RARE DISEASE
Fetal and neonatal alloimmune thrombocytopenia
Fetal and neonatal alloimmune thrombocytopenia
Fetal and neonatal alloimmune thrombocytopenia
Synonyms: FNAIT, NAIT
Synonyms: FNAIT, NAIT
Synonyms: FNAIT, NAIT
Drug discovery
7
drugs
With orphan designations
Overview
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare immune-mediated condition where maternal IgG antibodies target fetal platelet antigens inherited from the father, causing severe thrombocytopenia. It is the leading cause of intracranial hemorrhage (ICH) in term neonates, with up to 20% of cases involving antenatal bleeding. Unlike Rh disease, FNAIT often occurs in first pregnancies [1][2][4][15].
Therapies
Antenatal: Maternal IV immunoglobulin (IVIG) ± corticosteroids, stratified by risk [3][8][11].
Postnatal: Immediate HPA-matched platelet transfusion; unmatched platelets as temporary therapy [3][11][17].
Invasive interventions (e.g., intrauterine platelet transfusions) limited due to high complication risk [6][11].
Categories: rare hematological diseases
Research Papers
353 drug discovery papers about Fetal and neonatal alloimmune thrombocytopenia, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
353 drug discovery papers about Fetal and neonatal alloimmune thrombocytopenia, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-11-19 | Improvising neonatal thrombocytopenia management: Insights from split, volume-reduced, single-donor apheresis platelets (NeoVRs-SDAP).
Thrombocytopenia is common in neonates, managed with platelet transfusions at defined dose. The product type varies from neonatal-specific units using platelet additive solutions to adult products split into multiple paediatric units. In low-middle-income countries, whole blood-derived random donor platelets (RDP) are common while western countries use split adult single donor apheresis platelets (SDAP). We aimed to assess preliminary effectiveness of split, volume-reduced single donor apheresis platelets (NeoVRs-SDAP) in neonatal thrombocytopenia and observe early post-transfusion outcomes. Study was conducted from August 2024 to January 2025 at a tertiary healthcare centre. Persistent thrombocytopenic neonates admitted to the NICU were transfused with NeoVRs-SDAP prepared using Spectra Optia® with modified program yielding an adult dose (300 × 109) in a reduced 100 mL of product volume. These were split into 2-5 aliquots for transfusion. Post-transfusion platelet increments and percentage recovery were assessed after 20-24 h. Thirteen neonates' 77% preterm, 69.2% VLBW with sepsis received 46 NeoVRs-SDAP. 10 mL of this product contained nearly 3 times more platelets than RDP and 1.5 times more than adult SDAP of same volume. The mean transfused dose was 70.56 ± 14.21 × 109 platelets. Median platelet increment was 64 500/μL versus 15 477/μL for RDP (p < 0.001). Platelet recovery ranged from 7.5%-52.5%. Split products reduced donor exposure by 56.5%. Survival was 62%, without any transfusion-related adverse events. NeoVRs-SDAP may be potential alternative in persistent neonatal thrombocytopenia, offering better increments and recovery, reduced donor exposure, and leukoreduction. Further RCTs comparing NeoVRs-SDAP and RDP are recommended.
2025-09-30 | Integrating HLA and HPA in Precision Transfusion: Insights from Platelet Transfusion Refractoriness Driven by Anti-CD36 Alloimmunization and Multifactorial Hemostatic Complications
Background: CD36, recently recognized as a distinct blood group system, encodes a class-B scavenger receptor involved in hemostasis and innate immunity. Anti-CD36 alloantibodies are an often-overlooked cause of platelet transfusion refractoriness (PTR), fetal–neonatal alloimmune thrombocytopenia (FNAIT), and bleeding disorders. Although newer assays are available, the relative effectiveness of platelet antibody tests remains uncertain. We review the clinical features of CD36 deficiency and alloimmunization, compare the Solid Phase Red Cell Adherence Assay (SPRCA) with ELISA for antibody detection, and propose a streamlined diagnostic algorithm for PTR. Materials and Methods: A retrospective cohort study was conducted at a tertiary center over 6.5 years, involving 2,333 patients who underwent platelet antibody testing. Antibody screening used parallel SPRCA and qualitative solid-phase ELISA, with confirmatory tests including MAIPA, molecular genotyping, and flow cytometry for CD36 antigen expression. Six illustrative cases with genetically or phenotypically confirmed CD36 deficiency were examined in detail. Results: ELISA detected antiplatelet antibodies in 33.6% of samples, while SPRCA detected them in 18.7%, with an overall concordance of 78.2% (κ = 0.451). ELISA identified additional antibodies in 18.4% of cases, whereas SPRCA alone detected 3.4%. Dual positivity strongly indicates pathogenic alloantibodies responsible for transfusion refractoriness. Conclusions: CD36 deficiency poses a significant immunohematologic challenge in PTR and FNAIT. Employing both ELISA and SPRCA for screening, along with reflex confirmatory testing, improves diagnostic accuracy for anti-CD36 alloimmunization, enhances transfusion strategies with CD36-negative platelet transfusions, and increases patient safety. Establishing rare donor registries is crucial for providing personalized transfusion support to affected individuals.
2025-09-22 | Integrating HLA and HPA for Precision Transfusion: Anti-CD36–Mediated Refractoriness and Hemostatic Challenges
Background: CD36, recently designated as a distinct blood group system, is a multifunctional class-B scavenger receptor in hemostasis and immunity. Anti-CD36 alloimmunization remains an underrecognized cause of platelet transfusion refractoriness (PTR), fetal–neonatal alloimmune thrombocytopenia (FNAIT), and hemostatic complications. Despite the availability of advanced diagnostic assays, the clinical utility and concordance of different platelet antibody detection platforms remain poorly characterized.We aimed to delineate the clinical presentations of CD36 deficiency and alloimmunization, compare diagnostic performances of SPRCA and ELISA for antiplatelet antibody detection, and propose an optimized diagnostic algorithm for PTR management. Materials and Methods: A retrospective cohort of 2,333 patients undergoing platelet antibody workup was analyzed at a tertiary center over 5.5 years. Antibody screening employed parallel SPRCA and qualitative solid-phase ELISA, with confirmatory testing using MAIPA, molecular genotyping, and flow cytometry for CD36 antigen expression. Six illustrative cases with genetically or phenotypically confirmed CD36 deficiency were thoroughly evaluated. Results: ELISA detected antiplatelet antibodies in 33.6% of samples, while SPRCA detected them in 18.7%, with an overall concordance of 78.2% (κ = 0.45). ELISA identified additional antibodies in 18.4% of cases, whereas SPRCA alone identified 3.4%. Dual-positivity was highly predictive of pathogenic alloantibodies responsible for transfusion refractoriness. Conclusions: CD36 deficiency introduces a critical immunohematologic barrier in PTR and FNAIT. Parallel screening with ELISA and SPRCA, utilizing reflex confirmatory testing, enhances diagnostic precision for anti-CD36 alloimmunization, optimizes transfusion strategies using CD36-negative platelet transfusions, and improves patient safety. Establishing rare donor registries is essential for tailored transfusion support to affected individuals.
2024-07-16 | Why might cord blood be a better source of platelets for transfusion to neonates?
Thrombocytopenia (defined as a platelet count <150×109/L) is a common condition in preterm neonates and may occur in 18-35% of all infants admitted to the Neonatal Intensive Care Unit (NICU). Neonatal platelet functionality in terms of reactivity is often described as reduced compared to adults, even in healthy, term neonates. However, this platelet "hyporeactivity" does not correspond to a global functional impairment of the normal delicately balanced neonatal hemostatic system. The extent to which neonatal thrombocytopenia and platelet hyporeactivity contribute to the bleeding risk in preterm neonates remains unknown. Prophylactic platelet transfusions are often administered to them to reduce the risk of bleeding. However, recent literature indicates that adopting a higher platelet transfusion threshold than a lower one results in significantly higher death rates or major bleeding and can be harmful. Although the mechanism by which this occurs is not entirely clear, a mismatch between adult transfused platelets and the neonatal hemostatic system, as well as volume overload, are speculated to be potentially involved. Therefore, future research should consider novel transfusion products that may be more suitable for premature neonates. Blood products derived from umbilical cord blood (UCB) are promising, as they might perfectly match neonatal blood features. Here, we discuss the current knowledge about UCB-derived products, focusing on UCB-derived platelet concentrates and their potential for future clinical application. We will discuss how they may overcome the potential risks of transfusing adult-derived platelets to premature infants while maintaining efficacy.
