C1-inhibitor levels and venous thromboembolism: results from a Mendelian randomization study

Hereditary angioedema is a rare condition, occurring once in 50 000 to 100 000 persons [ [1] Aygören-Pürsün E. Magerl M. Maetzel A. Maurer M. Epidemiology of bradykinin-mediated angioedema: a systematic investigation of epidemiological studies. Orphanet J Rare Dis. 2018; 13: 73 Crossref PubMed Scopus (102) Google Scholar ]. It is characterized by recurrent swellings of cutaneous and submucosal tissue due to inadequate inhibition of bradykinin production caused by inherited C1-inhibitor deficiency. C1-inhibitor controls the complement, fibrinolytic, intrinsic coagulation, and contact systems by inhibition of several serine proteases, including complement C1a, C1r, Mannan-binding lectin serine proteases 1 and 2, plasmin, kallikrein, and coagulation factors XIa and XIIa [ [2] Petersen RS, Fijen LM, Levi M, Cohn DM. Hereditary angioedema: the clinical picture of excessive contact activation. Semin Thromb Hemost. Published online November 23, 2022. https://doi.org/10.1055/s-0042-1758820 Google Scholar ]. D-dimer levels may typically rise during angioedema attacks (presumably due to enhanced plasmin generation), but this increase during angioedema attacks is not associated with an increased thrombotic risk [ [3] Reshef A. Zanichelli A. Longhurst H. Relan A. Hack C.E. Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. Allergy. 2015; 70: 506-513 Crossref PubMed Scopus (60) Google Scholar ]. Several reviews state that hereditary angioedema, also outside the context of elevated D-dimer levels, is not associated with an enhanced risk of venous thromboembolism (VTE). Yet, no sources are available for this claim other than patients’ and physicians’ experience. However, a recent retrospective cohort study examining many potential comorbidities of hereditary angioedema with C1-inhibitor deficiency reported an association between hereditary angioedema and VTE [ [4] Sundler Björkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema-A population-based cohort study. Clin Transl Allergy. 2022; 12e12135 Crossref PubMed Scopus (11) Google Scholar , [5] Grover S.P. Sundler Björkman L. Egesten A. Moll S. Mackman N. Hereditary angioedema is associated with an increased risk of venous thromboembolism. J Thromb Haemost. 2022; 20: 2703-2706 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar ]. Notably, these findings could be confounded by the indication and misclassification of VTE [ [6] Petersen R.S. Fijen L.M. Cohn D.M. “Hereditary angioedema is associated with an increased risk of venous thromboembolism”: comment from Petersen et al. J Thromb Haemost. 2023; 21: 179 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar ]. It is difficult to investigate this finding further with prospective cohort studies given the extreme rarity of hereditary angioedema. If hereditary angioedema is indeed associated with VTE, one could postulate that less pronounced variations in C1-inhibitor levels could also be associated with VTE risk. Mendelian randomization (MR) is a suitable method to further investigate the potential causal association between C1-inhibitor levels and VTE. MR uses genetic variation as an instrument to assess the potential causal nature of an exposure and an outcome. The advantage of an MR approach is that it is much less affected by the risks of confounding and reverse causation that typically plague observational studies. A comprehensible overview of how MR works has been written by Davies et al. [ [7] Davies N.M. Holmes M.V. Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362: k601 Crossref PubMed Scopus (1049) Google Scholar ]. In order to explore the causality between lower C1-inhibitor levels and VTE, we performed an MR study.