To the Editor, Hereditary angioedema (HAE) is a congenital disorder primarily caused by mutations in the SERPING1 gene that lead to reduced plasma levels or functional activity of C1‐inhibitor (C1INH).1.Busse P.J. Christiansen S.C. Hereditary angioedema.N Engl J Med. 2020; 382: 1136-1148https://doi.org/10.1056/NEJMra1808012Crossref PubMed Scopus (136) Google Scholar A rare subtype of HAE with normal C1INH (HAE–nC1INH) can be caused by mutations in several other genes including those encoding coagulation factor XII (FXII), plasminogen, and high molecular weight kininogen.2.Veronez C.L. Csuka D. Sheikh F.R. Zuraw B.L. Farkas H. Bork K. The expanding spectrum of mutations in hereditary angioedema.J Allergy Clin Immunol Pract. 2021; 9: 2229-2234https://doi.org/10.1016/j.jaip.2021.03.008Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar HAE is a relatively rare disorder with an estimated prevalence of approximately 1 in 50 000 in the general population.1.Busse P.J. Christiansen S.C. Hereditary angioedema.N Engl J Med. 2020; 382: 1136-1148https://doi.org/10.1056/NEJMra1808012Crossref PubMed Scopus (136) Google Scholar Patients with HAE experience episodes of bradykinin‐induced swelling that can present as cutaneous angioedema or severe abdominal pain.1.Busse P.J. Christiansen S.C. Hereditary angioedema.N Engl J Med. 2020; 382: 1136-1148https://doi.org/10.1056/NEJMra1808012Crossref PubMed Scopus (136) Google Scholar HAE patients are at risk of laryngeal episodes that, although rare, can lead to fatal asphyxiation.1.Busse P.J. Christiansen S.C. Hereditary angioedema.N Engl J Med. 2020; 382: 1136-1148https://doi.org/10.1056/NEJMra1808012Crossref PubMed Scopus (136) Google Scholar While angioedema represents the primary clinical manifestation of this disorder it is possible that patients with HAE are at increased risk of developing other comorbidities. A recently published retrospective registry‐based study evaluated the incidence of comorbidities in a cohort of 239 individuals with a confirmed laboratory diagnosis of HAE compared to that in a control cohort of 2383 individuals in Sweden (approved by the Swedish Ethical Review Authority no. 2019‐01623).3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar Individuals with HAE caused by low plasma levels of C1INH or impaired plasma C1INH function were recruited through contacting treating physicians and an age‐, sex‐, and country of residence–matched control cohort assembled.3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar Validated health records that provided International Classification of Diseases 10th revision (ICD‐10)–coded annotations of inpatient and outpatient diagnoses were used to identify comorbidities in the case and control cohorts.3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar This study demonstrated that patients with HAE had an increased risk of autoimmune disease and cardiovascular disease.3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar Of particular interest, HAE patients had a significant increased risk of ICD‐based diagnoses of a subset of venous thromboembolic events (odds ratio [OR] 4.20, 95% confidence interval [CI] 2.47–7.19).3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar This category of venous thromboembolism (VTE) included ICD‐10 based codings of thrombophlebitis, portal vein thrombosis, and other VTE and included deep vein thrombosis (DVT). Trends toward increased ORs for DVT and pulmonary embolism (PE) were also observed. HAE patients were found to have a significantly increased risk of a subset of arterial thromboembolic events (OR 6.74, 95% CI 2.13–24.96).3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar This category of arterial thromboembolism (ATE) included ICD‐10–based codings of other arterial thrombosis and embolism not including those of the coronary, carotid, or cerebral vessels. However, no changes in the ORs for myocardial infarction of cerebral ischemia were observed. To evaluate the broader impact of HAE on thrombotic pathologies, we evaluated the association between HAE and either composite VTE or composite ATE using data from the previously published registry study.3.Sundler Bjorkman L. Persson B. Aronsson D. Skattum L. Nordenfelt P. Egesten A. Comorbidities in hereditary angioedema–a population‐based cohort study.Clin Transl Allergy. 