal values (214 x109 k/µl) on the 17^th day and increased further till 502 x109 k/µl on the 23^rd day that has been treated with IVIG initiation 1g/kg/day for four days. Platelet count increased gradually, and it reached to normal levels (PLT 219000k/µl) on the 17^th day (Figure 2). During hospitalization and follow-up of the infant till 18 months of life, no other episode of thrombocytopenia occurred. The baby grew up regularly and reached his developmental milestones on good health.

As far as the 6^th and 7th recorded patients are concerned, obstetric history has been of keen interest. The mother had a spontaneous abortion before her first gestation. An antiphospholipid syndrome has been diagnosed during the first pregnancy and therapy with heparin of low molecular weight has been initiated. Ultrasonographic evaluation on 28^th pregnancy week revealed an intracranial mass. MRI could not show the nature of the mass. A second intrauterine brain-MRI defined an increase of the lesion. Thus, on 31^st gestation week, it has been decided to deliver the baby by caesarean section. Neurological examination of the newborn has been within normal levels. Platelet counts immediately after birth were 30.000k/µl, and we initiated a platelet count from a random donor. The neonate had no apparent hemorrhagic tendency on sites of venipunctures. Repeated MRI evaluation failed to define real nature of the lesion. Due to the undefined value of Partial Time Thromboplastin, we repeatedly initiated fresh frozen plasma. Due to thrombocytopenia, we transfused platelets regularly for two days.

The neonate grew up and gained weight normally. At the age of four months, it was stable enough to have a brain neurosurgery. The surgery revealed that the mass was an intracranial hematoma. At the age of 9 months old, there were no Neurological symptoms, apart from a slight difficulty in the movement of the left hand, which improved gradually with physiotherapy. At 27^th week of the second gestation, we revealed that the fetus also had an intracranial hemorrhage, whereas the first infant was eight months old. We evaluated a laboratory investigation for alloimmune thrombocytopenia in parents and the first neonate that turned out to be positive (Table 4).

At 30^th gestation week, intracranial hemorrhage of the fetus has been even more extensive. Therefore, gynecologists have decided to deliver the baby by caesarean section. Mother’s compatible platelets were irradiated to be initiated to the neonate if needed. Immediately after birth, infant’s platelet count was 34000k/µl, and we transfused compatible platelets to the newborn. The neonate was hydrocephalus. Palpation of anterior fontanel assessed an increased intracranial pressure. Head ultrasound revealed extensive bilateral intracranial hemorrhage with hemorrhagic cyst and atrophy of parenchyma. The neonate had a brain neurosurgery at the age of two months old, but the prognosis is quite conservative.

The 8^th reported infant presented respiratory distress immediately after birth. The neonate needed oxygen administration for a few hours due to transient respiratory distress. However, the newborn had hemorrhagic tendency at sites of venipuncture. Blood analysis revealed thrombocytopenia (PLT: 10000k/µl). Intravenous immunoglobulin was initiated intravenously at a dose 1g/kg/d for the 1st day and 0,5 g/kg/d for two subsequent days. Irradiated mother’s platelets either platelets of compatible HPA-type could not be prepared immediately. Echo ultrasound did not reveal any abnormalities, and the neonate was stable enough not to be transfused with random donor’s platelets. Neonate’s platelet count increased to 48800 k/µl in an eight hours interval after initiation of IVIG. It further rose to 61000 k/µl twenty hours after initiation of IVIG, and it reached till 98000 k/µl on the 3^rd day of life, while it remained in levels > 150000k/µl after the 6^th day of life. No other episode of thrombocytopenia occurred ever since. Early-onset neutropenia without leucopenia presented on the 6^th day of life, and it gradually resolved on the 14^th day. An extensive investigation was negative for microbial or viral infection. We gradually increased enteral feeding, and the neonate reached to total enteral intake on the 7^th day of life. Neurological examination of the infant was normal at birth and remained healthy when the neonate discharged from the hospital at 16^th day of life.

As told by the family history, the neonate had the eldest brother reported healthy until then. From the obstetric history, the mother had multiple abortions after her first pregnancy. Due to HLA incompatibility between parents, the mother had HLA immunotherapy to conceive. After conception, there were no problems during gestation.

