{"doi":"10.1161/atvbaha.124.321178","title":"HRG to the Rescue","abstract":"Polyphosphate (polyP) consists of linear polymers of inorganic phosphates and is widespread throughout biology.Each internal phosphate in polyP carries a -1 charge, so the overall polymer is intensely anionic.Although the biological properties of polyP have been studied most extensively in unicellular organisms, roles for polyP in mammals have started coming to light in recent years.In 2004, polyP was revealed to be a major constituent of platelet dense granules and to be secreted in significant quantities upon platelet activation. 1 PolyP was subsequently reported to be strongly procoagulant, 2 acting at multiple points in the clotting cascade, including: triggering clotting via the contact pathway; 2, 3 accelerating the activation of factor (F) V and FXI; 4, 5 enhancing fibrin clot structure and slowing fibrinolysis; 6, 7 and abrogating TFPI's anticoagulant activity. 2,8 olyP is also secreted by activated mast cells and is abundant in many microorganisms, so there are multiple potential sources for polyP exposure in vivo. 9eviously, injecting large quantities of polyP intravenously into mice was reported to lead to rapid death, which was attributed to polyP's ability to trigger widespread thrombosis. 3n this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Malik and colleagues 10 report findings that challenge the idea that thrombosis is responsible for rapid lethality from high-dose intravenous polyP.They furthermore report that histidine-rich glycoprotein (HRG) protects against polyP-induced death.HRG is a 75-kDa glycoprotein that is quite abundant in plasma, circulating at 1 to 3 M and acting as a negative acute-phase reactant. 11HRG is implicated in multiple roles in vivo, including regulating blood coagulation and fibrinolysis, as well as exhibiting both proand antiangiogenic effects.Furthermore, HRG has been implicated in immune modulation/ antimicrobial action and cancer progression.To carry out its multiple functions, perhaps unsurprisingly HRG has many known ligands (Figure).In fact, HRG interacts with so many targets in vivo that it has been termed the \"the Swiss Army knife of mammalian plasma.\" 11A strong connection between HRG and polyP was previously established when, relative to wild-type mice, HRG-deficient mice exhibited exacerbated thrombosis following","journal":"Arteriosclerosis Thrombosis and Vascular Biology","year":2024,"id":491254,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":109638,"name":"James H. Morrissey","orcid":"0000-0002-1570-1569","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:08:41.211111Z","pmid":"38924441","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}