2022; 12https://doi.org/10.1002/clt2.12135Crossref PubMed Scopus (4) Google Scholar Composite VTE included ICD‐10–based codings of DVT, PE, thrombophlebitis, portal vein thrombosis, and other VTE. Composite ATE included ICD‐10–based codings of cerebral infarction, ischemic heart disease, and other ATE. Based on observations made in the original study we hypothesized that patients with HAE would retain a significantly increased risk of composite VTE but not composite ATE. Our analysis revealed that individuals with HAE had a significantly increased risk of composite VTE compared to controls (OR 3.59, 95% CI 2.17–5.84; Figure 1A). In contrast, individuals with HAE did not have a significantly increased risk of composite ATE (OR 1.3, 95% CI 0.81–2.09; Figure 1B). To explore the temporal relationship between HAE and risk of thrombotic pathologies cumulative incidence curves for both composite VTE and composite ATE were generated. HAE patients had a significantly increased cumulative incidence of composite VTE (p < .001; Figure 2A). In contrast, no significant difference in cumulative incidence of composite ATE (p = .8) was observed between HAE patients and controls (Figure 2B). Taken together this data indicates that patients with HAE are at increased risk of VTE but not ATE.FIGURE 2Cumulative incidence of composite venous thromboembolism (VTE) and arterial thromboembolism (ATE). Cumulative incidence of (A) composite VTE and (B) composite ATE events in cases with hereditary angioedema (HAE) vs. controls represented as a percentage of the total population. p values for log rank tests are provided.View Large Image Figure ViewerDownload Hi-res image Download (PPT) It is interesting to consider how reduced C1INH activity might result in an increased risk of VTE. Although C1INH was originally described as an inhibitor of complement C1 it is a multifunctional serine protease inhibitor.4.Davis 3rd, A.E. Mejia P. Lu F. Biological activities of C1 inhibitor.Mol Immunol. 2008; 45: 4057-4063https://doi.org/10.1016/j.molimm.2008.06.028Crossref PubMed Scopus (196) Google Scholar C1INH is a potent inhibitor of plasma kallikrein, which spans the kallikrein kinin pathway and intrinsic coagulation pathway, and the intrinsic coagulation pathway components activated FXII and activated factor XI.4.Davis 3rd, A.E. Mejia P. Lu F. Biological activities of C1 inhibitor.Mol Immunol. 2008; 45: 4057-4063https://doi.org/10.1016/j.molimm.2008.06.028Crossref PubMed Scopus (196) Google Scholar, 5.Grover S.P. Mackman N. Anticoagulant SERPINs: endogenous regulators of hemostasis and thrombosis.Front Cardiovasc Med. 2022; 9https://doi.org/10.3389/fcvm.2022.878199Crossref PubMed Scopus (5) Google Scholar Consistent with the function of C1INH as a critical negative regulator of the intrinsic coagulation pathway, patients with HAE in remission have significantly increased plasma levels of the coagulation biomarkers prothrombin fragment 1 + 2, thrombin–antithrombin (TAT) complexes, and D‐dimer compared to healthy controls.6.Csuka D. Veszeli N. Imreh E. et al.Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1‐inhibitor deficiency.Orphanet J Rare Dis. 2015; 10: 132https://doi.org/10.1186/s13023-015-0351-5Crossref PubMed Scopus (33) Google Scholar, 7.Cugno M. Cicardi M. Bottasso B. et al.Activation of the coagulation cascade in C1‐inhibitor deficiencies.Blood. 1997; 89: 3213-3218Crossref PubMed Google Scholar, 8.Cugno M. Zanichelli A. Bellatorre A.G. Griffini S. Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1‐inhibitor deficiency.Allergy. 2009; 64: 254-257https://doi.org/10.1111/j.1398-9995.2008.01859.xCrossref PubMed Scopus (74) Google Scholar The plasma level of these coagulation biomarkers are further increased in HAE patients during acute attacks compared to HAE patients in remission.6.Csuka D. Veszeli N. Imreh E. et al.Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1‐inhibitor deficiency.Orphanet J Rare Dis. 2015; 10: 132https://doi.org/10.1186/s13023-015-0351-5Crossref PubMed Scopus (33) Google Scholar, 7.Cugno M. Cicardi M. Bottasso B. et al.Activation of the coagulation cascade in C1‐inhibitor deficiencies.Blood. 1997; 89: 3213-3218Crossref PubMed Google Scholar, 8.Cugno M. Zanichelli A. Bellatorre A.G. Griffini S. Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1‐inhibitor deficiency.Allergy. 2009; 64: 254-257https://doi.org/10.1111/j.1398-9995.2008.01859.xCrossref PubMed Scopus (74) Google Scholar Patients with HAE in remission had significantly shortened activated partial thromboplastin time (APTT) but not prothrombin time compared to controls.6.Csuka D. Veszeli N. Imreh E. et al.Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1‐inhibitor deficiency.Orphanet J Rare Dis. 2015; 10: 132https://doi.org/10.1186/s13023-015-0351-5Crossref PubMed Scopus (33) Google Scholar The selective shortening of APTT is consistent with a disruption in the regulation of the intrinsic coagulation pathway. Importantly, shortened APTT, elevated plasma D‐dimer, and elevated plasma TAT complexes have all previously been associated with an increased risk of VTE.9.Zakai N.A. Ohira T. White R. Folsom A.R. Cushman M. Activated partial thromboplastin time and risk of future venous thromboembolism.Am J Med. 2008; 121: 231-238https://doi.org/10.1016/j.amjmed.2007.10.025Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 10.Tripodi A. Chantarangkul V. Martinelli I. Bucciarelli P. Mannucci P.M. