In January 2024 the National Health Service (NHS) (NHS England (NHSE) and NHS Blood and Transplant (NHSBT)), launched a programme of typing for 56 Human Erythroid Antigen (HEA) types and Human Leukocyte Antigen (HLA) Class I and II types, at first field resolution by Axiom array genotyping. The test was free at the point of testing, to all patients with sickle cell (SCD), thalassaemia and transfusion dependent rare inherited anaemias in England. This was the clinical deployment of a next version of the Universal Blood Donor Typing array (Gleadall, 2021) developed by the Blood transfusion Genomics Consortium (www.bgc.io) and the first step in the programme for algorithmically driven genomically informed matching of blood for SCD patients (www.haemmatch.org) which aims to reduce the harm caused by alloimmunisation. The pathway to delivery at a national level was challenging and included coordinating with multiple stakeholders: industry, government, healthcare and regulatory. However, it was highly collaborative and with meaningful public and patient involvement and engagement (PPIE), ensuring patient advocacy and voice were central to decision making. Transition for a research tool to a test that met clinically required standards was navigated and conducted through an international multi-centre pre-clinical study, which included the testing of 70,000 DNA samples from the National Institute for Health and Care Research (NIHR) BioResource STRIDES donor cohort (https://bioresource.nihr.ac.uk/) with the Axiom array. The DNA sample collection represented the five main genetic ancestry groups, with a total of 3530 DNA samples from Black people, with 62.9% and 37.1% being of African and Admixed American ancestry, respectively, and which included almost 600 Black people recruited into NIHR BioResource. Several working groups, under joint leadership from NHSE and NHSBT were set up to facilitate and provide governance oversight to the deployment for the selected patient cohorts across the NHS. The high-level work plan included: Governance and Project management; Patient Recruitment and Referral; Information Governance; Operational and Digital Capability working groups. Within these groups were subject matter experts, NHSE/NHSBT representatives, hospital specialists, nurses, blood transfusion scientists, patients and charity representatives. NHSE/NHSBT from England worked with Scotland, Wales and Northern Ireland to ensure access to the test nationally. For successful engagement several communication tools were used. These included: webinars for patients and staff; patient facing website; staff facing website; direct communications to senior leadership in the NHS and hospital senior management; communications through Hospital Update; communications through the National Haemoglobinopathy Panel to the Haemoglobinopathy Coordinating Centres; information leaflets and an educational film tailored to patients; digital assets and posters (QR codes); patient stories and a communications plan (https://www.nhsbt.nhs.uk/what-we-do/clinical-and-research/blood-group-genotyping/). The work aligned with the NHSE Health Inequalities Programme. To date 3890 samples have been referred to NHSBT from 103 hospitals from a population cohort of approximately 18,000. In conclusion, array genotyping for 56 HEA types has become available across the four nations of the United Kingdom to inform the more precise matching for HEA types between patients and donors. HLA typing results are used to determine whether SCD and thalassaemia patients are possibly eligible for curative treatment by stem cell transplantation or gene editing. Further attention is needed to complete test implementation and to maximise technological advances in blood typing at population scale.

Introduction Heparin is a negatively charged, heavily sulfated polysaccharide that is used in medicine as a highly effective anticoagulant. In about 1% of patients who receive unfractionated heparin, heparin-induced thrombocytopenia (HIT) can occur. This is a disorder characterized by an intensely prothrombotic phenotype and thrombocytopenia that typically occurs 5-10 days after heparin exposure. In HIT, heparin binds to positively charged platelet factor 4 (PF4), exposing neoepitopes on PF4 to which heparin-dependent anti-PF4 antibodies can bind. This results in immune complexes which activate platelets through the low affinity Fc receptor, FcγRIIA. Recently, heparin was shown to activate platelets by binding to platelet endothelial aggregation receptor 1 (PEAR1). We therefore hypothesized that heparin itself may have a role in platelet activation in HIT in cooperation with activation through FcγRIIA. Methods We assessed activation of healthy donor washed platelets (2 x 108/mL) to the HIT-like monoclonal antibody (mAb) 5B9 and HIT sera in the presence of heparin by light transmission aggregometry. Experiments were performed in the presence or absence of the PEAR1 nanobody, Nb138, which was raised against the heparin-binding domain of PEAR1. Results Heparin (0.5 IU/mL) but not the HIT-like mAb 5B9 (20 µg/mL) stimulated slow and sustained aggregation of washed platelets with a second, more rapid phase at ~20 min. The response to heparin was blocked by the PEAR1 nanobody, Nb138 (100 nM). In contrast, the combination of heparin and mAb 5B9 stimulated robust aggregation of washed platelets within 15 min (n=7). In 3/7 donors, the response was blocked by Nb138 and was delayed by over 30 seconds in two others. We then tested the effect of Nb138 on two HIT sera that also induce strong activation of platelets in the presence of heparin. Nb138 delayed aggregation to the first HIT serum in all 7 donors. Nb138 blocked aggregation to the second HIT serum in 4 donors and significantly delayed aggregation in 2 others. Conclusions The present results demonstrate that the platelet heparin receptor, PEAR1, potentiates the response to HIT-like mAb and HIT sera and that this is an important variable in diagnostic assays using HIT sera. Further studies are required to establish whether activation of PEAR1 contributes to the pathogenesis of HIT and whether this is due solely to binding of heparin to PEAR1 or to binding of heparin to PEAR1 when present in an immune complex. Acknowledgements RJB is supported by a British Heart Foundation Accelerator Award (AA/18/2/34218) and SJM by a British Heart Foundation Project grant (PG/23/11230). SPW holds a BHF Chair (CH03/003).