Hereditary angioedema (HAE) is a rare inherited disease that causes episodes of severe swelling that can be fatal. As HAE is a rare disease relatively little is known about the effect it has on other more common diseases. Patients with HAE have evidence of hyperactive blood clotting. Hyperactive blood clotting is known to be an important cause of common cardiovascular diseases. Recent research has shown that patients with HAE are at increased risk of cardiovascular disease. Based on data we have generated in experimental models we hypothesize that patients with HAE have an increased risk of forming blood clots in arteries, termed arterial thromboembolism, and veins, term venous thromboembolism. We would like to investigate if patients with HAE are more likely to suffer from venous thromboembolism or arterial thromboembolism when compared with the general population. If a relationship were to be demonstrated closer monitoring of HAE patients and/or use of treatments to reduce the risk of developing these events, might be supported.
Background: Hereditary Angioedema (HAE) is a relatively rare disorder and is primarily caused by a congenital deficiency in C1-inhibitor (C1NH). Recent evidence suggests that patients with HAE may be at an increased risk of developing other comorbidities including autoimmune disorders and cardiovascular disease. We and other have found that patients with HAE have a hyperactive coagulation system. Further our preclinical studies indicate that C1INH deficiency leads to increased thrombosis in preclinical disease models. Venous thromboembolism (VTE), that includes deep vein thrombosis and pulmonary embolism, and arterial thromboembolism (ATE), that includes myocardial infarction, embolic stroke and peripheral vascular disease, are common cardiovascular diseases that represent a significant source of morbidity and mortality.
Aims: To determine if patients with HAE are at increased risk of developing VTE or ATE.
Methods: We will implement a matched cohort study among patients aged 18 years and over with a diagnosis of HAE between 01/01/1992 and 31/12/2022. Patients with HAE will be matched (ratio 1:5) on age, gender, indexdate for HAE, and practice to patients never diagnosed with HAE. Drugs used to prevent or treat swelling will be included as effect modifiers (mediators or moderators) for the impact of HAE on study outcomes. The primary outcome measure will be new combined and specific VTE or ATE diagnoses. Secondary outcome measures will include all-cause mortality and QRISK score. Time to event analyses (Cox regression or conditional Poisson regression) will be used to compare the risk of study outcomes among HAE patients and the matched group. Data permitting, we will stratify patients by baseline thrombotic risk.
Outcomes: An association between HAE and VTE or ATE would provide important information that may inform clinical practice for the management of patients with HAE.
The primary outcome measures of the study are venous thromboembolism that includes deep vein thrombosis, pulmonary embolism and thrombosis of other veins, and arterial thromboembolism that includes ischaemic heart disease, ischemic stroke and peripheral vascular disease identified using read medical codes.
Alex Dregan - Chief Investigator - King's College London (KCL)
Alex Dregan - Corresponding Applicant - King's College London (KCL)
Prakash Saha - Collaborator - King's College London (KCL)
Steven Grover - Collaborator - University of North Carolina at Chapel Hill