Antiphospholipid syndrome is a platelet factor 4–centric immunothrombotic disorder
Abstract
Antiphospholipid syndrome (APS) is an immunothrombotic disorder, frequently attributed to autoantibodies that bind β2-glycoprotein I (β2GPI). A study showed that the platelet-specific chemokine, platelet factor 4 (PF4), binds to β2GPI, enhancing recognition of β2GPI by APS antibodies. APS antibodies induce the release of neutrophil extracellular traps (NETs), webs of decondensed chromatin that bind both PF4 and β2GPI. We propose that PF4 bridges β2GPI to NETs (and other PF4-targeted polyanions), leading to the formation of prothrombotic PF4:β2GPI:NET immunotargets in APS. Dynamic light-scattering studies of isolated immunoglobulin G from 4 patients with triple-positive APS show formation of PF4:β2GPI:NET complexes that bind APS antibodies. NETs released in a microfluidic system bound β2GPI, but only in the presence of PF4, forming a multimolecular APS antigenic target. Whole blood infused through a photochemically injured, endothelium-lined microfluidic channel formed platelet-, fibrin-, and complement-rich thrombi that bound APS antibodies only in the presence of PF4. Thrombi were reduced in size if either ADAMTS13 or DNase I was infused. In a murine APS model, wild-type and transgenic mice expressing human PF4 (hPF4) ± FcγRIIA developed more intense neutrophil rolling along veins and more extensive thrombus formation after laser injury to cremaster arterioles and venules, whereas mice lacking PF4 did not. Three antigenically distinct anti-hPF4 monoclonal antibodies blocked thrombosis in vitro and neutrophil rolling and thrombosis in vivo. Our studies provide new insights into the basis of APS that has mechanistic parallels to other known PF4 immunothrombotic disorders and offer potential diagnostic and nonanticoagulant therapeutic strategies for clinical management.
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BibTeX
@article{field2026antiphospholipid,
title = {{Antiphospholipid syndrome is a platelet factor 4–centric immunothrombotic disorder}},
author = {Conroy Field and Amrita Sarkar and Khalil Bdeir and Hyunjun Kim and Santosh Yadav and Jenna Oberg and Guohua Zhou and Steven Jiang and Manas Gumedelli and Keith Mccrae and Gowthami Arepally and Jérôme Rollin and Yves Gruel and Thomas Ortel and M. Anna Kowalska and Douglas Cines and Kandace Gollomp and Lubica Rauova and Mortimer Poncz},
journal = {Blood},
year = {2026},
month = jul,
doi = {10.1182/blood.2025032358},
url = {https://hal.science/hal-05849013v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Antiphospholipid syndrome is a platelet factor 4–centric immunothrombotic disorder
AU - Conroy Field
AU - Amrita Sarkar
AU - Khalil Bdeir
AU - Hyunjun Kim
AU - Santosh Yadav
AU - Jenna Oberg
AU - Guohua Zhou
AU - Steven Jiang
AU - Manas Gumedelli
AU - Keith Mccrae
AU - Gowthami Arepally
AU - Jérôme Rollin
AU - Yves Gruel
AU - Thomas Ortel
AU - M. Anna Kowalska
AU - Douglas Cines
AU - Kandace Gollomp
AU - Lubica Rauova
AU - Mortimer Poncz
PY - 2026
DA - 2026/07/02
JO - Blood
DO - 10.1182/blood.2025032358
UR - https://hal.science/hal-05849013v1
AB - Antiphospholipid syndrome (APS) is an immunothrombotic disorder, frequently attributed to autoantibodies that bind β2-glycoprotein I (β2GPI). A study showed that the platelet-specific chemokine, platelet factor 4 (PF4), binds to β2GPI, enhancing recognition of β2GPI by APS antibodies. APS antibodies induce the release of neutrophil extracellular traps (NETs), webs of decondensed chromatin that bind both PF4 and β2GPI. We propose that PF4 bridges β2GPI to NETs (and other PF4-targeted polyanions), leading to the formation of prothrombotic PF4:β2GPI:NET immunotargets in APS. Dynamic light-scattering studies of isolated immunoglobulin G from 4 patients with triple-positive APS show formation of PF4:β2GPI:NET complexes that bind APS antibodies. NETs released in a microfluidic system bound β2GPI, but only in the presence of PF4, forming a multimolecular APS antigenic target. Whole blood infused through a photochemically injured, endothelium-lined microfluidic channel formed platelet-, fibrin-, and complement-rich thrombi that bound APS antibodies only in the presence of PF4. Thrombi were reduced in size if either ADAMTS13 or DNase I was infused. In a murine APS model, wild-type and transgenic mice expressing human PF4 (hPF4) ± FcγRIIA developed more intense neutrophil rolling along veins and more extensive thrombus formation after laser injury to cremaster arterioles and venules, whereas mice lacking PF4 did not. Three antigenically distinct anti-hPF4 monoclonal antibodies blocked thrombosis in vitro and neutrophil rolling and thrombosis in vivo. Our studies provide new insights into the basis of APS that has mechanistic parallels to other known PF4 immunothrombotic disorders and offer potential diagnostic and nonanticoagulant therapeutic strategies for clinical management.
SN - 0006-4971
SN - 1528-0020
ER -