HPA-type and HLA antibodies’ investigation during first days after birth, in mother and neonate revealed that HPA antibodies (HPA-5b and HPA-1a) and HLA-I antibodies were present in both mother and infant (Table 4). Laboratory follows up of the neonate every ten days initially and every 20 days afterward were correct. The baby grew up and gained weight normally.

At four months of age, the neonate presented seizures of the left foot and arm. Magnetic Resolution Imagination (MRI) revealed a subdural hematoma (2cm) of the right parietal side. T2 signs announced that the subdural hematoma could emerge in a 48-hours interval before the episode of seizures. That was compatible with color appearance of hematoma on MRI. Subdural hematoma decreased gradually, and it reached a diameter of 0,7 cm, in a 15-day interval. No other episode of seizures occurred.

Results of investigation of specific platelet alloantibodies (HPAtype), HLA-I antibodies and HPA-systems’ genotyping in parents and neonates along with clinical manifestations of the disease in all patients are analyzed in (Table 3) (newborns with minor complications of alloimmune thrombocytopenia) and in (Table 4) (neonates with severe complications of the disease). 

One of the leading causes of isolated severe thrombocytopenia in term infants is neonatal alloimmune thrombocytopenia (NAIT). The incidence of fetal/neonatal thrombocytopenia is remarkably variable in different populations. It is reported to occur in approximately 1:1000 live births [1]. The exact rate in Greece is not known, as there is not a complete record of complaints cases.

Complications of the disease may present in intrauterine life or immediately after birth [3]. Since the illness affects the fetus, it may appear with extreme severity, and cause severe handicaps to the newborn, as in the 1^st, 6^th, and 7^th recorded patients for whom intracranial hemorrhage and hydrocephalus complicated the pregnancies. The disease may also present with extreme thrombocytopenia on the 1^st day of life and cause a subdural hematoma afterward as it happened to the 8th patient [4].

On the other hand, the disease may present with very mild symptoms like petechiae immediately after birth as it occurred in two out of three full-term neonates. It may also be entirely asymptomatic; thus thrombocytopenia may be revealed in a routine blood analysis for another problem, as it happened in two of the neonates that we present.

Clinical heterogeneity of the disease is remarkable. Study of clinical characteristics of the patients may help to approach explanations for the diversity of the disease. Apart from the history of previous gestations with dismal obstetric history and existence of brothers and sisters suffering from the disease, no other sign can apparently predict the disease [5]. Thus, the type of HPA-system mismatch may be the parameter to define the severity of the disease.

HPA-antigens connect to HPA antibodies that combine to glycoproteins on platelets’ membrane [6]. HPA-antigens belong to 16 different subtypes according to the chronological time of detection [7]. Most frequently identified are HPA-systems 1,2,3,4,5 and 15. Each HPA-system has two alleles (allele a and b). Allele a is presented in higher frequency compared to allele b. The frequency of each HPA-system in individuals varies according to the race involved. In Caucasians, anti-HPA-1a alloantibodies are involved in the majority of cases of alloimmune thrombocytopenia (75-95%) as they have a relatively low (97,9%) incidence of the HPA-1a antigen. Neonates that suffer HPA-1a system mismatch present intracranial hemorrhage in a percentage of 10-20% and half of these cases occur in intrauterine life, as it happened in the two neonates that we present.

In all three cases of neonates that suffered severe complications, we identified anti-HPA-1a alloantibodies in all three mothers. Genotyping of the patients revealed that all infants who suffered critical complications of the disease had HPA-1a system mismatch between parents. These strongly support that HPA-1a system mismatch between mother and neonate implicates in cases with severe prognosis [6].

About 5-25% of cases of NAIT are caused by other HPA-antibodies, most frequently anti-HPA-5b, anti-HPA-3a and anti-HPA-1b. AntiHPA-5b alloantibodies encounter as the second more frequent cause in alloimmune thrombocytopenia cases. They are implicated with mild symptoms of the disease, as it has been noticed to occur in the 4th neonate in our study

Clinical heterogeneity of the disease seems to interfere with the particular ability of each alloantibody to bind to specific sites of the platelets. These sites can differ in each patient, a fact that may smoothen or harden binding of alloantibodies to platelets and therefore evolution of the disease manifestations.