2023-08-31 | Prophylactic Platelet Transfusions
Preterm neonates are a highly transfused patient group, with platelet transfusions being the second most transfused cellular blood component. Historically, however, evidence to inform optimal platelet transfusion practice has been limited. In pediatrics , much of the evidence has been inferred from studies in adult patients, although neonatologists have generally applied more cautious and liberal platelet transfusion thresholds to mitigate the complications of intraventricular hemorrhage . A total of three randomized controlled trials have now been published comparing different platelet transfusion strategies in neonates.
small molecules
2026-04-14 | Maternal anti-HPA-1a antibodies block αIIbβ3 and αvβ3 integrin activation which correlates with FNAIT disease severity.
Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is a disorder caused by a mismatch in human platelet antigens (HPAs), leading to maternal antibody formation and platelet destruction in the fetus or neonate. The clinically most relevant antigen is HPA-1a on the b3 subunit of integrins aIIbb3 and avb3, which are conformationally regulated cell adhesion receptors on platelets and endothelial cells, crucial for hemostasis and vascular integrity. The clinical effects of anti-HPA-1a alloimmunization are highly heterogeneous and range from no symptoms to intracranial hemorrhage, potentially causing perinatal death or lifelong complications. However, determinants of disease severity are largely unknown, which hampers implementation of screening programs to identify alloimmunized high-risk women who will benefit from treatment. Using recombinant anti-HPA-1a antibodies and a cohort of retrospective FNAIT samples associated with mild or severe disease, we report here that the tested anti-HPA-1a antibodies inhibit binding of integrins avb3/aIIbb3 to ligands (vitronectin, fibronectin, and fibrinogen) and cell adhesion. Inhibition is dependent on antibody concentration, is mediated by the antibody Fab and does not require the Fc-tail, and is abolished when integrins are forced into a constitutively extended conformation. Furthermore, the extent of integrin inhibition correlates with disease severity. Together, our data demonstrate that anti-HPA-1a antibodies can block integrin activation, which likely contributes strongly to disease severity in FNAIT. These results aid development of a prenatal diagnostic test to identify pregnancies at high risk of developing FNAIT and associated severe complications. In addition, these data reveal novel opportunities for allosteric inhibition of b3 integrin activation.
2026-03-09 | High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation
Abstract Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by ‘bent/closed’ to ‘extended/open’ conformational changes. Integrin αIIbβ3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on β3 is recognized by pregnancy-associated maternal alloantibodies, potentially causing fetal/neonatal alloimmune thrombocytopenia (FNAIT) and even intracranial hemorrhage or perinatal death. However, severe disease determinants are largely unknown. We report the first structure of an anti-HPA-1a antibody fragment (Fab 26.4) in complex with integrin αIIbβ3 at high resolution by cryo-electron microscopy. Fab 26.4 binding traps αIIbβ3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits αIIbβ3-dependent fibrinogen binding and platelet aggregation. Thus, anti-HPA-1a antibodies directly impair integrin activation by preventing required conformational changes. These insights will improve FNAIT diagnostics and treatment, and spark the development of novel allosteric inhibitors against β3 integrins for future therapeutic applications.
2026-03-04 | Anti-HPA-1a fetal-neonatal alloimmune thrombocytopenia: reframing diagnostics, pathophysiology, and management.
Maternal alloantibodies directed to human platelet antigen 1a (HPA-1a) on fetal platelets can induce fetal-neonatal alloimmune thrombocytopenia (FNAIT), which causes intracranial hemorrhage in 10% to 20% of fetuses/newborns. Presentation is usually unexpected and identified by neonatal bleeding. This review synthesizes advances in diagnosis, pathophysiology, and management that reshape understanding of anti-HPA-1a-mediated FNAIT. Genomic and serologic testing, together with cell-free fetal DNA for fetal HPA typing, allow accurate identification of at-risk pregnancies. HPA-1bb women who carry DRB3∗01:01 are at greatest risk of forming clinically significant anti-HPA-1a. Not only anti-HPA-1a levels but also structural features, particularly decreased Fc fucosylation enhancing Fc gamma receptor-mediated effector functions, more accurately determine disease severity. Furthermore, increased Fc galactosylation may contribute by enhancing complement activation. Fab-mediated effects affect platelets, megakaryocytes, trophoblasts, and endothelial cells. Overall, this explains why anti-HPA-1a levels and neonatal platelet counts alone do not reliably predict bleeding, including intracranial hemorrhage. Anti-HPA-1a also induces placental inflammation, increasing risks of fetal growth restriction and long-term neurodevelopmental impairment, for example, autism. Neonatal management involves random donor and matched platelet transfusions, and IV immunoglobulin (IVIG), if needed. Antenatal IVIG, with/without prednisone administered in an affected pregnancy typically increases fetal platelet counts, with management strategies varying internationally. Blocking neonatal Fc receptor has emerged as an alternative approach to both reduce maternal anti-HPAa-1a levels and inhibit its transplacental transfer. Whether antenatal treatment reduces placental inflammation requires further study. These developments support the importance of identifying predictive biomarkers of fetal risk to guide antenatal management and of preventing affected pregnancies ideally by screening all pregnancies followed by prophylaxis.
2025-10-15 | Diagnosis and Management of Fetal and Neonatal Alloimmune Thrombocytopenia: An Update 2025.
Antibodies of the mother, which are directed against paternal antigens on platelets of the child, can lead to the destruction of the fetal blood cells in the circulation after diaplacental passage. The clinical picture of fetal-neonatal alloimmune thrombocytopenia (FNAIT) is characterized by bleeding, of which intracranial bleeding is particularly feared. Our understanding of the pathophysiology of FNAIT and its targeted prophylaxis and therapy has improved significantly in recent years. FNAIT by anti-HPA-1a is the best studied. How exactly the mother is immunized is not known for certain, but, in clinically apparent cases, immunization usually occurs in the first pregnancy of an HLA-DRB3*01:01-positive, HPA-1a-negative woman. There is no convincing basis for assigning immunization against HPA-5b and against HLA class I any significance in the development of fetal thrombocytopenia. Newborns of mothers with anti-HPA-1a present a broad clinical picture ranging from isolated, clinically unremarkable thrombocytopenia to intracranial hemorrhage (ICH; in approx. 1-10% of cases). ICH usually occurs intrauterine (before week 28). There are indications that, in addition to the fetal platelets, the placenta can also be affected by anti-HPA-1a. As there are no screening programmes, the index diagnosis of FNAIT is random. It is made by serological and genetic laboratory tests. Predicting outcome in a subsequent pregnancy is problematic if the child is antigen-positive. With a first-born child with severe thrombocytopenia, the probability of a recurrence of severe thrombocytopenia is around 70%. Without ICH, the probability of ICH in the subsequent pregnancy is low but not zero, and with ICH the recurrence rate is high. There is no established laboratory diagnostic method to predict the severity of thrombocytopenia or the occurrence of ICH. Prophylaxis with immunoglobulins (IVIgs) is considered effective. Pharmaceutics that block placental transport are currently undergoing clinical trials and may replace IVIgs in the future. Intrauterine platelet transfusions should no longer be performed. For the mature, thrombocytopenic newborn without internal hemorrhage, a platelet transfusion is advisable for platelet counts <25 g/L.
2022-08-11 | Current perspective and scope of fetal therapy: part 2.
Fetal therapy has been defined as any therapeutic intervention either invasive or noninvasive for correcting or treating any fetal malformation or condition. Invasive fetal therapy have its own set of maternal and fetal complications and invasive approach is not feasible in many of fetal conditions that are candidate for fetal therapy. Many such fetal conditions have been treated successfully by medical or noninvasive management. In medical fetal therapy, mothers are treated with medications which are transferred to fetus through placenta and exert positive effect on the fetus, thus avoiding complications that are seen secondary to invasive fetal therapy. The fetal conditions that have been managed with medical therapy includes fetal and neonatal alloimmune thrombocytopenia, neural tube defect, congenital adrenal hyperplasia, perinatal infections, respiratory distress syndrome, inborn error of metabolism, and congenital cystic adenomatoid malformation. This review will cover the medical or noninvasive aspect of fetal therapy and will highlight the progress made in the management of these fetal conditions.
proteins
2026-08-14 | Fusion of IgG antibodies to albumin inhibits transport across the placenta.
