Abstract
Objective: Coagulation and fibrinolysis are interrelated with the expression of vascular endothelial growth factor (VEGF), which frequently is increased in axial spondyloarthritis (axSpA). We tested whether (i) α2-antiplasmin (A2AP) Arg6Trp, (ii) fibrinogen, factor XIII A-subunit or B-subunit genotypes are associated with VEGF levels and assessed whether the known association between elevated VEGF and radiographic spinal progression in axSpA depends on genetic background. Methods: One hundred and eighty-six axSpA patients from the German Spondyloarthritis Inception Cohort were genotyped, characterized for VEGF levels, and statistically analyzed. The association between VEGF and radiographic spinal progression was assessed in dependence on genetic background in stratified analyses. Results: A2AP 6Trp carriage was associated with VEGF elevation (OR: 2.37, 95% CI: 1.06–5.29) and VEGF levels (6Trp, 455 ± 334 pg/mL; 6Arg/Arg, 373 ± 293 pg/mL; p < 0.008). Association between elevated VEGF and radiographic spinal progression in axSpA (OR: 3.11, 95% CI: 1.02–8.82) depended remarkably on the fibrinogen (FGA) genotype. When considering axSpA patients with elevated VEGF, in FGA rs6050A>G wild types, 42.1% of patients (8 of 19) progressed, while in G-allele carriers, no radiographic progression happened (0 of 13) (p < 0.04). Conclusions: The A2AP Arg6Trp genotype seems to influence VEGF levels in axSpA. The predictive value of VEGF elevations in respect of radiographic spinal progression in axSpA depends on FGA genotypes.
Highlights
There is a complex interrelation between coagulation, fibrinolysis, inflammation, and wound healing [1,2,3,4,5]
vascular endothelial growth factor (VEGF) is central in angiogenesis and tissue repair, and it contributes to inflammatory processes [8]
It is currently unknown whether this phenomenon is related to a reduced inhibition of plasmin, hereby increasing VEGF expression via the aforementioned plasminogen/thrombomodulin signaling or whether a>]. α2-Antiplasmin (A2AP) itself directly is involved in VEGF regulation
Summary
There is a complex interrelation between coagulation, fibrinolysis, inflammation, and wound healing [1,2,3,4,5]. Afterwards, proteins of the coagulation system as well as peptide fragments generated during coagulation and fibrinolysis allow for transendothelial leukocyte migration [6,7], and they support and modulate angiogenesis necessary for wound healing [1] In this context, vascular endothelial growth factor (VEGF) plays an important role as a decisive regulator of vascular permeability, angiogenesis, inflammation, and tissue repair [8]. (ii) Those genotype constellations of fibrinogen and factor XIII, which are known or assumed to be related to lower fibrin clot densities, i.e., reduced crosslinking and higher susceptibility to fibrinolysis, are associated with increased VEGF levels. (iii) we exploratorily tested whether the known association between elevated VEGF levels and radiographic spinal progression in axSpA [15] would depend on genotypes related to fibrinogen synthesis, fibrin clot formation, or fibrinolysis
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