Alloantibodies’ production may be easier by co-existence of specific HLA epitopes’. Mothers who developed anti-HPA-1a alloantibodies were in about 80% positive to HLA-DR52a epitope [8]. HLA-B8 and HLA-DR3 epitopes have also been positively correlated to anti-HPA-1a alloantibodies’ production [9]. Screening of these epitopes has been the base of a cost-effective screening for neonates that may manifest complications of the disease [10]. However, maternal HLA genotyping has not been found to be useful for predicting the severity of fetal and neonatal alloimmune thrombocytopenia [11].

30% of women who have had multiple pregnancies present positive HLA-antibodies. Anti-HLA-I may also be responsible for Thrombocytopenic Purpura syndrome with severe hemorrhagic manifestations that usually occurs 7-10 days after a transfusion.

As many mothers have transfusions, but they do not develop the syndrome, it is possible that antibodies’ production implicates an initial sensitization, whereas we do not know when alloantibodies may lose their specificity and become auto antibodies. Besides, antibodies’ binding on specific epitopes may activate platelets in different ways (internal signs), thus leading to the development of a distinct clinical syndrome.

10% of these patients develop both HLA and HPA antibodies (more frequently HPA-1a and HPA-5b). Multiple HLA-antibodies and HPA-antibodies were present in mother’s serum of the 8th neonate who suffered multiple hemorrhagic manifestations. However, the mother of the 3rd patient developed both HPA-1a and HLA-I antibodies, whereas her infant showed only petechiae.

In the majority of patients, we did not identify alloantibodies in infants’ serum. However, in the 8th patient, we identified anti- HPA1a, anti-HPA-3a, anti-HPA-5b and anti-HLA-I in both sera of mother and neonate. Alloantibodies are usually combined to alloantigens and thus destroyed on target tissues. Their presence in neonatal serum declares that they are still capable of connecting to alloantigens and killing target cells. That also implicates that severe complications may follow, which has been the case in the 8th neonate who suffered a subdural hematoma postnatally. The exact time of occurrence of the hematoma cannot be exactly defined. The fact that seizures occurred at the age of 4 months, whereas there were no other neurological complications, supports the opinion that the hematoma took place at a close interval to seizures’ occurrence. Magnetic Resonance Imaging (MRI) examination also helped the reflection that the hematoma developed at a time close to seizures’ occurrence.

Platelet transfusion was not initiated to the neonate on the 1^st day of life because compatible irradiated platelets were not ready and the infant was considered to be stable enough as not to be given platelets from a random donor. The platelet count increased right after the 1st dose of IVIG and reached normal levels on the 7^th day and remained in levels > 150.000k/µl ever after.

Whereas particular alloantigens were supposed to be detected on platelets and platelet precursors, the alloantigen systems HPA1 and HPA-4 have been identified to be expressed by endothelial cells, vascular smooth muscle cells, and foreskin fibroblasts. The alloantigen system HPA-5 also expresses on endothelial cells and activated T-lymphocytes. It is possible that free alloantibodies were combined to vascular smooth muscle cells and endothelial cells and therefore provoked the subdural hematoma in the case of the 8th patient that we present. As a conclusion, the existence of plenty free alloantibodies in neonatal serum should keep neonatologists in alert despite normal platelet count levels.

It is also interesting that two of the mothers of newborns with severe complications had spontaneous abortions that could not be attributed to a pathological cause, despite an extensive laboratory investigation. That may implicate that fetal alloimmune thrombocytopenia could cause spontaneous abortions. We should exclude it in repeated abortions with no other reason identified.

Furthermore, the mother of the 8^th patient had HLAimmunotherapies to get pregnant; thus, it has been expected for her to have HLA antibodies. There were HLA-I antibodies in both mother’s and neonate’s serum. Human Leucocyte Antigens type I (HLA class I) are mainly absorbed on platelets from plasma. Probably their coexistence with alloantibodies of HPA-systems may act synergistically to provoke complications.

Maternal anti-HLA-I antibodies have been associated with reduced birth weight in thrombocytopenia neonates [14], which has been the case in the 5^th patient that we present but has not been the case for our 3^rd and 8^th patient.

HLA-I antibodies were identified in mother’s serum in 3rd and 5th patient and the 8th patient in both mother’s and neonate’s serum. This identification of HLA-I antibodies contradicts the opinion that they cannot enter the fetal circulation. They are usually of IgG class and therefore capable of crossing the placenta. HLA-I antibodies could have passed through placental tissues to enter fetal circulation as they could have been created since mother’s sensitization in a previous unsuccessful gestation. That could have also been the case with HPA-5b alloantibodies inherited from the mother after an alloimmunization in another gestation.