Immunoglobulin G (IgG)-based monoclonal antibodies are effective therapies for cancer, autoimmune diseases, and migraine. However, they are actively transported across the placenta by the neonatal Fc receptor (FcRn), limiting their use during pregnancy. Using mouse models and an ex vivo human placental perfusion system, we show that although FcRn binds albumin independently of IgG, albumin is not transported to the fetus in mice or across human placental tissue. Fusion of IgG to albumin markedly reduced transplacental transport in both models while preserving the prolonged plasma half-life conferred by FcRn. Similarly, fragment antigen-binding fragments fused to engineered albumin with enhanced FcRn binding showed minimal fetal exposure. In a mouse model of fetal and neonatal alloimmune thrombocytopenia, albumin fusion of an anti-human platelet antigen IgG reduced fetal antibody transfer and attenuated thrombocytopenia in the offspring. These findings identify albumin as an attractive fusion partner for biologics intended to minimize fetal exposure during pregnancy.
2017-05-26 | Developmental differences between newborn and adult mice in response to romiplostim
Thrombocytopenia is frequent among sick neonates. While most cases are transient, some neonates experience prolonged and severe thrombocytopenia. These infants often pose diagnostic and therapeutic challenges, and may receive large numbers of platelet transfusions. Romiplostim (ROM) is a thrombopoietin (TPO)-receptor-agonist approved for treatment of adults with chronic immune thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure of newly produced platelets, which could aid with the diagnostic evaluation of thrombocytopenic neonates. This study had the following two objectives: (1) compare the response of newborn and adult mice to escalating doses of ROM in vivo and (2) assess the correlation between IPF and megakaryocyte (MK) mass in newborn and adult treated and untreated mice. In the first set of studies, newborn (day 1) and adult mice received a single subcutaneous (SC) dose of ROM ranging from 0 to 300 ng/g, and platelet counts were followed every other day for 14 days. Both sets of mice responded with dose-dependent platelet and IPF increases, peaking on days 5–7 post-treatment, but neonates had a blunted response (2.1-fold compared to 4.2-fold maximal increase in platelet counts, respectively). On day 5 post-treatment with 300 ng/g ROM, MKs in the bone marrow (BM) and spleen of adult mice were significantly increased in numbers and size (p < 0.0001 for both) compared to controls. MKs in the spleen and BM (but not liver) of treated neonates also increased in number, but not in size. The immature platelet count (IPC, calculated as IPF x platelet count) was highly correlated with the MK number and size in neonatal and adult BM and spleen, but not neonatal liver. The lack of response of neonatal liver MKs was not due to a cell-intrinsic reduced responsiveness to TPO, since neonatal liver progenitors were more sensitive to murine TPO (mTPO) in vitro than adult BM progenitor. In vivo treatment of newborn mice with high mTPO doses or with higher doses of ROM (900 ng/g) resulted in peak platelet counts approaching 3-fold of controls. Taken together, our data indicate that newborn mice are less responsive to ROM than adult mice in vivo, due to a combination of likely pharmacokinetic differences and developmental differences in the response of MKs to thrombopoietic stimulation, evidenced by neonatal MKs increasing in numbers but not in size. PK/PD studies in human infants treated with ROM are warranted.
2002-10-01 | Developmental biology of thrombopoietin in the human fetus and neonate
This review focuses on the biology of thrombopoietin (Tpo) during human development. It summarizes the current understanding on molecular biological aspects of Tpo, cellular effects of Tpo on fetal and neonatal megakaryopoiesis, regulation of Tpo production, and circulating Tpo concentrations in human fetuses and neonates. Some important aspects on the developmental biology of Tpo are highlighted. They include the finding of high Tpo gene expression in the bone marrow during the onset of medullary hematopoiesis, higher circulating Tpo concentrations in fetuses and neonates than in children or adults, and a higher sensitivity of neonatal megakaryocyte progenitor cells to Tpo. However, other aspects of the developmental biology of Tpo are incompletely understood. Conclusion: More carefully designed studies are needed to provide the necessary background for an optimal treatment of fetal and neonatal thrombocytopenia.
2002-09-01 | Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit
Phlebotomy‐induced anaemia excepted, thrombocytopenia is the most common haematological abnormality in neonatal intensive care unit (NICU) patients. Roughly one‐quarter of all NICU patients and half of all sick preterm neonates develop thrombocytopenia. Whereas a large number of varied precipitating conditions has been identified, early‐onset thrombocytopenia (>72 h) is most commonly associated with fetomaternal conditions complicated by placental insufficiency and/or fetal hypoxia, e.g. maternal pre‐eclampsia and fetal intrauterine growth restriction. The resulting neonatal thrombocytopenia is usually mild to moderate, resolves spontaneously and requires no specific therapy. Deviation from this pattern of thrombocytopenia suggests the presence of more significant precipitating conditions. The most important of these are the immune thrombocytopenias, and every NICU should develop investigation and treatment protocols to manage these cases promptly and avoid unnecessary risk of haemorrhage. In contrast, late‐onset thrombocytopenia (>72 h) is almost always associated with sepsis or necrotizing enterocolitis and the associated thrombocytopenia is severe, prolonged and often requires treatment by platelet transfusion. Unfortunately, evidence‐based guidelines for platelet transfusion therapy in NICU patients are currently unavailable, making it difficult to define widely accepted thresholds for transfusion and leading to a significant variation in transfusion practice between centres. Conclusion : While improving this situation remains a pressing need, the growing evidence that impaired megakaryocytopoiesis and platelet production are major contributors to many neonatal thrombocytopenias suggests that recombinant haemopoietic growth factors, including thrombopoietin and interleukin‐11, may be useful future therapies to ameliorate neonatal thrombocytopenia.
2002-07-24 | Thrombopoietin in thrombocytopenias of childhood.
This review summarizes the biology of thrombopoietin (TPO) in childhood. Studies on TPO and its receptor (c-mpl) have improved the understanding of inherited and acquired thrombocytopenias in childhood. Data are presented in this review regarding the molecular biology of TPO, differences in cellular effects on megakaryopoiesis, the regulation of TPO production, and TPO concentrations in health and disease. For neonatal thrombocytopenia, the focus is on early-onset thrombocytopenia associated with maternal diabetes, pregnancy-induced hypertension, intrauterine growth retardation, hypoxia, and sepsis. Fetal alloimmune thrombocytopenia allows insight into the biology of TPO when fetal megakaryopoiesis is chronically stimulated. In the thrombocytopenia absent radii syndrome and congenital amegakaryocytic thrombocytopenia, thrombocytopenia is caused by a disorder in the signal transduction at the c-mpl level and respectively directly on c-mpl. TPO concentrations in other inherited thrombocytopenias such as Fanconi anemia, Shwachman syndrome, Wiskott-Aldrich syndrome, and Bernard-Soulier syndrome are discussed. For acquired thrombocytopenias, data on TPO in aplastic anemia, immune thrombocytopenia, human immunodeficiency virus infection, and liver disease are given. Possible indications for a treatment with recombinant TPO in childhood are discussed, but the criteria to identify patients who would benefit need detailed evaluation.
antibodies
2026-09-27 | A functionally distinct HPA-1a-specific alloantibody associated with fetal/neonatal alloimmune thrombocytopenia that activates platelets via FcγRIIa.
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies directed against fetal platelet antigens, most commonly human platelet antigen-1a (HPA-1a). These antibodies mediate platelet destruction and can lead to fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds. Antibody titer and isotype do not reliably predict disease severity, suggesting additional heterogeneity among anti-HPA-1a antibodies. We evaluated the effects of five previously characterized HPA-1a-specific monoclonal antibodies (mAbs) on platelet activation, platelet aggregation, and induction of intracellular signaling. The involvement of FcγRIIa was examined using FcγRIIa-blocking antibody IV.3, protein tyrosine kinase inhibitors, and selected monoclonal antibody Fab fragments. At saturating concentrations, all five mAbs inhibited thrombin-induced aggregation. At sub-saturating concentrations, however, mAb M-204 uniquely induced spontaneous aggregation and α-granule secretion in HPA-1a-positive human, but not mouse, platelets, which lack FcγRIIa. M-204-induced aggregation was abolished by mAb IV.3 and inhibitors of Src- and Syk-family kinases and was absent using M-204 Fab fragments. M-204 induced tyrosine phosphorylation of Syk and PLCγ2 in an FcγRIIa-dependent manner. Finally, despite persistent platelet activation induced by M-204, saturating concentrations of this antibody blocked the binding of the fibrinogen mimetic antibody, PAC-1, to HPA-1a homozygous, but not HPA-1a/1b heterozygous, platelets, consistent with the known ability of HPA-1a-specific antibodies to sterically interfere with ligand binding to HPA-1a-positive αIIbβ3. These findings identify a previously unrecognized, functionally distinct subset of HPA-1a antibodies capable of activating platelets via FcγRIIa, suggesting a potential mechanism contributing to variability in disease severity in FNAIT.
