In 2015 I wrote this post on ACEi-induced angioedema. I still think it was a pretty good post (particularly for 2015), but it’s become increasingly clear recently that the post was fundamentally flawed. Let’s try to straighten this out.
old model of bradykinin-mediated angioedema
This is a conceptual model of how bradykinin-mediated angioedema occurs. Several enzymes activate one another in a linear cascade. Ultimately, this leads to the generation of bradykinin, which causes tissue edema. ACEi-induced angioedema is due to inadequate degradation of bradykinin, causing bradykinin accumulation.
This model suggests that Icatibant (a bradykinin receptor blocker) should be an ideal treatment for ACE-inhibitor induced angioedema (because both ACE inhibitors and Icatibant interact with bradykinin).
why this model is incomplete
As more data has emerged, it’s become clear that this model fails to explain the following phenomena:
- Icatibant doesn’t work great for ACEi-induced angioedema. The original study suggesting that Icatibant worked was published in the NEJM, receiving enormous attention.1 Subsequent RCTs and meta-analysis have found that icatibant wasn’t effective.2,3 The truth may lie somewhere in between – icatibant probably has some efficacy for ACEi-induced angioedema, but it’s not a silver bullet (and likely not worth its enormous price).
- Tranexamic acid (an inhibitor of fibrinolysis) appears effective against several forms of bradykinin-mediated angioedema.4 It has a long track-record of use in hereditary angioedema.5 A model of bradykinin-mediated angioedema should explain why tranexamic acid works for these conditions.
- Patients with bradykinin-mediated angioedema are fine for long periods of time, but then they can deteriorate suddenly. What is the physiology underlying these sudden exacerbations?
new model of bradykinin-mediated angioedema
Below is a more complete model of bradykinin-mediated angioedema. The individual steps described in this model are neither new nor controversial (they’ve been sitting in hematology textbooks for over a decade).
Construction of this more complete model immediately explains why patients suddenly develop progressive attacks of angioedema. Angioedema is caused by a series of enzymes, which catalyze the activation of one another. These enzymes subsequently loop back upon themselves, creating an vicious cycle. This works a bit like a nuclear chain reaction:
The cyclical nature of this pathway is reminiscent of similar pathways involved in coagulation (example below, note the green arrows showing how thrombin doubles back to activate factors V, XI, and VII). Evolution has designed these auto-amplification pathways to allow prompt responsiveness (e.g. rapid coagulation). Of course, this enhanced responsiveness can run amok, leading to disease.
implications for ACEi-angioedema: why doesn’t icatibant work well?
ACEi-induced angioedema must be a two-hit phenomenon (because most patients treated with ACEi don’t develop angioedema, nor do patients develop this complication immediately upon exposure to ACE inhibitors). One could hypothesize that this works as follows:
- Some patients are prone to episodes of bradykinin accumulation (perhaps due to various mutations in one or more proteins involved in this pathway). At times, the above spiral spins out of control, leading to high levels of bradykinin production. Generally, these episodes are asymptomatic due to degradation of bradykinin by ACE.
- If such patients are on an ACE inhibitor, these episodes of bradykinin generation lead to bradykinin accumulation which is clinically symptomatic.
Icatibant is a competitive inhibitor of bradykinin. It’s possible that once the enzymatic spiral really gets revved up, icitabant simply can’t compete. Bradykinin-induced angioedema is driven by a cyclical, enzymatic chain reaction. For example, a single molecule of plasmin may generate several molecules of XIIa, and each of those may in turn generate several molecules of kallekrine. Once this enzymatic spiral becomes uncontrolled, it may generate so much bradykinin that icatibant’s ability to competitively inhibit the bradykinin receptor is overwhelmed.
implications for treating bradykinin-induced angioedema: universal therapies?
Bradykinin-induced angioedema may be caused by a variety of factors. For example:
- ACE inhibitors.
- Exogenous tPA may trigger angioedema by activation of plasminogen.
- Congenital deficiency of C1-inhibitor.
- Congenital abnormalities in factor XII may lead to excess generation of XIIa and angioedema.
Regardless of the precise cause, it’s likely that the spiral of enzyme activation is the same (involving plasmin, XIIa, and kallekrine as shown above). This would imply that universal treatments could be effective for all types of bradykinin-mediated angioedema, regardless of the specific cause.
One example of this phenomenon is the utility of tranexamic acid to prevent angioedema episodes in patients with congenital C1-inhibitor deficiency. The underlying cause of angioedema in these patients has nothing to do with plasminogen or fibrinolysis. However, plasmin is required for the amplification spiral. Therefore, tranexamic acid can help these patients – even though it has a molecular effect on a different target. Essentially, bradykinin-induced angioedema involves the generation of an auto-amplification circuit. Breaking this circuit anywhere will work, regardless of where the circuit is interrupted.
Other examples of the universality of therapies includes:
- The use of tranexamic acid for patients with ACEi-induced angioedema.
- The use of C1-esterase inhibitor for patients with ACEi-induced angioedema.
The best treatments for bradykinin-mediated angioedema may therefore be medications which will stop the auto-amplification loop involving plasmin, XIIa, and kallekrine (not medications that block bradykinin). This would include tranexamic acid, C1-inhibitor concentrate, and possibly ecallantide. Given the ability of C1-inhibitor to block two fundamental steps in the auto-amplification loop, this could be the single drug which is best positioned for efficacy. (Evolution designed C1-esterase for a reason – it wasn’t just messing around.)
Universality of therapies across a range of sub-types of bradykinin-induced angioedema may be very useful clinically. This would imply that it is sufficient to diagnose a patient with some form of bradykinin-induced angioedema, in order to initiate treatment. If the precise subtype of angioedema were incorrect or unknown, this could still allow for prompt and appropriate therapy.
- A vicious spiral of enzymatic activation is proposed as a new model to explain bradykinin-mediated angioedema. This spiral may be a universal feature in every type of bradykinin-mediated angioedema.
- The most effective treatments might be drugs which effectively inhibit this spiral of activation. Tranexamic acid and C1-inhibitor concentrate seem well positioned to achieve this.
- These medications may be effective in all types of bradykinin-mediated angioedema.
Stay tuned for the full Internet Book of Critical Care chapter on angioedema coming tomorrow.
- 1.Baş M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372(5):418-425. https://www.ncbi.nlm.nih.gov/pubmed/25629740.
- 2.Jeon J, Lee Y, Lee S. Effect of icatibant on angiotensin-converting enzyme inhibitor-induced angioedema: A meta-analysis of randomized controlled trials. J Clin Pharm Ther. July 2019. https://www.ncbi.nlm.nih.gov/pubmed/31290163.
- 3.Sinert R, Levy P, Bernstein J, et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017;5(5):1402-1409.e3. https://www.ncbi.nlm.nih.gov/pubmed/28552382.
- 4.Beauchêne C, Martins-Héricher J, Denis D, Martin L, Maillard H. [Tranexamic acid as first-line emergency treatment for episodes of bradykinin-mediated angioedema induced by ACE inhibitors]. Rev Med Interne. 2018;39(10):772-776. https://www.ncbi.nlm.nih.gov/pubmed/29735174.
- 5.Sheffer A, Austen K, Rosen F. Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med. 1972;287(9):452-454. https://www.ncbi.nlm.nih.gov/pubmed/4558045.