Human platelet antigen

Human platelet antigens (HPA) are polymorphisms in platelet antigens. These can stimulate production of alloantibodies (that is, antibodies against other people's antigens) in recipients of transfused platelets from donors with different HPAs. These antibodies cause neonatal alloimmune thrombocytopenia, post-transfusion purpura, and some cases of platelet transfusion refractoriness to infusion of donor platelets.^[1]

Glycoprotein

Overview and nomenclature

Human platelet antigens (HPAs) are alloantigenic determinants expressed as variable sequences on platelet surface glycoproteins. The variants are distinguished by single nucleotide polymorphisms (SNPs), leading to single amino‑acid substitutions, except for HPA‑14bw which involves a more complex variant.^[2]

To date, more than 33 HPAs have been identified on six major platelet glycoprotein complexes: GPIIb, GPIIIa, GPIa, GPIbα, GPIbβ and CD109.^[3] Typically, twelve of these antigens form six biallelic systems (HPA‑1, ‑2, ‑3, ‑4, ‑5, and ‑15); the others, while serologically confirmed as antigens, lack recognized antithetical counterparts.^[4] The International Society of Blood Transfusion (ISBT) established standardized numeric nomenclature for HPAs, resolving prior inconsistencies.

Each major HPA system corresponds to a specific platelet glycoprotein. HPA‑1 resides on integrin β3 (GPIIb/IIIa). The HPA‑1a/1b polymorphism involves a leucine-to-proline substitution and is the most immunogenic system in Caucasians.^[4] HPA‑2, ‑3, ‑4, ‑5, and ‑15 are localized respectively to GPIbα, GPIIb/IIIa integrin α‑subunits, GPIbα or GPIbβ, and CD109, each with different amino acid substitutions.^[2][3]

The remaining minor HPAs are also mapped to these glycoprotein complexes but typically are less immunogenic or of limited geographic frequency.^[3]

Clinical importance

The two major clinical conditions associated with HPA proteins are neonatal alloimmune thrombocytopenia and platelet transfusion refractoriness. Fetal/neonatal alloimmune thrombocytopenia occurs when an HPA-negative mother (commonly lacking HPA‑1a) is exposed to paternal antigens on the fetus, generating anti‑HPA antibodies. These IgG alloantibodies cross the placenta, leading to fetal thrombocytopenia. Severe cases can result in intracranial hemorrhage or neonatal death.^[5][3][6] In platelet transfusion refractoriness, antibodies to HPAs may form after platelet transfusion. These antibodies destroy donor platelets (causing "refractoriness" to the transfusion), which may lead to post-transfusion purpura.^[3][2] Platelet refractoriness can also result from anti‑HLA class I alloantibodies, which may elevate risk more than 100‑fold compared to platelet antigen mismatches.^[7][6]

Emerging and Expanded Roles of HPAs

While historically focused on alloimmune complications, current research explores broader roles for HPA polymorphisms in immunity and disease:

• HPAs may influence platelet‑microbial interactions, potentially modulating susceptibility or clearance in infectious diseases. For example, polymorphisms on CD36 (GP IV / HPA‑Naka) have been linked to adhesion of Plasmodium falciparum–infected erythrocytes and cerebral malaria severity.
• Platelet-mediated tumor surveillance and inflammation might be affected by specific HPA variants, though detailed mechanistic data are still emerging.^[2][4]

Prevention and Management of NAIT and Transfusion Reactions

NAIT

• Prenatal screening and monitoring: In at-risk pregnancies (e.g., mother with previously affected infant), genotyping and serial ultrasounds guide early intervention.
• IVIG therapy (often with or without steroids) is used to suppress maternal antibody formation and reduce fetal platelet destruction.
• In severe cases, fetal platelet transfusion or early delivery planning may be necessary.