2026-09-02 | Generation and Use of an Alloantigen-Specific Preclinical Humanized Mouse Model of Fetal and Neonatal Alloimmune Thrombocytopenia.
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies targeting a paternally inherited alloantigen present on the surface of fetal platelets. The human platelet alloantigen HPA-1a/HPA-1b, also known as the PlA1/PlA2 alloantigen, is the most frequently implicated HPA for causing FNAIT in Caucasians. A single Leu33Pro amino acid polymorphism residing within the plexin/semaphorin/integrin (PSI) domain of the integrin β3 subunit (platelet membrane glycoprotein (GP), GPIIIa) is responsible for generating the HPA-1a and HPA-1b epitopes. In mice, the GPIIIa gene encodes a glutamine at position 33, making it challenging to model the alloimmune response, thereby hindering studies on the underlying mechanisms and therapeutic interventions of this alloimmune disorder. This chapter outlines the development and use of a humanized, alloantigen-specific preclinical mouse model of FNAIT, aiming to advance basic and translational research in this field. Basic protocols are provided for (1) generating an HPA-1a transgenic mouse by introducing humanized residues A30P32L33D39 within the PSI domain and Q470 in the EGF1 domain of mouse integrin β3 using CRISPR/Cas9 gene editing technology, (2) developing a preclinical alloantigen-specific humanized mouse model of FNAIT using the HPA-1a transgenic APLDQ mice, and (3) examining the efficacy of a prophylactic treatment regimen in preventing alloimmunization and FNAIT development using this alloantigen-specific mouse model. This humanized mouse model faithfully recapitulates many clinically important aspects of human FNAIT, serving as a valuable tool for studying the pathophysiological mechanisms underlying the alloimmune response and assessing prophylactic and therapeutic interventions in translational research.
2026-06-11 | Inhibition of human FcγRIII prevents platelet destruction in a dual-humanized murine model of FNAIT.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when maternal anti-fetal platelet antibodies, most frequently against HPA-1a, cause fetal platelet destruction. The precise pathogenic mechanisms remain incompletely understood. Here, we examined potential mechanisms underlying anti-HPA-1a-mediated platelet clearance, focusing on phagocytosis, complement fixation, platelet activation, and desialylation. Anti-HPA-1a antibodies in pooled plasma and in 9 of 10 individual FNAIT patient samples induced FcγR-dependent platelet phagocytosis in vitro, indicating this as the major contributor to platelet destruction. In contrast, complement fixation, platelet activation (CD62P expression), and desialylation (RCA-I binding) were observed in only a minority of patients. To model anti-HPA-1a-mediated platelet clearance in vivo, we developed a dual-humanized mouse model combining HPA-1a-expressing platelets (from APLDQ transgenic mice) with mice engineered to express human FcγRs in place of murine FcγRs. Platelets from APLDQ mice sensitized with anti-HPA-1a sera underwent rapid clearance in these FcγR-humanized recipients. Pre-treatment with an FcγRIII-blocking monovalent antibody significantly reduced clearance, confirming FcγRIII's central role in mediating platelet destruction. These results demonstrate that FcγRIII-dependent phagocytosis is a dominant mechanism in anti-HPA-1a-driven platelet clearance in this model. Although complement activation and platelet desialylation were observed in a minority of samples, their contribution to platelet destruction remains speculative. Together, these findings highlight the complexity of FNAIT pathophysiology yet identify FcγRIII blockade as a promising strategy to prevent platelet clearance in this disease.
2026-04-17 | New perspectives on fetal and neonatal alloimmune thrombocytopenia for obstetricians.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a serious disorder that arises when a mother produces alloantibodies against specific human platelet antigens (HPAs) expressed on fetal platelets. These maternal alloantibodies cross the placenta and destroy fetal platelets, significantly increasing the risk of fetal or neonatal intracranial hemorrhage (ICH). Indeed, FNAIT is the leading cause of isolated severe thrombocytopenia in otherwise healthy neonates. In this review, we summarize recent advances to provide obstetricians and maternal-fetal medicine specialists with an updated overview of FNAIT, encompassing its pathophysiology, clinical features, diagnostic strategies, antenatal management, delivery planning, and postnatal care. Although the prophylactic interventions remain at an early stage, HPA histo-incompatibility prescreening is already available at a suitable cost, and the development of NAITgam, a targeted immunoglobulin preparation, represents a promising advance. While the widespread implementation of screening and prophylaxis may take years, such measures have the potential to significantly reduce the incidence and severity of FNAIT. Currently, the antenatal administration of intravenous immunoglobulin (IVIg), with or without corticosteroids, remains the safest and most effective treatment for high-risk pregnancies. Looking ahead, animal model data continue to provide valuable insights that may inform the development of novel preventive and therapeutic strategies. Ultimately, the implementation of a national screening program could prevent severe complications and help mitigate the long-term societal and healthcare burden of FNAIT.
2025-12-31 | The Ethics of Clinical Research on Diseases of the Fetus and Newborn: Balancing Benefit-Risk, Autonomy, and Maternal-Fetal Interests.
Pregnant persons historically have been excluded from clinical trials. Recently, there has been a shift from exclusion toward inclusion of pregnant persons in research while acknowledging the complexity of reproductive ethics and the intertwined interests of the pregnant person and fetus. Our objective was to use a principle-based approach to review the ethics of clinical research concerning pregnancy-related disorders that predominantly affect fetal well-being. Ethical principles are applied to the design of interventional trials in two rare conditions of pregnancy, hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT). Severe HDFN and FNAIT are fetal and neonatal diseases caused by maternal alloantibodies with potential outcomes including maternal and neonatal morbidity, preterm delivery, and fetal or neonatal death. Early-onset severe HDFN was the initial indication for a phase 2 open-label study of nipocalimab in pregnancy, given poor outcomes after prior severe HDFN pregnancy(s). After establishing proof of concept, a phase 3 randomized placebo-controlled study was initiated based on the ethical principles of equipoise and generating socially valuable data to support the efficacy and safety of nipocalimab in severe HDFN. However, off-label use of antenatal intravenous immunoglobulin (IVIg) in standard-risk FNAIT pregnancies made a randomized placebo-controlled study challenging. Thus, the FNAIT clinical program for nipocalimab in pregnant persons with standard-risk FNAIT includes a randomized, placebo-controlled study limited to sites that do not use antenatal IVIg, and a global randomized open-label study of nipocalimab or IVIg. Knowledge of the clinical course and management of severe HDFN and FNAIT, the non-clinical and non-pregnant human clinical evidence, and input from physicians, patients, and health authorities permitted the design of clinical protocols that satisfy the principles of beneficence and non-maleficence in these rare and complex diseases. · Ethical principles apply to pregnancy-related disorders affecting fetal well-being.. · Placebo-controlled randomized trials in HDFN are based on equipoise.. · FNAIT programs must account for the off-label use of IVIg..
other
2026-02-12 | Immunoglobulin therapy for the fetus and neonate.
Maternal immunity is modulated during pregnancy at the placental interface to prevent alloreactivity with the developing fetus. Importantly, however, maternal immunoglobulin G (IgG) freely crosses the placenta, and the presence of pre-existing alloreactive antibodies can lead to injury of fetal tissues and/or cells. Because maternal IgG continues to circulate up to 6 months after birth, these antibodies can also continue to affect the newborn, causing a variety of disease conditions including haemolytic disease of the newborn, neonatal alloimmune thrombocytopenia, neonatal lupus, neonatal Graves' disease, gestational alloimmune liver disease and others. Ig therapy, most typically in the form of intravenous Ig, is indicated in these disorders, as pooled IgG molecules can interfere with the circulating maternal IgG, lessening the interactions with the fetal or neonatal binding targets. Ig is an increasingly used therapy in this population; however, most fetal and neonatal providers do not receive comprehensive training in its development or use. Here, we review the formulation, mechanisms of action, therapeutic indications and administration of intravenous Ig in the context of fetal and neonatal medicine.
cell therapies
2025-11-19 | Improvising neonatal thrombocytopenia management: Insights from split, volume-reduced, single-donor apheresis platelets (NeoVRs-SDAP).
