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PubMed2026

Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.

Glanzmann thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. Although patients with GT typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 patients with GT, 8 consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized MK cell lines (imMKCLs), focusing on 2 modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3-dimensional silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production independent of the type of variant. Although thrombin receptor activating protein-activated, in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 before activation, mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3-deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, whereas reexpression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.

Humans↗
PubMed2026

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.

Humans↗
PubMed1992

Western blotting is a sensitive technique for the detection of anti-PlA1.

Western (immuno-) blotting was evaluated as a technique for anti-PlA1 detection, using untreated and chloroquine or low pH-treated platelets. Chloroquine-treated platelet membranes generated the cleanest blots, giving end-point titres of 4000-16,000 for three different anti-PlA1 sera. These titres were between three and eight doubling dilutions higher than those obtained in solid phase, ELISA or indirect immunofluorescence tests. Nitrocellulose strips used for blotting could be stored for at least six months at room temperature without significant loss of PlA1 activity. However, immunoblotting still failed to detect anti-PlA1 in the sera of four of fivePl (A1-) women whose infants were born with neonatal thrombocytopenia of probable alloimmune origin.

Antibodies↗
PubMed1992

[Frequency of platelet specific alloantigens HPA-1a (P1A1) and HPA-4a (Pen(a)) expression in Chilean population].

The phenotype frequency of platelet-specific alloantigens has been reported to vary with the ethnic composition of the population under study and the only two HPA-4a negative individuals found in the United States were of Hispanic origin; therefore, the aim of this work was to define the frequency of expression of these systems in the Chilean population. Using an ELISA with captured antigen by monoclonal antibodies, 604 blood donors were typed for the platelet-specific antigen systems HPA-1 and HPA-4. Eight samples typed negative for HPA-1a (1.32%) and 596 typed positive (98.68%). The calculated gene frequencies were 0.88 for HPA-1a (gene frequency > 0.99). Since these antigens are involved in thrombocytopenic disorders such as neonatal alloimmune thrombocytopenia and post-transfusion purpura, their frequency in a population is of clinical relevance. The gene frequency found for HPA-1a is higher than in Europeans (0.85) and lower than in Mapuche Indians (0.99), which is to be expected from the ethnic origin of our population. The absence of HPA-4a negatives in this study does not support our original hypothesis of a higher polymorphism of this system among hispanics.

Antigens, Human Platelet↗