Complexes of platelet factor 4 and heparin activate Toll-like receptor 4 Journal Article

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Authors: Prechel, M. M.; Walenga, J. M.
Article Title: Complexes of platelet factor 4 and heparin activate Toll-like receptor 4
Abstract: BACKGROUND: In some patients, the anticoagulant heparin elicits formation of antibodies that can cause the life and/or limb-threatening syndrome known as heparin-induced thrombocytopenia (HIT). HIT antibodies target complexes formed at specific molar ratios of heparin and platelet factor 4 (PF4). The unpredictable occurrence and the mechanism of this atypical immune response to PF4:heparin complexes are poorly understood. OBJECTIVE: We investigated whether complexes formed at specific PF4:heparin ratios (PHRs) might resemble molecular patterns associated with host defense responses. METHODS: We used an in vitro cytokine release assay to determine whether defined PHRs caused cytokine release from human whole blood. Lipopolysaccharide (LPS) was used as a positive assay control, and some experiments included antibodies to block Toll-like receptor 4 (TLR4). RESULTS: PF4:heparin complexes caused release of the biomarker interleukin 8 in whole blood, and the level of response varied with the stoichiometric ratio of PF4 to heparin. The profile of response to LPS and to PF4:heparin complexes varied among blood donors, and the interleukin 8 response to both LPS and PF4:heparin was inhibited by TLR4-blocking antibodies. CONCLUSIONS: Specific PF4-heparin complexes can elicit a TLR4-mediated response, suggesting that these complexes can mimic a pathogen-associated molecular pattern, and supporting the suggestion that the HIT immune response represents a misdirected host defense mechanism.
Journal Title: Journal of thrombosis and haemostasis : JTH
Volume: 13
Issue: 4
ISSN: 1538-7836; 1538-7836
Publisher: International Society on Thrombosis and Haemostasis  
Date Published: 2015
Start Page: 665-70
Language: ENG
DOI/URL:

10.1111/jth.12847
Notes: LR: 20150213; CI: (c) 2015; JID: 101170508; OTO: NOTNLM; 2014/06/26 [received]; 2015/01/10 [accepted]; aheadofprint