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Summary: In fetal/neonatal alloimmune thrombocytopenia (FNAIT), maternal alloantibodies against paternal human platelet antigens (HPA) cross the placenta and lead to platelet destruction. The extent of thrombocytopenia varies among neonates, and inflammation may constitute an important trigger. A set of stable inflammatory markers was measured in serum samples from neonates with low platelet counts, of which n = 50 were diagnosed with FNAIT due to anti‐HPA‐1a antibodies and n = 50 were thrombocytopenic without detectable maternal HPA antibodies. Concentrations of C‐reactive protein, soluble CD14, procalcitonin, and sFlt‐1 did not differ between the two cohorts. There was no correlation between C‐reactive protein or soluble CD14 and the platelet count, but a negative correlation between procalcitonin concentrations and the neonatal platelet count in both cohorts. sFlt‐1 concentration and the platelet count were correlated in FNAIT cases exclusively. None of the inflammatory markers was statistically different between cases with and without intracranial haemorrhage. We were unable to identify systemic inflammation as a relevant factor for thrombocytopenia in FNAIT. The antiangiogenic enzyme sFlt‐1, released by the placenta, did correlate with the platelet count in FNAIT cases. Our findings may give rise to the hypothesis that placental inflammation rather than systemic inflammation modulates disease severity in FNAIT. [ABSTRACT FROM AUTHOR]

Summary: Most cases of fetal and neonatal thrombocytopenia (FNAIT) are caused by maternal anti‐human platelet antigen‐1a antibodies (anti‐HPA‐1a). Anti‐HPA‐5b antibodies are the second most common antibodies in suspected FNAIT cases. Given the high prevalence of anti‐HPA‐5b antibodies in pregnant women delivering healthy newborns, the association with FNAIT may be coincidental. This review of the literature related to FNAIT using the MEDLINE database was conducted according to PRISMA guidelines. A retrospective analysis of a single‐centre cohort of 817 suspected FNAIT cases was conducted. The pooled prevalence of anti‐HPA‐5b antibodies in unselected pregnant women of European descent was 1.96% (n = 3113), compared with 3.4% (n = 5003) in women with suspected FNAIT. We found weak evidence that a small proportion of pregnant women presenting with anti‐HPA‐5b antibodies will give birth to a newborn with mild thrombocytopenia. The neonatal platelet counts were not different between suspected FNAIT cases (n = 817) with and without maternal anti‐HPA‐5b antibodies. The prevalence of maternal anti‐HPA‐5b antibodies was not different between neonates with intracranial haemorrhage and healthy controls. The current experimental and epidemiological evidence does not support the hypothesis that anti‐HPA‐5b antibodies cause severe thrombocytopenia or bleeding complications in the fetus or newborn. [ABSTRACT FROM AUTHOR]

Summary: The causative role of maternal, anti‐human leukocyte antigen (anti‐HLA) class I antibodies in foetal and neonatal alloimmune thrombocytopenia (FNAIT) remains controversial. Furthermore, in FNAIT cases caused by anti‐human platelet antigen‐1a (anti‐HPA‐1a) antibodies, the possible additive effect of maternal anti‐HLA class I antibodies on outcomes is unclear. Among 817 mother–father–neonate trios of suspected FNAIT, we assessed the possible association of maternal anti‐HLA class I antibodies with neonatal platelet count, and the incidence of FNAIT caused by anti‐HPA‐1a antibodies. In 144 FNAIT cases caused by anti‐HPA‐1a antibodies, we investigated the possible association of maternal anti‐HLA class I antibodies with neonatal platelet count, birth weight, and the incidence of intracranial haemorrhage (n = 16). Maternal anti‐HLA class I antibodies were not associated with neonatal platelet count in suspected cases of FNAIT. There was no significant interaction between the presence of anti‐HLA class I antibodies and anti‐HPA‐1a antibodies. In FNAIT cases caused by anti‐HPA‐1a antibodies, there was no association between the presence of anti‐HLA class I antibodies and neonatal platelet count, birth weight, or occurrence of intracranial haemorrhage. This study's findings do not support the concept that maternal anti‐HLA class I antibodies represent a risk factor of FNAIT or disease severity. [ABSTRACT FROM AUTHOR]

Background: Most cases of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are caused by maternal alloantibodies against human platelet antigen-1a (HPA-1a). Alloimmunization mainly occurs in HPA-1a-negative mothers who are carriers of the HLA-DRB3*01:01 allele. Recently, it has been reported that the combined presence of HLA-DRB3*01:01 and HLA-DRB4*01:01P was associated with severity of FNAIT. We tested this hypothesis by analyzing a large cohort of cases and controls.Study Design and Methods: In total, 101 mothers with a history of FNAIT caused by anti-HPA-1a were investigated. HLA-DRB1, -DRB3, -DRB4, and -DRB5 genotypes were determined by Luminex technology. Haplotype frequencies were compared between cases and 100 controls. The platelet (PLT) counts of neonates and the incidence of intracranial hemorrhage (ICH) were compared between subgroups defined by genotype.Results: Of the HPA-1a-immunized mothers, 98% (99/101) carried at least one copy of HLA-DRB3*01:01. Carriage of HLA-DRB3*01:01 was significantly associated with immune response to HPA-1a (odds ratio, 92.3; 95% confidence interval, 26.9-317.1; p = 1.34 × 10-12 ). No association between HLA-DRB3*01:01 and HLA-DRB4*01:01P alone or in combination with the PLT count of the newborns or the incidence of ICH was detected.Conclusion: In contrast to HLA-DRB4*01:01P, the inheritance of HLA-DRB3*01:01 is strongly associated with the propensity for mounting a humoral immune response against fetal HPA-1a antigen. Neither a homozygous nor a compound heterozygous gene dose predicts the severity of the disease. Testing for the presence of HLA-DRB3*01:01 might be very useful in counseling women at risk of FNAIT due to anti-HPA-1a. [ABSTRACT FROM AUTHOR]

BACKGROUND Fetal human platelet antigen (HPA) genotyping is required to determine whether the fetus is at risk and whether prenatal interventions to prevent fetal bleeding are required in pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT). Methods for noninvasive genotyping of HPA alleles with the use of maternal plasma cell-free DNA were published recently but do lack internal controls to exclude false-negative results. STUDY DESIGN AND METHODS Cell-free DNA was isolated from plasma of four pregnant women with a history of FNAIT caused by anti-HPA-1a and controls. A primer panel was designed to target sequences flanking single-nucleotide polymorphisms (SNPs)/exonic regions of ITGB3 (HPA-1), ITGA2B (HPA-3), ITGA2 (HPA-5), CD109 (HPA-15), RHD, RHCE, KEL, DARC, SLC14A1, GYPA, GYPB, and SRY. These regions and eight anonymous SNPs were massively parallel sequenced by semiconductor technology. RESULTS The mean (±SD) number of reads for targeted SNPs was 5255 (±2838). Fetal DNA was detected at a median of 4.5 (range, 2-8) polymorphic loci. The mean fractional fetal DNA concentration in cell-free maternal plasma was 8.36% (range, 4.79%-15.9%). For HPA-1, nonmaternal ITGB3 sequences (c.176T, HPA-1a) were detected in all HPA-1ab fetuses. One HPA-1bb fetus was unequivocally identified, showing the pregnancy was not at risk of FNAIT. CONCLUSION We have successfully established massively parallel sequencing as a novel reliable method for noninvasive genotyping of fetal HPA-1a alleles. This technique may also allow the safe detection of other fetal blood group polymorphisms frequently involved in FNAIT and hemolytic disease of the newborn. [ABSTRACT FROM AUTHOR]