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. 2024 Mar 12;8(5):1295-1304.
doi: 10.1182/bloodadvances.2023011937.

The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-associated vasculitis

Matthias H Busch  1   2 , Renée Ysermans  2 , Joop P Aendekerk  2 , Sjoerd A M E G Timmermans  1   2 , Judith Potjewijd  1 , Jan G M C Damoiseaux  3 , Henri M H Spronk  2 , Hugo Ten Cate  2   4 , Chris P Reutelingsperger  2 , Magdolna Nagy  2 , Pieter van Paassen  1   2
Affiliations

The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-associated vasculitis

Matthias H Busch et al. Blood Adv. .

Abstract

The risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.

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Conflict of interest statement

Conflict-of-interest disclosure: H.t.C. and H.M.H.S. received funding for research from Bayer and Pfizer, and are stakeholders in Coagulation Profile. H.t.C. is a consultant for Alveron and has served on advisory boards for Bayer, Pfizer, Daiichi, Leo, Gilead, Novostia, Galapagos, Viatris and AstraZeneca. C.P.R. is a co-inventor of a patent describing use of low anticoagulant heparins in sepsis and owned by Maastricht University, and is a scientific consultant for Matisse Pharmaceuticals and Annexin Pharmaceuticals. S.A.M.E.G.T. participated in TMA expert meetings and received travel/speaker fees from Alexion Pharmaceuticals Inc (AstraZeneca). The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Correlation matrix between the different coagulation factors and D-dimers in patients with active AAV. Spearman rank correlation coefficients were used. Blue indicates a positive correlation, and red indicates a negative correlation. ∗Indicates a P value <.05. α1AT, α1-antitrypsin; AT, antithrombin; C1Inh, C1 esterase inhibitor; FVIIa, activated FVII; FXa, activated factor X; FXIa, activated factor XI; FXIIa, activated factor XII; FIXa, activated factor IX; T:AT, thrombin in complex with antithrombin.
See this image and copyright information in PMC

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