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism.Blood. 2004; 104: 3631-3634https://doi.org/10.1182/blood-2004-03-1042Crossref PubMed Scopus (159) Google Scholar, 11.Andreescu A.C. Cushman M. Rosendaal F.R. D‐dimer as a risk factor for deep vein thrombosis: the Leiden thrombophilia study.Thromb Haemost. 2002; 87: 47-51Crossref PubMed Scopus (67) Google Scholar, 12.Hansen E.S. Rinde F.B. Edvardsen M.S. et al.Elevated plasma D‐dimer levels are associated with risk of future incident venous thromboembolism.Thromb Res. 2021; 208: 121-126https://doi.org/10.1016/j.thromres.2021.10.020Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 13.Ginsberg J.S. Brill‐Edwards P. Panju A. et al.Pre‐operative plasma levels of thrombin‐antithrombin III complexes correlate with the development of venous thrombosis after major hip or knee surgery.Thromb Haemost. 1995; 74: 602-605Crossref PubMed Scopus (36) Google Scholar, 14.Cofrancesco E. Cortellaro M. Corradi A. Ravasi F. Bertocchi F. Coagulation activation markers in the prediction of venous thrombosis after elective hip surgery.Thromb Haemost. 1997; 77: 267-269Crossref PubMed Scopus (50) Google Scholar There may also be a role for complement activation in the VTE phenotype observed in patients with HAE. In addition to being an inhibitor of complement C1 of the classical pathway, C1INH is also an inhibitor of mannose‐associated serine protease (MASP) 1 and MASP2 of the lectin pathway.15.Presanis J.S. Hajela K. Ambrus G. Gal P. Sim R.B. Differential substrate and inhibitor profiles for human MASP‐1 and MASP‐2.Mol Immunol. 2004; 40: 921-929https://doi.org/10.1016/j.molimm.2003.10.013Crossref PubMed Scopus (117) Google Scholar Epidemiological studies have found high plasma levels of complement factors MASP2, C3, and C5 to be associated with an increased risk of VTE.16.Damoah C.E. Snir O. Hindberg K. et al.High levels of complement activating enzyme MASP‐2 are associated with the risk of future incident venous thromboembolism.Arterioscler Thromb Vasc Biol. 2022; 42: 1186-1197https://doi.org/10.1161/ATVBAHA.122.317746Crossref PubMed Scopus (1) Google Scholar, 17.Norgaard I. Nielsen S.F. Nordestgaard B.G. Complement C3 and high risk of venous thromboembolism: 80517 individuals from the Copenhagen general population study.Clin Chem. 2016; 62: 525-534https://doi.org/10.1373/clinchem.2015.251314Crossref PubMed Scopus (36) Google Scholar, 18.Skjeflo E.W. Braekkan S.K. Ludviksen J.K. et al.Elevated plasma concentration of complement factor C5 is associated with risk of future venous thromboembolism.Blood. 2021; 138: 2129-2137https://doi.org/10.1182/blood.2021010822Crossref PubMed Scopus (6) Google Scholar Importantly, patients with HAE typically have low plasma levels of functional complement factor C4, likely caused by aberrant activation of the complement system and consumption of this factor.19.Aabom A. Bygum A. Koch C. Complement factor C4 activation in patients with hereditary angioedema.Clin Biochem. 2017; 50: 816-821https://doi.org/10.1016/j.clinbiochem.2017.04.007Crossref PubMed Scopus (22) Google Scholar The advent of C1INH replacement therapies, including purified plasma C1INH and recombinant C1INH preparations, represented an important advance in the treatment of patients with HAE.20.Henry Li H. Riedl M. Kashkin J. Update on the use of C1‐esterase inhibitor replacement therapy in the acute and prophylactic treatment of hereditary angioedema.Clin Rev Allergy Immunol. 2019; 56: 207-218https://doi.org/10.1007/s12016-018-8684-1Crossref PubMed Scopus (24) Google Scholar, 21.Banerji A. Riedl M.A. Craig T.J. Radojicic C. Insights into the treatment burden of hereditary angioedema in the evolving treatment landscape.Allergy Asthma Proc. 2021; 42: S1-S3https://doi.org/10.2500/aap.2021.42.210018Crossref PubMed Scopus (5) Google Scholar The use of these therapies in the acute or prophylactic setting has been shown to be effective in reducing the severity and frequency of attacks.20.Henry Li H. Riedl M. Kashkin J. Update on the use of C1‐esterase inhibitor replacement therapy in the acute and prophylactic treatment of hereditary angioedema.Clin Rev Allergy Immunol. 