Janus kinase inhibitors enhance prostanoid biosynthesis in human whole blood in vitro: implications for cardiovascular side effects and prevention strategies

Objectives: Janus kinase inhibitors (JAKis) effectively treat chronic inflammatory diseases but are associated with cardiovascular side effects through unknown mechanisms. This study aimed to investigate the impact of JAKis on prothrombotic thromboxane (TX)A2 production in human whole blood (WB) as a possible mechanism. Methods: We evaluated the effects of 4 JAKis— tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)—on TXB2 biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA2 generation. Additionally, we assessed the impact of these JAKis on TXB2 production in WB from healthy subjects, patients with systemic lupus erythematosus (SLE), and treatment-naïve patients with axial spondyloarthritis (axSpA) after 24-hour lipopolysaccharide (LPS) stimulation, as a marker of platelet and leukocyte prostanoid biosynthesis. Results: All JAKis increased serum TXB2 production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB2 production in healthy subjects (HSs) (42% ± 33%, n = 17), patients with SLE (57% ± 39%, n = 12), and patients with axSpA (31% ± 23%, n = 15). Baricitinib (1 μM) also increased TXB2 in HSs (30% ± 22%, n = 10). Upadacitinib showed a trend towards increased TXB2 (46% ± 40%, n = 7), while filgotinib did not (21% ± 19%, n = 7). Aspirin (100 μM) almost completely reduced serum TXB2 in the presence of all JAKis. Conclusions: The enhanced biosynthesis of TXA2 in platelets, with a minor contribution from leukocytes, may contribute to the increased cardiovascular risk associated with JAKis. Low-dose aspirin may offer a protective effect, warranting further investigations.