{"doi":"10.1002/art.70001","title":"Prothrombotic Activation of Platelet Pannexin‐1 Channels in Antiphospholipid Syndrome","abstract":"OBJECTIVE: ATP is released from platelets through both degranulation and pannexin-1 (PANX1) channels. ATP then activates P2X receptors to amplify platelet activation via calcium-dependent signaling. The objective of this study was to evaluate the role of platelet PANX1 channels in the pathophysiology of antiphospholipid syndrome (APS), an acquired thromboinflammatory disorder characterized by platelet-activating antiphospholipid antibodies. METHODS: Extracellular ATP release was measured in platelets isolated from patients with persistently positive antiphospholipid antibodies (n = 36), patients with systemic lupus erythematosus (n = 10), and healthy controls (n = 16). In some assays, purified platelets were pretreated with the PANX inhibitor carbenoxolone. Platelet signaling, P-selectin exposure, and aggregation were assessed. RESULTS: Basal ATP release was significantly higher in APS platelets than in controls (P < 0.0001) and normalized in the presence of carbenoxolone (P = 0.03). Carbenoxolone also reduced platelet ATP release and surface P-selectin expression induced by thrombin (P = 0.002 and P = 0.02, respectively) and convulxin (P = 0.0001 and P = 0.0012). Control platelets stimulated with IgG from patients with APS demonstrated enhanced phosphorylation of PANX1 at tyrosine-308 (P = 0.03), which was accompanied by enhanced ATP release (P = 0.0004). APS IgG boosted ADP-induced aggregation (P = 0.0011), which was reduced by carbenoxolone (P = 0.0007). The calcium chelator BAPTA-AM decreased APS IgG-mediated ATP release (P = 0.03), P-selectin expression (P = 0.0005), and aggregation (P = 0.0007). Desensitizing P2X1 receptors with α,β-MeATP decreased APS IgG-induced P-selectin expression (P = 0.0002) and aggregation (P = 0.01). CONCLUSION: PANX1 channels appear to be important mediators of platelet activation in APS. Agents that block PANX1 may restore platelet homeostasis and limit thrombosis without impairing hemostasis.","journal":"Arthritis & Rheumatology","year":2025,"id":583827,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1042718,"name":"Somanathapura K. NaveenKumar","orcid":"0000-0002-8991-5041","position":1,"is_corresponding":false},{"id":105691,"name":"Srilakshmi Yalavarthi","orcid":"0009-0005-9128-572X","position":2,"is_corresponding":false},{"id":1406874,"name":"Kavya Sugur","orcid":null,"position":3,"is_corresponding":false},{"id":1406872,"name":"Thalia G. Newman","orcid":null,"position":4,"is_corresponding":false},{"id":647125,"name":"Claire K. Hoy","orcid":null,"position":5,"is_corresponding":false},{"id":1011680,"name":"Cyrus Sarosh","orcid":"0009-0004-5371-1700","position":6,"is_corresponding":false},{"id":330749,"name":"Jordan K. Schaefer","orcid":"0000-0002-7166-386X","position":7,"is_corresponding":false},{"id":902802,"name":"Ajay Tambralli","orcid":"0000-0001-9056-9513","position":8,"is_corresponding":false},{"id":105695,"name":"Jacqueline A. Madison","orcid":"0000-0003-1745-8133","position":9,"is_corresponding":false},{"id":259811,"name":"Yu Zuo","orcid":"0000-0001-6721-7755","position":10,"is_corresponding":false},{"id":1235830,"name":"Fernanda Andrade Orsi","orcid":"0000-0002-7908-9073","position":11,"is_corresponding":false},{"id":277616,"name":"Michael Holinstat","orcid":"0000-0001-5100-1933","position":12,"is_corresponding":false},{"id":105701,"name":"Jason S. Knight","orcid":"0000-0003-0995-9771","position":13,"is_corresponding":false},{"id":1406439,"name":"Bruna de Moraes Mazetto","orcid":"0000-0002-8778-4658","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:59:07.970345Z","pmid":"41327823","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":[]}