Platelet Transfusion Reactions

• Provision of HPA‑matched or negative platelet units (e.g. HPA‑1a negative donors) is essential when alloantibody-mediated refractoriness occurs.
• Antibody screening prior to transfusion may help prevent PTP or refractoriness, but availability of matched donors remains a logistical challenge.^[6][5]

Research Trends and Future Directions

• Next-generation sequencing and whole-genome approaches are enabling comprehensive typing of HPAs and prediction based on extended blood group polymorphisms.
• Improved platelet purification and proteomic analysis methods are revealing age- and variant-related differences in platelet protein composition, with implications for biomarker discovery and precision transfusion medicine.^[8]
• Machine learning is being explored in related platelet disorders (e.g., ITP), highlighting a future intersection of immunogenetics and predictive modeling for thrombocytopenic syndromes.^[9]

Topic	Details
Number of HPAs	>33 identified; ~12 biallelic systems (HPA‑1 to ‑5, ‑15)
Glycoproteins involved	GPIIb/IIIa, GPIa/IIa, GPIb/IX, CD109
Genetic basis	Mostly single SNP causing single amino acid substitutions
Major alloantigens	HPA‑1a (most immunogenic), HPA‑5b, HPA‑3a
Clinical conditions	NAIT/FNAIT, platelet transfusion refractoriness, PTP
Laboratory methods	Serological (MAIPA/bead) and molecular genotyping (PCR, NGS)
Population variation	HPA‑1a common in Europeans; other alleles vary worldwide
Immunogenetics	Role of maternal HLA haplotypes (e.g. DRB3*0101)
Emerging roles	Pathogen binding, inflammation, cancer-related platelet biology
Research tools	NGS, proteomics, machine learning, genomic typing

Expanded Roles of HPA Polymorphisms in Pregnancy and Placental Development

Recent studies have shown that maternal anti‑HPA‑1a antibodies may impair early placental development by targeting trophoblasts in addition to fetal platelets. In vitro experiments using the monoclonal anti‑HPA‑1a antibody clone 26.4 demonstrated impaired adhesion, migration, and invasion of extravillous trophoblast (EVT) cells—processes essential for placental development and uterine spiral artery remodeling. These functional impairments may contribute to placental insufficiency, fetal growth restriction, and an increased risk of miscarriage and preterm birth.^[5]

This evidence suggests that anti‑HPA‑1a antibodies may bind to the integrin αVβ3 (which carries the HPA‑1a epitope) expressed on trophoblasts, disrupting vascular remodeling and placental perfusion. Such effects could help explain the poor fetal outcomes observed in severe cases of neonatal alloimmune thrombocytopenia (NAIT) even when platelet counts alone do not predict severity.^[5]

Clinical Practice Implications and Transfusion Strategy

A recent 2025 review highlighted the importance of identifying immune versus non-immune causes of platelet transfusion refractoriness (PTR), which is common in chronically transfused patients. While most PTR is non-immune, alloantibodies—especially against HPA antigens—can lead to poor platelet recovery. The review emphasizes the value of HPA genotyping and antibody screening in patients with refractory thrombocytopenia.^[7]

In the United States, HPA genotyping is performed in CLIA-certified laboratories and is considered medically necessary in pregnancies with a prior affected child, suspected NAIT, or unexplained intracranial hemorrhage. However, FDA-cleared commercial kits for HPA testing are not yet available.

Potential Broader Health Impacts and Future Research Directions

Beyond alloimmunization, HPA polymorphisms may influence other health outcomes. For instance, CD36 (HPA‑Naka) is involved in interactions with Plasmodium falciparum and may affect malaria pathogenesis. HPAs also influence platelet–tumor interactions and immune surveillance, although these mechanisms remain under investigation.^[2]

Proteomic methods such as label-free quantitative (LFQ) data-independent acquisition (DIA) mass spectrometry are now being used to examine how platelet proteomes vary by age and potentially by HPA genotype, offering new insights into platelet function and disease associations.^[8] In parallel, synthetic platelet-like nanoparticles are being developed to bypass alloimmune complications and offer therapeutic potential in hemostasis, antimicrobial delivery, or cancer therapy.^[10]

System	Antigen	Original names	Glycoprotein	CD
HPA-1	HPA-1a	1aZw	GPIIIa	CD61
	HPA-1b	Zwb	GPIIIa	CD