HPA-genotyping of parents and neonates helped to this clarification. That supports that genotyping is preferable than phenotyping as no platelets and specific antisera are necessary. Furthermore, paternal heterozygosity/homozygosity can be easily identified and used to predict the risk of NAIT in the next pregnancy

That has also been the case in the 6th and 7^th patients who suffered the disease whereas genotyping defined that the father was homozygous to HPA-1a alloantigen. Therefore, the next neonate would also be heterozygous; thus it would experience complications of the disease. Actually, at the time of diagnosis, the fetus (second in the family) had already developed intracranial hemorrhage.

When pregnancies follow one another in a close interval, the risk of thrombocytopenia and its complications emerge in an even higher grade, as alloantibodies are already present and ready to destroy platelets. The fact that the disease evolves through an alloimmunization mechanism explains the increased severity in subsequent pregnancies. Sensitization of the mother makes easier and therefore accelerates the production of alloantibodies that provoke even more severe complications of the disease. Alloantibodies remain in mother’s blood for many years after the first pregnancy. In a second pregnancy, treatment has to be initiated early in order to protect the fetus.

In the case of the 1^st patient, diagnosis of alloimmune thrombocytopenia was defined by detection of antiplatelet alloantibodies in mother’s serum a few months after the abortion of her first fetus. Parents’ genotyping followed that confirmed the diagnosis. High clinical indications (met hemorrhagic hydrocephalus of the first fetus) were compatible with genotyping’ results of his parents. Fetal HPA genotyping of chorion villi of the second fetus defined that it was also heterozygous and would suffer from the disease unless appropriately supported. As there was sufficient time between the first and the second gestation, intrauterine therapy of the second fetus helped to achieve a positive outcome.

The mother followed prophylactic treatment with weekly administered intravenous immunoglobulin (1g/kg) during her second pregnancy. Nevertheless, fetal platelet count did not increase. Studies have shown that the effect of intravenously initiated immunoglobulin on raising fetal platelet count is inconsistent. Effect of therapy seems to be influenced by maternal or placental factors rather than a direct inhibition of fetal platelet destruction by immunoglobulin [12]. Intravenous immunoglobulin was initiated to the mother and  not to the fetus. Administration of IVIG to the fetus has not been superior to administration of IVIG to the mother. Moreover, severe hemorrhagic complications may occur during cordocentesis that may not be avoided by platelet transfusion during procedure. According to recent studies, administration of intravenous immunoglobulin to the mother seems to be superior to administration to the fetus [12].

Certainly, early diagnosis gives the possibility to adequately manage subsequent pregnancies and achieve a favorable outcome [13]. In order to early detect Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT), there have been efforts to establish programs for FNAIT prevention in national level [14]. However, a screening test for NAIT is not in routine use. Pregnant women are not usually screened for HPA type. Laboratory investigation for NAIT is performed after delivery of a neonate with symptoms of hemorrhage. As a consequence, first cases of NAIT in a family remain untreated. A cost-effective screening program has been performed, in more than 100.000 women, in Norway. According to this program, pregnant women were HPA-1a typed. Anti-HPA-1a antibodies levels were assessed in HPA 1a negative women and these women were closely followed-up. Caesarean section was performed in 36-38 gestation week and compatible platelets had been prepared for transfusion for the neonate in case that its platelet counts was less than 35 x109/ µL. This strategy has been proved that it reduced morbidity and mortality due to NAIT. Until a screening test like that could be widely available, first cases of NAIT will remain untreated antenatally [10]. 

Clinical heterogeneity of neonatal alloimmune thrombocytopenia is remarkable and may cause difficulties on laboratory investigation. This clinical diversity may be mainly due to the variability of HPAsystems [15]. HPA-system mismatch seems to be of paramount importance for increased severity of illness, whereas HLA-specific epitopes’ co-existence may have a supplementary role.

Neonatal alloimmune thrombocytopenia is a rare disease that may be disastrous to fetuses and neonates. Neonatologists and gynecologists should be alert to early recognize such cases, initiate appropriate therapy to the neonates and advise parents upon future pregnancies. Pregnant women who have developed alloantibodies should be under close follow-up. Adequate antenatal and postnatal treatment of a sensitized pregnant woman against HPA-1a antigen is of paramount importance so that her second offspring to have an excellent developmental and neurological outcome.

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