Natural pathways for factor XII activation : Implications for hereditary angioedema

Abstract

It is well known that the swelling of tissue (edema) that occurs during an inflammation is the result of local vascular leakage. While histamine is the most well-known mediator of vascular leakage, other mediators such as bradykinin have also shown to be of importance. The contact system is an enzyme system in the blood plasma that mediates coagulation and bradykinin production. Remarkably, patients or animals that are deficient in contact system factors do not have any bleeding problems. However, hyperactivity of the contact system has been linked to attacks of extensive tissue swelling in hereditary angioedema (HAE) patients. During these attacks, pathological levels of bradykinin are formed which result in local vascular leakage, allowing for fluid extravasation into the surrounding tissue. While the contact system has been investigated extensively by its activation upon negatively charged surfaces, its natural pathway of activation and function have remained enigmatic. In this thesis we have attempted to unravel several of these natural activation pathways. Hereto we have developed several novel assays to detect contact system activation in plasma samples using llama derived nanobodies. Using these assays we show that three HAE related mutations in the contact system enzyme factor XII (FXII) increased its activation rate by the enzyme plasmin. As a result, contact system activation ensues leading to extensive bradykinin formation. Furthermore, when HAE mutations are absent we show that FXII can become primed for activation by neutrophil elastase. Subsequent exposure to an activating enzyme, such as plasma kallikrein, leads to a strong impulse in FXII activity. Our findings provide novel insights into several possible natural contact system activation pathways which can occur independently of negatively charged surfaces. Moreover, our data fits various observations in pathology, where contact system activity was observed alongside plasmin or immune cells activation. In conclusion, our findings will contribute to a better understanding and new insights into the role of the contact system in both human physiology and pathology.