Augmentation of immunothrombosis as a key mechanism underlying JAK inhibition associated hypercoagulability in rheumatoid arthritis

David, P; Macleod, T; Altaie, A; Shi, Y; Abacar, K; Giryes, S; Santos, GM; Ganguly, P; Harland, M; Wong, C; Scarsbrook, A; Emery, P; Mankia, K; Dass, S; Di Matteo, A; Saleem, B; Duval, C; Ariëns, R; McGonagle, D

doi:10.1016/j.ard.2025.09.002

Rheumatoid arthritis

Augmentation of immunothrombosis as a key mechanism underlying JAK inhibition associated hypercoagulability in rheumatoid arthritis

Ann Rheum DisPublished 26 Sep 2025Mechanistic study

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Authors' conclusion

Immunothrombosis offers a novel explanation for JAKi-associated VTE in RA.

Study context

Population: Patients with rheumatoid arthritis (RA) and healthy controls; patients with RA with JAK-associated pulmonary embolism

Comparison: Peripheral blood leukocytes (PBLs) treated with JAKi before TLR4 or TLR3) stimulation vs agonist alone
Outcome: Clot formation (plasma turbidity) with conditioned media from PBLs treated with LPS and tofacitinib vs LPS alone, and immunothrombosis mechanisms

Methodological detailsin vitro, plasma turbidity assays, bulk RNA sequencing

In vitro
Plasma turbidity assays
Bulk RNA sequencing

Main finding

As reported in the abstract

RA patients with JAK-associated PE: interstitial changes compatible with immunothrombosis

4 of 6

67%

Reference

Authors: David P, Macleod T, Altaie A, Shi Y, Abacar K, Giryes S, et al.
All 19 authors
David P, Macleod T, Altaie A, Shi Y, Abacar K, Giryes S, Santos GM, Ganguly P, Harland M, Wong C, Scarsbrook A, Emery P, Mankia K, Dass S, Di Matteo A, Saleem B, Duval C, Ariëns R, McGonagle D
Journal: Annals of the Rheumatic Diseases
Published: 26 Sep 2025
DOI: 10.1016/j.ard.2025.09.002
PubMed: 41006174

Topic: Rheumatoid arthritis

Comparison

PBLs treated with JAKi before TLR4 (LPS) or TLR3 (poly(I:C)) stimulation vs agonist alone

Group definitions

RA: PBLs isolated from patients with RA
Healthy controls: PBLs isolated from healthy controls

Key notes

Conditioned media from PBLs treated with LPS and tofacitinib significantly accelerated clot formation vs LPS alone; tissue factor pathway dependent
Accompanied by elevations in immunothrombotic cytokines, incl. TNF α, IL-1β and IL-6

More notes

PBLs from patients with active RA: significantly greater immunothrombotic potential vs low disease activity, despite comparable baseline cytokine levels
RNA sequencing in tofacitinib/LPS-treated PBLs: activation of Nuclear Factor (NF)-κB pathways, increased tissue factor expression, reduced anticoagulant factors such as protein S
JAK1/tyrosine kinase 2-dependent effect underscored increased thrombosis; selective JAK3 inhibition did not reproduce the prothrombotic effects

Original publication

Augmentation of immunothrombosis as a key mechanism underlying JAK inhibition associated hypercoagulability in rheumatoid arthritis. Ann Rheum Dis. Published 26 September 2025. doi:10.1016/j.ard.2025.09.002

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