Understanding the Role of Bradykinin in Hereditary Angioedema Attacks

This is a Pharvaris sponsored and written post with collaboration by Marc A. Riedl, MD, MS, Raffi Tachdjian, MD, MPH, and Autumn Burnette, MD

Hereditary angioedema (HAE) is a rare, recurrent genetic disease characterized by unpredictable episodes of swelling that can occur in the face, gastrointestinal tract, extremities, genitals, and most concerning, the larynx.

What triggers these attacks? It’s difficult to say, as recent research has been unable to confirm definitive, universal causes. Many patients report that physical trauma, including surgical procedures, can lead to acute swelling attacks. Other times, anxiety or changes in female hormones may be a factor. Even certain foods and changes in the weather can play a role. Often though, attacks occur with no identifiable trigger at all. And conversely, events that triggered past attacks may have no effect in the future.

This, understandably, can lead patients with HAE to completely shape their lives around the persistent threat of an attack. They may be in a constant state of hypervigilance, always worrying about when the next surprise attack will strike.

In an effort to bring awareness and understanding about what happens to the body during an HAE attack, let’s begin with the science behind the underlying physiological factors at work in HAE.

Bradykinin and B2 Receptors

Bradykinin is a naturally occurring amino acid peptide that was first identified in 1949, and has been extensively researched in the decades since.

What we’ve learned is that our bodies produce bradykinin in response to physical trauma, injury, or infection. When functioning at normal levels, bradykinin plays a pivotal role in the healing process. It helps repair tissue and blood vessel injuries by widening the vessels (vasodilation) and allowing essential fluids to reach the site of injury more easily. It also supports the ability to break down blood clots and functions as a key element of the body’s immune response.

The physiological progression typically unfolds like this: once an injury or infection triggers bradykinin production, these molecules seek out and bind to bradykinin B2 receptors located on the walls of blood vessels. This signal tells the vessels to expand and become more porous, ensuring that fluids can be delivered where they are needed most.

HAE: A Bradykinin-Mediated Disease

In patients with HAE, bradykinin production is insufficiently regulated. Simply put, HAE attacks are the direct result of the body’s excess production of bradykinin. For the vast majority of patients with HAE, be it Type 1 or Type 2, this is due to a specific inherited defect in the SERPING1 gene that controls production of C1-INH proteins. These C1-INH proteins are the body’s built-in mechanism for properly controlling bradykinin production. In patients with HAE, C1-INH does not behave as it should.

Between attacks, the body looks normal, but remains biologically primed. When an HAE attack occurs, the kallikrein-kinin system becomes acutely amplified, leading to excessive local generation of bradykinin, which floods the bradykinin B2 receptors. The subsequent hyperactivation causes nearby blood vessels to widen uncontrollably and begin leaking fluid into surrounding tissues. This vascular fluid is released through the adherens junction opening caused by sustained bradykinin signaling of the receptors. The resulting fluid buildup causes disruptive, even debilitating, swelling of angioedema that can last for days if untreated.

The Current HAE Treatment Landscape

There are several HAE treatments currently available, all targeting different stages in the biological pathways that contribute to the formation of bradykinin:

• C1-inhibitor infusions supplement the body’s ability to regulate bradykinin production with functioning C1-INH proteins
• Plasma kallikrein inhibitors can interrupt the kallikrein-kinin system’s upstream production of bradykinin
• B2 receptor antagonists actively prevent bradykinin from binding to the receptors. Though all treatments effectively seek to prevent bradykinin from activating B2 receptors, B2 antagonists have the potential to impact bradykinin-mediated effects independently of the mechanism of bradykinin production

What’s Next for HAE?

As stated in the recently released update to the World Allergy Organization’s guidelines, the treat-to-target goal of HAE treatment should be “achieving complete disease control and sustained improvement in health-related quality of life.” If you’re currently unsatisfied with your HAE treatment, you should have a conversation with your doctor about your treatment approach and expectations.

To learn more about bradykinin and how current treatments can impact quality of life, visit https://deflatehae.com. You’ll find interactive tools, patient stories, and resources to support informed conversations about the future of HAE care.