Thrombocytopenia is common in neonates, managed with platelet transfusions at defined dose. The product type varies from neonatal-specific units using platelet additive solutions to adult products split into multiple paediatric units. In low-middle-income countries, whole blood-derived random donor platelets (RDP) are common while western countries use split adult single donor apheresis platelets (SDAP). We aimed to assess preliminary effectiveness of split, volume-reduced single donor apheresis platelets (NeoVRs-SDAP) in neonatal thrombocytopenia and observe early post-transfusion outcomes. Study was conducted from August 2024 to January 2025 at a tertiary healthcare centre. Persistent thrombocytopenic neonates admitted to the NICU were transfused with NeoVRs-SDAP prepared using Spectra Optia® with modified program yielding an adult dose (300 × 109) in a reduced 100 mL of product volume. These were split into 2-5 aliquots for transfusion. Post-transfusion platelet increments and percentage recovery were assessed after 20-24 h. Thirteen neonates' 77% preterm, 69.2% VLBW with sepsis received 46 NeoVRs-SDAP. 10 mL of this product contained nearly 3 times more platelets than RDP and 1.5 times more than adult SDAP of same volume. The mean transfused dose was 70.56 ± 14.21 × 109 platelets. Median platelet increment was 64 500/μL versus 15 477/μL for RDP (p < 0.001). Platelet recovery ranged from 7.5%-52.5%. Split products reduced donor exposure by 56.5%. Survival was 62%, without any transfusion-related adverse events. NeoVRs-SDAP may be potential alternative in persistent neonatal thrombocytopenia, offering better increments and recovery, reduced donor exposure, and leukoreduction. Further RCTs comparing NeoVRs-SDAP and RDP are recommended.
2025-09-30 | Integrating HLA and HPA in Precision Transfusion: Insights from Platelet Transfusion Refractoriness Driven by Anti-CD36 Alloimmunization and Multifactorial Hemostatic Complications
Background: CD36, recently recognized as a distinct blood group system, encodes a class-B scavenger receptor involved in hemostasis and innate immunity. Anti-CD36 alloantibodies are an often-overlooked cause of platelet transfusion refractoriness (PTR), fetal–neonatal alloimmune thrombocytopenia (FNAIT), and bleeding disorders. Although newer assays are available, the relative effectiveness of platelet antibody tests remains uncertain. We review the clinical features of CD36 deficiency and alloimmunization, compare the Solid Phase Red Cell Adherence Assay (SPRCA) with ELISA for antibody detection, and propose a streamlined diagnostic algorithm for PTR. Materials and Methods: A retrospective cohort study was conducted at a tertiary center over 6.5 years, involving 2,333 patients who underwent platelet antibody testing. Antibody screening used parallel SPRCA and qualitative solid-phase ELISA, with confirmatory tests including MAIPA, molecular genotyping, and flow cytometry for CD36 antigen expression. Six illustrative cases with genetically or phenotypically confirmed CD36 deficiency were examined in detail. Results: ELISA detected antiplatelet antibodies in 33.6% of samples, while SPRCA detected them in 18.7%, with an overall concordance of 78.2% (κ = 0.451). ELISA identified additional antibodies in 18.4% of cases, whereas SPRCA alone detected 3.4%. Dual positivity strongly indicates pathogenic alloantibodies responsible for transfusion refractoriness. Conclusions: CD36 deficiency poses a significant immunohematologic challenge in PTR and FNAIT. Employing both ELISA and SPRCA for screening, along with reflex confirmatory testing, improves diagnostic accuracy for anti-CD36 alloimmunization, enhances transfusion strategies with CD36-negative platelet transfusions, and increases patient safety. Establishing rare donor registries is crucial for providing personalized transfusion support to affected individuals.
2025-09-22 | Integrating HLA and HPA for Precision Transfusion: Anti-CD36–Mediated Refractoriness and Hemostatic Challenges
Background: CD36, recently designated as a distinct blood group system, is a multifunctional class-B scavenger receptor in hemostasis and immunity. Anti-CD36 alloimmunization remains an underrecognized cause of platelet transfusion refractoriness (PTR), fetal–neonatal alloimmune thrombocytopenia (FNAIT), and hemostatic complications. Despite the availability of advanced diagnostic assays, the clinical utility and concordance of different platelet antibody detection platforms remain poorly characterized.We aimed to delineate the clinical presentations of CD36 deficiency and alloimmunization, compare diagnostic performances of SPRCA and ELISA for antiplatelet antibody detection, and propose an optimized diagnostic algorithm for PTR management. Materials and Methods: A retrospective cohort of 2,333 patients undergoing platelet antibody workup was analyzed at a tertiary center over 5.5 years. Antibody screening employed parallel SPRCA and qualitative solid-phase ELISA, with confirmatory testing using MAIPA, molecular genotyping, and flow cytometry for CD36 antigen expression. Six illustrative cases with genetically or phenotypically confirmed CD36 deficiency were thoroughly evaluated. Results: ELISA detected antiplatelet antibodies in 33.6% of samples, while SPRCA detected them in 18.7%, with an overall concordance of 78.2% (κ = 0.45). ELISA identified additional antibodies in 18.4% of cases, whereas SPRCA alone identified 3.4%. Dual-positivity was highly predictive of pathogenic alloantibodies responsible for transfusion refractoriness. Conclusions: CD36 deficiency introduces a critical immunohematologic barrier in PTR and FNAIT. Parallel screening with ELISA and SPRCA, utilizing reflex confirmatory testing, enhances diagnostic precision for anti-CD36 alloimmunization, optimizes transfusion strategies using CD36-negative platelet transfusions, and improves patient safety. Establishing rare donor registries is essential for tailored transfusion support to affected individuals.
2024-07-16 | Why might cord blood be a better source of platelets for transfusion to neonates?
Thrombocytopenia (defined as a platelet count <150×109/L) is a common condition in preterm neonates and may occur in 18-35% of all infants admitted to the Neonatal Intensive Care Unit (NICU). Neonatal platelet functionality in terms of reactivity is often described as reduced compared to adults, even in healthy, term neonates. However, this platelet "hyporeactivity" does not correspond to a global functional impairment of the normal delicately balanced neonatal hemostatic system. The extent to which neonatal thrombocytopenia and platelet hyporeactivity contribute to the bleeding risk in preterm neonates remains unknown. Prophylactic platelet transfusions are often administered to them to reduce the risk of bleeding. However, recent literature indicates that adopting a higher platelet transfusion threshold than a lower one results in significantly higher death rates or major bleeding and can be harmful. Although the mechanism by which this occurs is not entirely clear, a mismatch between adult transfused platelets and the neonatal hemostatic system, as well as volume overload, are speculated to be potentially involved. Therefore, future research should consider novel transfusion products that may be more suitable for premature neonates. Blood products derived from umbilical cord blood (UCB) are promising, as they might perfectly match neonatal blood features. Here, we discuss the current knowledge about UCB-derived products, focusing on UCB-derived platelet concentrates and their potential for future clinical application. We will discuss how they may overcome the potential risks of transfusing adult-derived platelets to premature infants while maintaining efficacy.
2023-08-31 | Prophylactic Platelet Transfusions
Preterm neonates are a highly transfused patient group, with platelet transfusions being the second most transfused cellular blood component. Historically, however, evidence to inform optimal platelet transfusion practice has been limited. In pediatrics , much of the evidence has been inferred from studies in adult patients, although neonatologists have generally applied more cautious and liberal platelet transfusion thresholds to mitigate the complications of intraventricular hemorrhage . A total of three randomized controlled trials have now been published comparing different platelet transfusion strategies in neonates.
small molecules
2026-04-14 | Maternal anti-HPA-1a antibodies block αIIbβ3 and αvβ3 integrin activation which correlates with FNAIT disease severity.
Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is a disorder caused by a mismatch in human platelet antigens (HPAs), leading to maternal antibody formation and platelet destruction in the fetus or neonate. The clinically most relevant antigen is HPA-1a on the b3 subunit of integrins aIIbb3 and avb3, which are conformationally regulated cell adhesion receptors on platelets and endothelial cells, crucial for hemostasis and vascular integrity. The clinical effects of anti-HPA-1a alloimmunization are highly heterogeneous and range from no symptoms to intracranial hemorrhage, potentially causing perinatal death or lifelong complications. However, determinants of disease severity are largely unknown, which hampers implementation of screening programs to identify alloimmunized high-risk women who will benefit from treatment. Using recombinant anti-HPA-1a antibodies and a cohort of retrospective FNAIT samples associated with mild or severe disease, we report here that the tested anti-HPA-1a antibodies inhibit binding of integrins avb3/aIIbb3 to ligands (vitronectin, fibronectin, and fibrinogen) and cell adhesion. Inhibition is dependent on antibody concentration, is mediated by the antibody Fab and does not require the Fc-tail, and is abolished when integrins are forced into a constitutively extended conformation. Furthermore, the extent of integrin inhibition correlates with disease severity. Together, our data demonstrate that anti-HPA-1a antibodies can block integrin activation, which likely contributes strongly to disease severity in FNAIT. These results aid development of a prenatal diagnostic test to identify pregnancies at high risk of developing FNAIT and associated severe complications. In addition, these data reveal novel opportunities for allosteric inhibition of b3 integrin activation.
2026-03-09 | High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation
Abstract Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by ‘bent/closed’ to ‘extended/open’ conformational changes. Integrin αIIbβ3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on β3 is recognized by pregnancy-associated maternal alloantibodies, potentially causing fetal/neonatal alloimmune thrombocytopenia (FNAIT) and even intracranial hemorrhage or perinatal death. However, severe disease determinants are largely unknown. We report the first structure of an anti-HPA-1a antibody fragment (Fab 26.4) in complex with integrin αIIbβ3 at high resolution by cryo-electron microscopy. Fab 26.4 binding traps αIIbβ3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits αIIbβ3-dependent fibrinogen binding and platelet aggregation. Thus, anti-HPA-1a antibodies directly impair integrin activation by preventing required conformational changes. These insights will improve FNAIT diagnostics and treatment, and spark the development of novel allosteric inhibitors against β3 integrins for future therapeutic applications.
2026-03-04 | Anti-HPA-1a fetal-neonatal alloimmune thrombocytopenia: reframing diagnostics, pathophysiology, and management.
Maternal alloantibodies directed to human platelet antigen 1a (HPA-1a) on fetal platelets can induce fetal-neonatal alloimmune thrombocytopenia (FNAIT), which causes intracranial hemorrhage in 10% to 20% of fetuses/newborns. Presentation is usually unexpected and identified by neonatal bleeding. This review synthesizes advances in diagnosis, pathophysiology, and management that reshape understanding of anti-HPA-1a-mediated FNAIT. Genomic and serologic testing, together with cell-free fetal DNA for fetal HPA typing, allow accurate identification of at-risk pregnancies. HPA-1bb women who carry DRB3∗01:01 are at greatest risk of forming clinically significant anti-HPA-1a. Not only anti-HPA-1a levels but also structural features, particularly decreased Fc fucosylation enhancing Fc gamma receptor-mediated effector functions, more accurately determine disease severity. Furthermore, increased Fc galactosylation may contribute by enhancing complement activation. Fab-mediated effects affect platelets, megakaryocytes, trophoblasts, and endothelial cells. Overall, this explains why anti-HPA-1a levels and neonatal platelet counts alone do not reliably predict bleeding, including intracranial hemorrhage. Anti-HPA-1a also induces placental inflammation, increasing risks of fetal growth restriction and long-term neurodevelopmental impairment, for example, autism. Neonatal management involves random donor and matched platelet transfusions, and IV immunoglobulin (IVIG), if needed. Antenatal IVIG, with/without prednisone administered in an affected pregnancy typically increases fetal platelet counts, with management strategies varying internationally. Blocking neonatal Fc receptor has emerged as an alternative approach to both reduce maternal anti-HPAa-1a levels and inhibit its transplacental transfer. Whether antenatal treatment reduces placental inflammation requires further study. These developments support the importance of identifying predictive biomarkers of fetal risk to guide antenatal management and of preventing affected pregnancies ideally by screening all pregnancies followed by prophylaxis.
2025-10-15 | Diagnosis and Management of Fetal and Neonatal Alloimmune Thrombocytopenia: An Update 2025.
Antibodies of the mother, which are directed against paternal antigens on platelets of the child, can lead to the destruction of the fetal blood cells in the circulation after diaplacental passage. The clinical picture of fetal-neonatal alloimmune thrombocytopenia (FNAIT) is characterized by bleeding, of which intracranial bleeding is particularly feared. Our understanding of the pathophysiology of FNAIT and its targeted prophylaxis and therapy has improved significantly in recent years. FNAIT by anti-HPA-1a is the best studied. How exactly the mother is immunized is not known for certain, but, in clinically apparent cases, immunization usually occurs in the first pregnancy of an HLA-DRB3*01:01-positive, HPA-1a-negative woman. There is no convincing basis for assigning immunization against HPA-5b and against HLA class I any significance in the development of fetal thrombocytopenia. Newborns of mothers with anti-HPA-1a present a broad clinical picture ranging from isolated, clinically unremarkable thrombocytopenia to intracranial hemorrhage (ICH; in approx. 1-10% of cases). ICH usually occurs intrauterine (before week 28). There are indications that, in addition to the fetal platelets, the placenta can also be affected by anti-HPA-1a. As there are no screening programmes, the index diagnosis of FNAIT is random. It is made by serological and genetic laboratory tests. Predicting outcome in a subsequent pregnancy is problematic if the child is antigen-positive. With a first-born child with severe thrombocytopenia, the probability of a recurrence of severe thrombocytopenia is around 70%. Without ICH, the probability of ICH in the subsequent pregnancy is low but not zero, and with ICH the recurrence rate is high. There is no established laboratory diagnostic method to predict the severity of thrombocytopenia or the occurrence of ICH. Prophylaxis with immunoglobulins (IVIgs) is considered effective. Pharmaceutics that block placental transport are currently undergoing clinical trials and may replace IVIgs in the future. Intrauterine platelet transfusions should no longer be performed. For the mature, thrombocytopenic newborn without internal hemorrhage, a platelet transfusion is advisable for platelet counts <25 g/L.
2022-08-11 | Current perspective and scope of fetal therapy: part 2.
Fetal therapy has been defined as any therapeutic intervention either invasive or noninvasive for correcting or treating any fetal malformation or condition. Invasive fetal therapy have its own set of maternal and fetal complications and invasive approach is not feasible in many of fetal conditions that are candidate for fetal therapy. Many such fetal conditions have been treated successfully by medical or noninvasive management. In medical fetal therapy, mothers are treated with medications which are transferred to fetus through placenta and exert positive effect on the fetus, thus avoiding complications that are seen secondary to invasive fetal therapy. The fetal conditions that have been managed with medical therapy includes fetal and neonatal alloimmune thrombocytopenia, neural tube defect, congenital adrenal hyperplasia, perinatal infections, respiratory distress syndrome, inborn error of metabolism, and congenital cystic adenomatoid malformation. This review will cover the medical or noninvasive aspect of fetal therapy and will highlight the progress made in the management of these fetal conditions.
proteins
2026-08-14 | Fusion of IgG antibodies to albumin inhibits transport across the placenta.
Immunoglobulin G (IgG)-based monoclonal antibodies are effective therapies for cancer, autoimmune diseases, and migraine. However, they are actively transported across the placenta by the neonatal Fc receptor (FcRn), limiting their use during pregnancy. Using mouse models and an ex vivo human placental perfusion system, we show that although FcRn binds albumin independently of IgG, albumin is not transported to the fetus in mice or across human placental tissue. Fusion of IgG to albumin markedly reduced transplacental transport in both models while preserving the prolonged plasma half-life conferred by FcRn. Similarly, fragment antigen-binding fragments fused to engineered albumin with enhanced FcRn binding showed minimal fetal exposure. In a mouse model of fetal and neonatal alloimmune thrombocytopenia, albumin fusion of an anti-human platelet antigen IgG reduced fetal antibody transfer and attenuated thrombocytopenia in the offspring. These findings identify albumin as an attractive fusion partner for biologics intended to minimize fetal exposure during pregnancy.
