Thrombocytopenia of the newborn caused by maternally transmitted diaplacental alloantibodies directed against paternally-inherited human platelet antigens (HPA).
The pathogenesis is analogous to that of haemolytic disease of the newborn.

Incidence
1:1000 births. As many as 60% of the NAIT cases involve first-born children. NAIT cases are unfortunately often overlooked and therefore incorrectly treated. The consequences of this can be grave. Similar observations have been made in other countries such as Great Britain (Murphy et al. 1999, Turner et al. 2005, Tiller et al. 2009). About one third of all neonatal thrombocytopenias <150,000/µl and the majority of cases of neonatal thrombocytopenia <30-50,000/µl are caused by platelet antibodies. The course of NAIT is severe (see below) and the incidence is greater than for several other neonatal diseases for which screening programmes exist.
In our opinion, a blood count, including a platelet count, should be carried out on every neonate at birth.

Antibody specificity
~75% anti-HPA 1a (Zwa or PlA1), ~15% anti-HPA 5b (Bra), ~4% anti-HPA 15b and other.

Clinical picture
In the majority of cases there is initially only petechial haemorrhaging. More extensive haemorrhages have already occurred or may still happen. The course of the disease varies greatly and does not generally depend on the antibody specificity. The course occasionally worsens during the first 48 hours following birth. The thrombocytopenia lasts between a few days and 2 weeks, occasionally it lasts longer than 5 weeks. Approximately 15%-20% of the affected children suffer from intra-cranial haemorrhaging (50% of these whilst still in utero!). Possible consequences: hydrocephalus, blindness, mental and physical disability. The risk to subsequent pregnancies is between 50% and 100% subject to whether the father is hetero- or homozygous. It is therefore crucial to monitor later pregnancies in a specialised clinic. Cf. Foetal Alloimmune Thrombocytopenia (FAIT)!

Diagnosis
Clinical indication: Diagnosis by exclusion! Every isolated case of thrombocytopenia in a neonate which has no other explanation initially points to the presence of NAIT. Petechial or extensive haemorrhaging is often observed. Neurological symptomatology, results from an ultra-sound scan of the brain. See table for differential diagnosis.

Laboratory: Thrombocytopenia, possibly combined with anaemia and/or a hyperbilirubinaemia through haemorrhaging and haematoresorption. The mother usually shows no thrombocytopenia.
The mother types negative, the father positive for an antigen (gene). Allogenic platelet samples often show the presence of the corresponding platelet antibody in the maternal blood, more seldom in that of the father. A negative serological antibody test does not exclude the presence of NAIT. Even in severe cases of NAIT it is occasionally only possible to detect the antibodies after several days and in approximately 10% of the cases it is not possible to detect them at all. The father is serologically tested and/or genotyped to check whether the antigen is homo- or heterozygous.
It is important to detect the presence of maternal antibodies to human leukocyte antigens (HLA) to ensure that the transfusion with foreign platelets will be successful. Similarly the ABO blood groups of the mother, father and child have to be determined to ensure the significance of the interpretation of the various blood tests.

Examination material required
Mother: 30ml EDTA blood, 10ml clotted blood, 10ml heparinised blood;
Father: 10ml EDTA blood, 10ml heparinised blood;
Child: 0.5ml clotted blood for the blood typing.

Therapy
Transfusion (indication and aim of treatment): due to its severe consequences, in particular to prevent permanent damage to the central nervous system, even the slightest indication for this disease necessitates immediate treatment: an immediate platelet transfusion should be carried out at levels of <50 000/µl, regardless of signs of haemorrhaging in order to raise the neonate's platelet level to much higher than 100 000/µl. This relatively high level of 50,000/µl is given because the platelet levels often fall quickly in comparison to oncological patients.

Initial transfusion: stored HPA-1a negative (only if not available: HPA unselected: Kiefel et al. 2006, te Pas et al. 2007), HLA unselected, foreign platelets should be used for the first, immediate transfusion. Due to the urgency of the situation, the platelets are unwashed, but they need to be irradiated. The ABO blood group of the platelets is that of the child (to avoid haemolysis of the child's erythrocytes). If the child's blood group is not yet known, the platelets used should be blood group AB, or if these are not available then A.

Subsequent transfusions as required: Initial choice of therapy is the transfusion of HPA-1a negative platelets which are in stock, or HPA-negative thrombocyte concentrate from foreign donors when the specificity of the maternal antibody is known. If the donor has antibodies against the child's group A or B antigens, the platelets have to be washed (centrifuged once, donor plasma should be substituted with AB plasma). If such platelets are not available (this is possible even in large centres) washed platelets from the mother are transfused. They are useful if the platelet increment in the child after transfusion of foreign thrombocytes is small and of short duration. Washing is necessary to eliminate the maternal platelet antibody. The platelet concentrate has to be irradiated. The concentrate should be HLA-compatible. To ensure the ease and safety of the transfusions, it is recommended that the platelets originate from group O donors and that they be washed. If necessary the mother's siblings could act as the donor (after performing the necessary antigen analyses).

Dosage: 10ml/kg body weight of the platelet concentration over one hour. It has to be ensured that the platelets do not sediment and therefore do not remain in the syringe or the bag (e.g. by ensuring the infusion machine is upright or by frequent agitation)

Monitoring therapy effectiveness: daily platelet counts, also prior to and 1 hour following transfusion. Haemorrhaging has stopped (including no new petechial haemorrhaging), cerebral ultra-sound scans, etc. Even after the child's platelet level has stabilised, thrombocytopenia can still occur after several weeks in some rare cases. It is therefore crucial that the paediatrician performs necessary laboratory and ultra-sound examinations after the child has been discharged from hospital. These should continue until levels have normalised.

