“Why is trauma considered a “trigger” for HAE attacks?”

Mar 17, 2016
Dr. C: We thank our reader for this thought-provoking question. Our answer will need to be mainly speculative, like many things in HAE we can document what occurs but are uncertain why. It is well known that certain types of trauma such as dental work are associated with attacks of swelling. I have always found it surprising how well HAE patients do giving birth—also a rather traumatic event. I wonder whether the body senses “good” and “bad” trauma in different ways in the same way our immune system responds differently to invasive pathogens vs a still “foreign” developing fetus. At a basic level Hsp 90 may have a role. This protein is important in wound healing and control of inflammation. Hsp 90 has also been shown to activate prekallikrein to active plasma kallikrein—the enzyme which generates bradykinin. In HAE patients we could speculate that in the absence of functional C1 inhibitor that this may trigger contact system activation for type I and II HAE. Until we better understand the pathophysiology of HAE XII and HAE U it would be difficult to even speculate. Bruce could you elaborate on what we actually know about trauma activating the contact system and bradykinin generation for our reader?


Dr Z:As the question suggests, trauma is considered to be one of the more common provocateurs of HAE attacks. Trauma presumably leads to local activation of the contact system and hence generation of bradykinin. We don’t fully understand how this happens, although there are several possible explanations. One mechanism is that trauma induces local activation of the contact system via exposure of blood to molecules that can assemble and activate the contact system. We speculate that trauma may slightly damage the cells that line small blood vessels, exposing the negatively charged proteins that lie beneath the endothelium and can activate the contact system. Alternatively, trauma may cause release of microparticles from cells that can activate the contact system. In either case, the localized generation of bradykinin may explain why the swelling starts at a particular location. Another way to look at this is that the trauma changes the response of the local tissue to bradykinin that is generated and present in the blood. In this model the trauma may influence the expression of receptors or signaling molecules that determine whether the endothelial cells become leaky in response to bradykinin. We’ve seen that the trauma does not have to be very severe to cause swelling in HAE patients. Even normal activities such as clapping hands or sitting on a hard seat can be sufficient.


Dr C: Thank you Bruce, very interesting. Marc you have had a lot of experience treating HAE, do you have any wisdom to share with our reader?


Dr R:While many HAE attacks are unpredictable, without a clear exacerbating event, physical trauma is a well-recognized trigger. Cutting, bruising, or impact injuries to soft tissue can sometimes result in subsequent development of localized angioedema that can be protracted and severe. This doesn’t happen in every person with every trauma and we don’t understand why some people are more susceptible to certain triggers than others. But it’s common enough to be an important management tip: Be prepared with effective acute medication for HAE if a physical injury or trauma occurs. It’s particularly important to remember this for “planned traumas”, such as dental, surgical, or medical procedures that may be required for optimal health. Once in a while, patients have reported that in addition to the local swelling at the injured site, they’ve experienced angioedema symptoms at another distant location as part of the attack (such as abdominal or facial swelling after a hand injury). This phenomenon is poorly studied, but suggests some “systemic” activation of the bradykinin system from even local tissue trauma. The precise reasons for trauma causing angioedema remain a bit nebulous, but are almost certainly related to inflammatory proteins, cytokines, and tissue factors released from damaged cells activating the contact system and increasing bradykinin production. This is a normal process in humans since bradykinin is an inflammatory protein that has important roles in vasodilation and the sensation of pain as part of the body’s usual response to injury. However, in HAE, the “brakes” for the bradykinin system are missing (clearly in Types 1 and 2, and possibly in Type 3) and this activation of bradykinin leads to excessive and uncontrolled tissue swelling – the angioedema attack.


Dr. C: Thank you Bruce and Marc—I hope that our discussion was helpful for our reader and followers with HAE. We look forward to hearing from you and our next “Question of the Week”.

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