2017-05-26 | Developmental differences between newborn and adult mice in response to romiplostim
Thrombocytopenia is frequent among sick neonates. While most cases are transient, some neonates experience prolonged and severe thrombocytopenia. These infants often pose diagnostic and therapeutic challenges, and may receive large numbers of platelet transfusions. Romiplostim (ROM) is a thrombopoietin (TPO)-receptor-agonist approved for treatment of adults with chronic immune thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure of newly produced platelets, which could aid with the diagnostic evaluation of thrombocytopenic neonates. This study had the following two objectives: (1) compare the response of newborn and adult mice to escalating doses of ROM in vivo and (2) assess the correlation between IPF and megakaryocyte (MK) mass in newborn and adult treated and untreated mice. In the first set of studies, newborn (day 1) and adult mice received a single subcutaneous (SC) dose of ROM ranging from 0 to 300 ng/g, and platelet counts were followed every other day for 14 days. Both sets of mice responded with dose-dependent platelet and IPF increases, peaking on days 5–7 post-treatment, but neonates had a blunted response (2.1-fold compared to 4.2-fold maximal increase in platelet counts, respectively). On day 5 post-treatment with 300 ng/g ROM, MKs in the bone marrow (BM) and spleen of adult mice were significantly increased in numbers and size (p < 0.0001 for both) compared to controls. MKs in the spleen and BM (but not liver) of treated neonates also increased in number, but not in size. The immature platelet count (IPC, calculated as IPF x platelet count) was highly correlated with the MK number and size in neonatal and adult BM and spleen, but not neonatal liver. The lack of response of neonatal liver MKs was not due to a cell-intrinsic reduced responsiveness to TPO, since neonatal liver progenitors were more sensitive to murine TPO (mTPO) in vitro than adult BM progenitor. In vivo treatment of newborn mice with high mTPO doses or with higher doses of ROM (900 ng/g) resulted in peak platelet counts approaching 3-fold of controls. Taken together, our data indicate that newborn mice are less responsive to ROM than adult mice in vivo, due to a combination of likely pharmacokinetic differences and developmental differences in the response of MKs to thrombopoietic stimulation, evidenced by neonatal MKs increasing in numbers but not in size. PK/PD studies in human infants treated with ROM are warranted.
2002-10-01 | Developmental biology of thrombopoietin in the human fetus and neonate
This review focuses on the biology of thrombopoietin (Tpo) during human development. It summarizes the current understanding on molecular biological aspects of Tpo, cellular effects of Tpo on fetal and neonatal megakaryopoiesis, regulation of Tpo production, and circulating Tpo concentrations in human fetuses and neonates. Some important aspects on the developmental biology of Tpo are highlighted. They include the finding of high Tpo gene expression in the bone marrow during the onset of medullary hematopoiesis, higher circulating Tpo concentrations in fetuses and neonates than in children or adults, and a higher sensitivity of neonatal megakaryocyte progenitor cells to Tpo. However, other aspects of the developmental biology of Tpo are incompletely understood. Conclusion: More carefully designed studies are needed to provide the necessary background for an optimal treatment of fetal and neonatal thrombocytopenia.
2002-09-01 | Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit
Phlebotomy‐induced anaemia excepted, thrombocytopenia is the most common haematological abnormality in neonatal intensive care unit (NICU) patients. Roughly one‐quarter of all NICU patients and half of all sick preterm neonates develop thrombocytopenia. Whereas a large number of varied precipitating conditions has been identified, early‐onset thrombocytopenia (>72 h) is most commonly associated with fetomaternal conditions complicated by placental insufficiency and/or fetal hypoxia, e.g. maternal pre‐eclampsia and fetal intrauterine growth restriction. The resulting neonatal thrombocytopenia is usually mild to moderate, resolves spontaneously and requires no specific therapy. Deviation from this pattern of thrombocytopenia suggests the presence of more significant precipitating conditions. The most important of these are the immune thrombocytopenias, and every NICU should develop investigation and treatment protocols to manage these cases promptly and avoid unnecessary risk of haemorrhage. In contrast, late‐onset thrombocytopenia (>72 h) is almost always associated with sepsis or necrotizing enterocolitis and the associated thrombocytopenia is severe, prolonged and often requires treatment by platelet transfusion. Unfortunately, evidence‐based guidelines for platelet transfusion therapy in NICU patients are currently unavailable, making it difficult to define widely accepted thresholds for transfusion and leading to a significant variation in transfusion practice between centres. Conclusion : While improving this situation remains a pressing need, the growing evidence that impaired megakaryocytopoiesis and platelet production are major contributors to many neonatal thrombocytopenias suggests that recombinant haemopoietic growth factors, including thrombopoietin and interleukin‐11, may be useful future therapies to ameliorate neonatal thrombocytopenia.
2002-07-24 | Thrombopoietin in thrombocytopenias of childhood.
This review summarizes the biology of thrombopoietin (TPO) in childhood. Studies on TPO and its receptor (c-mpl) have improved the understanding of inherited and acquired thrombocytopenias in childhood. Data are presented in this review regarding the molecular biology of TPO, differences in cellular effects on megakaryopoiesis, the regulation of TPO production, and TPO concentrations in health and disease. For neonatal thrombocytopenia, the focus is on early-onset thrombocytopenia associated with maternal diabetes, pregnancy-induced hypertension, intrauterine growth retardation, hypoxia, and sepsis. Fetal alloimmune thrombocytopenia allows insight into the biology of TPO when fetal megakaryopoiesis is chronically stimulated. In the thrombocytopenia absent radii syndrome and congenital amegakaryocytic thrombocytopenia, thrombocytopenia is caused by a disorder in the signal transduction at the c-mpl level and respectively directly on c-mpl. TPO concentrations in other inherited thrombocytopenias such as Fanconi anemia, Shwachman syndrome, Wiskott-Aldrich syndrome, and Bernard-Soulier syndrome are discussed. For acquired thrombocytopenias, data on TPO in aplastic anemia, immune thrombocytopenia, human immunodeficiency virus infection, and liver disease are given. Possible indications for a treatment with recombinant TPO in childhood are discussed, but the criteria to identify patients who would benefit need detailed evaluation.
antibodies
2026-09-27 | A functionally distinct HPA-1a-specific alloantibody associated with fetal/neonatal alloimmune thrombocytopenia that activates platelets via FcγRIIa.
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies directed against fetal platelet antigens, most commonly human platelet antigen-1a (HPA-1a). These antibodies mediate platelet destruction and can lead to fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds. Antibody titer and isotype do not reliably predict disease severity, suggesting additional heterogeneity among anti-HPA-1a antibodies. We evaluated the effects of five previously characterized HPA-1a-specific monoclonal antibodies (mAbs) on platelet activation, platelet aggregation, and induction of intracellular signaling. The involvement of FcγRIIa was examined using FcγRIIa-blocking antibody IV.3, protein tyrosine kinase inhibitors, and selected monoclonal antibody Fab fragments. At saturating concentrations, all five mAbs inhibited thrombin-induced aggregation. At sub-saturating concentrations, however, mAb M-204 uniquely induced spontaneous aggregation and α-granule secretion in HPA-1a-positive human, but not mouse, platelets, which lack FcγRIIa. M-204-induced aggregation was abolished by mAb IV.3 and inhibitors of Src- and Syk-family kinases and was absent using M-204 Fab fragments. M-204 induced tyrosine phosphorylation of Syk and PLCγ2 in an FcγRIIa-dependent manner. Finally, despite persistent platelet activation induced by M-204, saturating concentrations of this antibody blocked the binding of the fibrinogen mimetic antibody, PAC-1, to HPA-1a homozygous, but not HPA-1a/1b heterozygous, platelets, consistent with the known ability of HPA-1a-specific antibodies to sterically interfere with ligand binding to HPA-1a-positive αIIbβ3. These findings identify a previously unrecognized, functionally distinct subset of HPA-1a antibodies capable of activating platelets via FcγRIIa, suggesting a potential mechanism contributing to variability in disease severity in FNAIT.
2026-09-02 | Generation and Use of an Alloantigen-Specific Preclinical Humanized Mouse Model of Fetal and Neonatal Alloimmune Thrombocytopenia.