Legal aspects
Standardised documentation of clinical, laboratory, functional and medical history data. Documentation of the exact time the diagnosis was established. The mother should be informed about the possible occurrence of possible mental and physical disabilities. She should also be informed about the probability of recurrence in any future pregnancy and about the importance of consulting a specialised medical centre at the beginning of any future pregnancy. She should be made aware of the necessity to transfuse the thrombocytopenic child with HPA and HLA-compatible platelet concentrates until such a time as the thrombocytopenia has been overcome and that she also has to be transfused with HPA and HLA-compatible platelet concentrates whenever in the future she needs treatment for thrombocytopenia. She should be informed about the necessity for her paediatrician to monitor the child's platelet levels and general state of health when the child has been discharged from hospital with an elevated platelet level which is not yet within the normal range. This information should be documented in a medical letter for her family doctor and for herself. The mother should carry a warning document specifying her HPA and, if present, her HLA antibody.

Further reading

Historical

Moulinier J: Iso-immunisation maternelle antiplaquettaire et purpura néo-natal. Proc 6th Congr Europe Soc Haematol Copenhagen, (1957): 817-820 [mit gedruckten Diskussionsbeiträgen von J. Dausset und anderen].
Adner MM: Use of "compatible" platelet transfusions in treatment of congenital isoimmune thrombocytopenic purpura. N England J Med 280 (1969): 244-247.

Textbooks

Mueller-Eckhardt C: Transfusionsmedizin. 3. Auflg. Springer (2004): 509-513.
Hadley A and Soothill P: Alloimmune disorders of pregnancy. Cambridge University Press (2002).
Herman JH and Manno CS: Pediatric transfusion therapy. AABB Press (2003).
Committee by Judd WJ: Guidelines for prenatal and perinatal immunohematology. AABB Press (2005).
Roseff SD and Gottschall JL: Pediatric transfusion. A physicians’s handbook. AABB Press (2006).

Overview

Blanchette VS et al.: The management of alloimmune neonatal thrombocytopenia. Bailliere’s Clin Haematol 13 (2000): 365–390.
Bussel JB and Sola-Visner M: Current approaches to the evaluation and management of the fetus and neonate with immune thrombocytopenia. Seminars Perinatol 33 (2009): 35-42.
Murphy MF and Bussel JB: Advances in the management of alloimmune thrombocytopenia. Brit J Haematol 136 (2007): 366-378.
Serrarens-Janssen VML et al.: Fetal/neonatal allo-immune thrombocytopenia (FNAIT) : Past, present, and future. Obstet Gynecol Survey 63 (2008) : 239-252.

Miscellanous

Ahya R et al.: Fetomaternal alloimmune thrombocytopenia. Transfusion and Apheresis Science 25 (2001): 139-145.
Kaplan C: Alloimmune thrombocytopenia of the fetus and the newborn. Blood Rev 16 (2002): 69-72.
Husebekk A et al.: Is it time to implement HPA-1 screening in pregnancy ? Curr Opin Hematol 16 (2009): 497-502.
Kiefel V et al.: Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT).
Blood 109 (2006): 3761-3763.
Murphy MF et al.: Inadequacies in the postnatal management of feto-maternal alloimmune thrombocytopenia. Brit J Haematol 105 (1999): 123-126.
Overton TG et al.: Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: platelet dynamics and perinatal outcome. Am J Obstet Gynecol 186 (2002): 826-831.
Radder CM et al.: A less invasive treatment strategy to prevent intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia. Am J Obstet Gynecol 185 (2001): 683–688.
Ranasinghe E: Fetal transfusions for severe fetomaternal alloimmune thrombocytopenia: Experience in London and the south east of England. Transfusion Med 10 (2000), suppl. 1: 17.
Rayment R et al: Cryptic neonatal alloimmune thrombocytopenia. Transfusion Med 10 (2000), suppl 1, 34.
Taaning E: HLA antibodies and fetomaternal alloimmune thrombocytopenia: Myth or meaningful. Transfusion Med Rev 14 (2000): 275-280.
te Pas AB et al.: Postnatal management of fetal and neonatal alloimmune thrombocytopenia: the role of matched platelet transfusion and IVIG. Eur J Pediatr 166 (2007): 1057-1063.
Tiller H et al.: Neonatal alloimmune thrombocytopenia in Norway: poor detection rate with nonscreening versus a general programme. Brit J Obstet Gynecol 116 (2009): 594-598.
Turner ML et al.: Prospective epidemiologic study of the outcome and cost-effectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-1a. Transfusion 45 (2005): 1945-1956.
v. Witzleben-Schürholz E et al.: Neonatale Alloimmunthrombozytopenie durch Anti-HPA 1a bei nur einem von Drillingen. Pädiatrische Praxis 62 (2003): 375-378.
van den Akker ES et al.: Noninvasive antenatal management of fetal and neonatal alloimmune thrombocytopenia: safe and effective. Brit J Obstet Gynecol 114 (2007): 469-473.
Yazicioglu HF et al.: Fetal bradycardia following intrauterine platelet transfusion: might elevated levels of donor soluble CD40 ligand play a role? Acta Obstet Gynecol Scand 83 (2004): 868–869.

Hamburg and Bad Bramstedt 2011, Dr. med. J. Neppert, Dr. med. E. v. Witzleben-Schürholz