Whereas HAE type II patients are characterized by low functional, but normal or increased antigen C1-inh plasma levels. This classification has however been challenged by observations of intermediary HAE types, when small amounts of dysfunctional C1-inh is present in the blood stream. As no evidence regarding clinical consistencies between the type I and type II patients have been observed, this classification describes as such, only the 
biochemical profile of HAE patients. Both types of patients suffer from episodic swellings, where bradykinin is suspected to play a central role. The edema formation is primarily caused by a transient increased BK release from high molecular weight kininogen. The BK release is mediated by uncontrolled activation of the coagulation factor XII dependent kallikrein kinin system. C1-inh circulates in plasma in a stressed high energetic metastable conformation, which is characterized by a reactive center loop protruding from the central part of the serpin. The amino acid sequence of the RCL serves as a bait region for a limited number of proteases. When a protease recognizes and cleaves the P1�CP19 scissile bond in the RCL, the RCL domain inserts into the central beta-sheet A of C1-inh together with the covalently attached protease. After cleavage C1-inh obtains a low energetic stable conformation, and the protease is irreversibly inhibited. Polymerized C1-inh represents another stable and low energetic conformation, which can be attained upon mutations in the SERPING1 gene. A few studies have in vitro addressed the ability of mutated C1-inh to form polymers. The studies focused on distinct mutations resulting in C1-inh polymerization, and recombinantly expressed mutated C1-inh proteins were utilized to demonstrate polymerization of the C1-inh in vitro. For example Zahedi et al. demonstrated that the C1-inh mutant C1-inh-Ta had an increased propensity to polymerize when expressed recombinantly. One group did observe a multimeric form of C1-inh in fractions from sucrose gradient centrifugation of a patient plasma sample, and this suggested that C1-inh polymers might exist in the plasma of HAE patients. Extracellular serpin polymers have been observed in other AZD2281 diseases involving mutations in serpin encoding genes. A classic example hereof is the presence of a1-antitrypsin polymers in lung lavage of patients suffering from the Z-mutation in the a1-antitrypsin encoding gene. The clinical relevance of C1-inh polymers in the plasma of HAE patients remains hitherto uncertain, and therefore we aimed to elucidate the presence and nature of C1-inh polymers in plasma from HAE patients. In the present study we aimed to elucidate whether certain HAE genotypes produced C1-inh polymers identified with a specific monoclonal antibody. All Danish HAE families were tested for a putative polymerized C1-inh phenotype. We demonstrated that C1-inh polymers were present in plasma of six HAE patients in three of 31 HAE families affected by different SERPING1 mutations. In vitro experiments using LY2157299 citations recombinant C1-inh strategy have demonstrated that certain C1-inh mutations are prone to polymerization, but these experiments did not demonstrate the presence of polymerized C1-inh in patient plasma. Others have used patient plasma samples subjected to gel filtration or sucrose density gradient centrifugation analysis or C1-inh purified from patient plasma, and the results of these studies advocate for the presence of polymeric C1-inh in patient plasma. However, the presence of C1-inh polymers in untreated patient plasma samples has not previously been demonstrated. C1-inh polymers were detected in HAE patient plasma samples, with determination of the sizes of the polymers.