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies targeting a paternally inherited alloantigen present on the surface of fetal platelets. The human platelet alloantigen HPA-1a/HPA-1b, also known as the PlA1/PlA2 alloantigen, is the most frequently implicated HPA for causing FNAIT in Caucasians. A single Leu33Pro amino acid polymorphism residing within the plexin/semaphorin/integrin (PSI) domain of the integrin β3 subunit (platelet membrane glycoprotein (GP), GPIIIa) is responsible for generating the HPA-1a and HPA-1b epitopes. In mice, the GPIIIa gene encodes a glutamine at position 33, making it challenging to model the alloimmune response, thereby hindering studies on the underlying mechanisms and therapeutic interventions of this alloimmune disorder. This chapter outlines the development and use of a humanized, alloantigen-specific preclinical mouse model of FNAIT, aiming to advance basic and translational research in this field. Basic protocols are provided for (1) generating an HPA-1a transgenic mouse by introducing humanized residues A30P32L33D39 within the PSI domain and Q470 in the EGF1 domain of mouse integrin β3 using CRISPR/Cas9 gene editing technology, (2) developing a preclinical alloantigen-specific humanized mouse model of FNAIT using the HPA-1a transgenic APLDQ mice, and (3) examining the efficacy of a prophylactic treatment regimen in preventing alloimmunization and FNAIT development using this alloantigen-specific mouse model. This humanized mouse model faithfully recapitulates many clinically important aspects of human FNAIT, serving as a valuable tool for studying the pathophysiological mechanisms underlying the alloimmune response and assessing prophylactic and therapeutic interventions in translational research.
2026-06-11 | Inhibition of human FcγRIII prevents platelet destruction in a dual-humanized murine model of FNAIT.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when maternal anti-fetal platelet antibodies, most frequently against HPA-1a, cause fetal platelet destruction. The precise pathogenic mechanisms remain incompletely understood. Here, we examined potential mechanisms underlying anti-HPA-1a-mediated platelet clearance, focusing on phagocytosis, complement fixation, platelet activation, and desialylation. Anti-HPA-1a antibodies in pooled plasma and in 9 of 10 individual FNAIT patient samples induced FcγR-dependent platelet phagocytosis in vitro, indicating this as the major contributor to platelet destruction. In contrast, complement fixation, platelet activation (CD62P expression), and desialylation (RCA-I binding) were observed in only a minority of patients. To model anti-HPA-1a-mediated platelet clearance in vivo, we developed a dual-humanized mouse model combining HPA-1a-expressing platelets (from APLDQ transgenic mice) with mice engineered to express human FcγRs in place of murine FcγRs. Platelets from APLDQ mice sensitized with anti-HPA-1a sera underwent rapid clearance in these FcγR-humanized recipients. Pre-treatment with an FcγRIII-blocking monovalent antibody significantly reduced clearance, confirming FcγRIII's central role in mediating platelet destruction. These results demonstrate that FcγRIII-dependent phagocytosis is a dominant mechanism in anti-HPA-1a-driven platelet clearance in this model. Although complement activation and platelet desialylation were observed in a minority of samples, their contribution to platelet destruction remains speculative. Together, these findings highlight the complexity of FNAIT pathophysiology yet identify FcγRIII blockade as a promising strategy to prevent platelet clearance in this disease.
2026-04-17 | New perspectives on fetal and neonatal alloimmune thrombocytopenia for obstetricians.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a serious disorder that arises when a mother produces alloantibodies against specific human platelet antigens (HPAs) expressed on fetal platelets. These maternal alloantibodies cross the placenta and destroy fetal platelets, significantly increasing the risk of fetal or neonatal intracranial hemorrhage (ICH). Indeed, FNAIT is the leading cause of isolated severe thrombocytopenia in otherwise healthy neonates. In this review, we summarize recent advances to provide obstetricians and maternal-fetal medicine specialists with an updated overview of FNAIT, encompassing its pathophysiology, clinical features, diagnostic strategies, antenatal management, delivery planning, and postnatal care. Although the prophylactic interventions remain at an early stage, HPA histo-incompatibility prescreening is already available at a suitable cost, and the development of NAITgam, a targeted immunoglobulin preparation, represents a promising advance. While the widespread implementation of screening and prophylaxis may take years, such measures have the potential to significantly reduce the incidence and severity of FNAIT. Currently, the antenatal administration of intravenous immunoglobulin (IVIg), with or without corticosteroids, remains the safest and most effective treatment for high-risk pregnancies. Looking ahead, animal model data continue to provide valuable insights that may inform the development of novel preventive and therapeutic strategies. Ultimately, the implementation of a national screening program could prevent severe complications and help mitigate the long-term societal and healthcare burden of FNAIT.
2025-12-31 | The Ethics of Clinical Research on Diseases of the Fetus and Newborn: Balancing Benefit-Risk, Autonomy, and Maternal-Fetal Interests.
Pregnant persons historically have been excluded from clinical trials. Recently, there has been a shift from exclusion toward inclusion of pregnant persons in research while acknowledging the complexity of reproductive ethics and the intertwined interests of the pregnant person and fetus. Our objective was to use a principle-based approach to review the ethics of clinical research concerning pregnancy-related disorders that predominantly affect fetal well-being. Ethical principles are applied to the design of interventional trials in two rare conditions of pregnancy, hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT). Severe HDFN and FNAIT are fetal and neonatal diseases caused by maternal alloantibodies with potential outcomes including maternal and neonatal morbidity, preterm delivery, and fetal or neonatal death. Early-onset severe HDFN was the initial indication for a phase 2 open-label study of nipocalimab in pregnancy, given poor outcomes after prior severe HDFN pregnancy(s). After establishing proof of concept, a phase 3 randomized placebo-controlled study was initiated based on the ethical principles of equipoise and generating socially valuable data to support the efficacy and safety of nipocalimab in severe HDFN. However, off-label use of antenatal intravenous immunoglobulin (IVIg) in standard-risk FNAIT pregnancies made a randomized placebo-controlled study challenging. Thus, the FNAIT clinical program for nipocalimab in pregnant persons with standard-risk FNAIT includes a randomized, placebo-controlled study limited to sites that do not use antenatal IVIg, and a global randomized open-label study of nipocalimab or IVIg. Knowledge of the clinical course and management of severe HDFN and FNAIT, the non-clinical and non-pregnant human clinical evidence, and input from physicians, patients, and health authorities permitted the design of clinical protocols that satisfy the principles of beneficence and non-maleficence in these rare and complex diseases. · Ethical principles apply to pregnancy-related disorders affecting fetal well-being.. · Placebo-controlled randomized trials in HDFN are based on equipoise.. · FNAIT programs must account for the off-label use of IVIg..
other
2026-02-12 | Immunoglobulin therapy for the fetus and neonate.
Maternal immunity is modulated during pregnancy at the placental interface to prevent alloreactivity with the developing fetus. Importantly, however, maternal immunoglobulin G (IgG) freely crosses the placenta, and the presence of pre-existing alloreactive antibodies can lead to injury of fetal tissues and/or cells. Because maternal IgG continues to circulate up to 6 months after birth, these antibodies can also continue to affect the newborn, causing a variety of disease conditions including haemolytic disease of the newborn, neonatal alloimmune thrombocytopenia, neonatal lupus, neonatal Graves' disease, gestational alloimmune liver disease and others. Ig therapy, most typically in the form of intravenous Ig, is indicated in these disorders, as pooled IgG molecules can interfere with the circulating maternal IgG, lessening the interactions with the fetal or neonatal binding targets. Ig is an increasingly used therapy in this population; however, most fetal and neonatal providers do not receive comprehensive training in its development or use. Here, we review the formulation, mechanisms of action, therapeutic indications and administration of intravenous Ig in the context of fetal and neonatal medicine.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
7 orphan drug designations for Fetal and neonatal alloimmune thrombocytopenia.
7 orphan drug designations for Fetal and neonatal alloimmune thrombocytopenia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Nipocalimab | antibodies | EMA | Janssen Cilag International N.V. | |
nipocalimab | antibodies | FDA | Janssen Research & Development, LLC | |
recombinant human IgG monoclonal HPA-1a antibody | antibodies | FDA | Rallybio IPA, LLC | |
Anti-(integrin beta-3) human monoclonal antibody | antibodies | EMA | — | FGK Representative Service GmbH |
human platelet antigen-1a immunoglobulin (anti-HPA-1a) | antibodies | FDA | Rallybio IPA, LLC | |
Human platelet antigen 1a immunoglobulin | antibodies | EMA | — | FGK Representative Service GmbH |
Eptacog alfa (activated) | — | EMA | Novo Nordisk A/S |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.