2019; 56: 207-218https://doi.org/10.1007/s12016-018-8684-1Crossref PubMed Scopus (24) Google Scholar, 21.Banerji A. Riedl M.A. Craig T.J. Radojicic C. Insights into the treatment burden of hereditary angioedema in the evolving treatment landscape.Allergy Asthma Proc. 2021; 42: S1-S3https://doi.org/10.2500/aap.2021.42.210018Crossref PubMed Scopus (5) Google Scholar Recent evidence indicates that the use of these therapies may also have important beneficial effects on coagulation. HAE patients receiving prophylactic C1INH replacement therapy had markedly reduced plasma levels of both prothrombin fragment 1 + 2 and D‐dimer compared to placebo‐treated HAE patient controls.22.Reshef A. Levy D. Longhurst H. et al.Effects of continuous plasma‐derived subcutaneous C1‐esterase inhibitor on coagulation and fibrinolytic parameters.Thromb Haemost. 2021; 121: 690-693https://doi.org/10.1055/s-0040-1721147Crossref PubMed Scopus (5) Google Scholar Importantly, HAE patients receiving C1INH replacement therapy administered acutely or as intermittent prophylaxis had a significantly reduced incidence of VTE compared to HAE patients not receiving therapy.23.Farkas H. Kohalmi K.V. Veszeli N. Zotter Z. Varnai K. Varga L. Risk of thromboembolism in patients with hereditary angioedema treated with plasma‐derived C1‐inhibitor.Allergy Asthma Proc. 2016; 37: 164-170https://doi.org/10.2500/aap.2016.37.3933Crossref PubMed Scopus (20) Google Scholar There are a number of limitations with the retrospective ICD‐10 coding–based approach used. The ICD‐10–based approach does not give additional information on whether VTE events were provoked or unprovoked. The prevalence of provoking events, such as prolonged hospitalization or immobility, in patients with HAE may independently contribute to VTE risk. Although the control cohort was matched for age, sex, and country of residence the impact of other baseline differences between the case and control cohorts cannot be excluded. The retrospective nature of this study does not account for the rapidly evolving therapeutic landscape. The increasing use of short‐term prophylactic therapy and the introduction of long‐term prophylactic therapy may modulate VTE risk in HAE patients. This analysis focused on HAE caused by quantitative or functional deficiencies in C1INH. It is unclear to what extent the observed association between HAE and VTE will hold in HAE–nC1INH. The clinical presentation of HAE–nC1INH differs somewhat from that of HAE caused by C1INH deficiency.24.Bork K. Machnig T. Wulff K. Witzke G. Prusty S. Hardt J. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence.Orphanet J Rare Dis. 2020; 15: 289https://doi.org/10.1186/s13023-020-01570-xCrossref PubMed Scopus (41) Google Scholar HAE–nC1INH, particularly when driven by FXII mutations, has been associated with more frequent facial swelling and less frequent abdominal swelling compared to HAE caused by C1INH and is not associated with erythema marginatum.25.Bork K. Gul D. Hardt J. Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course.Am J Med. 2007; 120: 987-992https://doi.org/10.1016/j.amjmed.2007.08.021Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Future studies that also include cases of HAE–nC1INH may provide additional insights into comorbidities associated with this rare subtype. These considerations notwithstanding, evidence of a relationship between HAE and VTE raises some interesting questions. Patients with HAE have a broad range of residual C1INH activity. Does the severity of C1INH deficiency have an impact on VTE risk? HAE has a variable presentation. Does the frequency and severity of HAE attacks affect VTE risk? How might the new classes of kallikrein and activated FXII inhibitors being developed as novel therapies for HAE affect VTE risk? Further research in this area is needed to provide additional insights. In summary, the present study indicates that patients with HAE have a significantly increased risk of composite VTE but not composite ATE. However, prospective studies are needed to further explore this association, particularly regarding unprovoked VTE and the impact of prophylactic HAE therapies on VTE risk. S.P. Grover analyzed and interpreted the data and drafted the manuscript. L. Sundler Björkman analyzed and interpreted the data and edited the manuscript. A. Egesten, S. Moll, and N. Mackman interpreted the data and edited the manuscript. S.P. Grover, L. Sundler Björkman, and A. Egesten have received research support from CSL Behring. L. Sundler Björkman and A. Egesten have received honoraria as speakers from Biocryst. The other authors have no relevant conflicts of interest to disclose. S.P. Grover was supported by the National Heart Blood and Lung Institute of the National Institutes of Health (T32HL007149) and The American Society of Hematology (Scholar Award).American Society of HematologyNational Heart, Lung, and Blood InstituteT32HL007149