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Hereditary angioedema (HAE) is a genetically heterogeneous disease that is characterized by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The two classic types, HAE types I and II, are both caused by mutations in the complement C1 inhibitor (SERPING1) gene resulting either in a quantitative or a qualitative deficiency of C1 inhibitor. In so-called HAE type III, in contrast, patients show normal C1 inhibitor measurements in plasma ('HAE with normal C1 inhibitor'). As previously shown by us, one subgroup of 'HAE with normal C1 inhibitor' is caused by mutations of the coagulation factor XII (F12) gene. For the present study, following the exclusion of numerous candidate genes, we screened eight unrelated index patients representing eight 'HAE families with normal C1 inhibitor and no F12 mutation' for mutations in the plasminogen (PLG) gene. A rare non-conservative missense mutation was newly identified in exon 9 of the PLG gene. This mutation (c.1100A > G), encountered in three out of eight patients, predicts a lysine-to-glutamic acid substitution in position 311 of the mature protein (p.Lys311Glu). Using isoelectric focusing of plasma samples followed by an immunoblotting procedure we demonstrated that the presence of the mutation is associated with a dysplasminogenemia, namely the presence of an aberrant plasminogen protein. The predicted structural and functional impact of the mutation, its absence in 139 control individuals, and its co-segregation with the phenotype in three large families provide strong support that it causes disease. Extending a previously proposed gene-based alphabetic nomenclature for the various HAE types one may use the term 'HAE type C' for the HAE entity described here., (Copyright © 2017. Published by Elsevier Inc.)

Background: Factor XII (FXII) is a serine protease that is involved in activation of the intrinsic blood coagulation, the kallikrein-kinin system and the complement cascade. Although the binding of FXII to the cell surface has been demonstrated, the consequence of this event for proteolytic processing of membrane-anchored proteins has never been described., Methods: The effect of FXII on the proteolytic processing of the low-density lipoprotein receptor-related protein 1 (LRP1) ectodomain was tested in human primary lung fibroblasts (hLF), alveolar macrophages (hAM) and in human precision cut lung slices (hPCLS). The identity of generated LRP1 fragments was confirmed by MALDI-TOF-MS. Activity of FXII and gelatinases was measured by S-2302 hydrolysis and zymography, respectively., Results: Here, we demonstrate a new function of FXII, namely its ability to process LRP1 extracellular domain. Incubation of hLF, hAM, or hPCLS with FXII resulted in the accumulation of LRP1 ectodomain fragments in conditioned media. This effect was independent of metalloproteases and required FXII proteolytic activity. Binding of FXII to hLF surface induced its conversion to FXIIa and protected FXIIa against inactivation by a broad spectrum of serine protease inhibitors. Preincubation of hLF with collagenase I impaired FXII activation and, in consequence, LRP1 cleavage. FXII-triggered LRP1 processing was associated with the accumulation of gelatinases (MMP-2 and MMP-9) in conditioned media., Conclusions: FXII controls LRP1 levels and function at the plasma membrane by modulating processing of its ectodomain., General Significance: FXII-dependent proteolytic processing of LRP1 may exacerbate extracellular proteolysis and thus promote pathological tissue remodeling., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Sulfated galactans are polysaccharides with heterogeneous structures that frequently show anticoagulant activity. Their anticoagulant mechanisms are complex and distinct from those observed for heparin. Sulfated galactans act through a combination of effects involving serpin-dependent and serpin-independent mechanisms. Interestingly, these polymers can also induce blood coagulation due to activation of factor XII (FXII)., Objectives: The structure of a complex sulfated galactan from the red alga Acanthophora muscoides was characterized by solution nuclear magnetic resonance. This polysaccharide and another previously characterized algal sulfated galactan from Botryocladia occidentalis were each used in in vitro and in vivo anticoagulant and antithrombotic assays to understand the possible structural determinants of their functional effects., Results and Conclusions: The serpin-dependent anticoagulant effects and FXII-related procoagulant effects of the sulfated galactans decreased in parallel with the molecular size. The serpin-independent anticoagulation also correlated with the chemical structure of the sulfated galactans. The sulfated galactan from A. muscoides, which showed mostly serpin-independent anticoagulant activity and reduced activation of FXII, drastically reduced arterial thrombus formation. However, the sulfated galactans produced opposite effects on venous thrombosis; this difference appears to result from the tenuous balance between the various effects on coagulation, including serpin-dependent and serpin-independent anticoagulation and FXIIa-dependent procoagulation. This study of novel sulfated polysaccharides with distinct effects on coagulation and thrombosis helps to establish the minimal structural-function relationship required for the development of antithrombotic drugs., (© 2013 International Society on Thrombosis and Haemostasis.)

Human blood coagulation factor XII (FXII) is the one chain 80 kDa zymogen form of the active serine protease α-FXIIa, which consists of a heavy and light chain linked by a disulfide bond, the light chain being responsible for the proteolytical activity. FXII is the first component of the contact dependent pathway of coagulation, but its physiological role is still subject to debate. In the present study we utilized two monoclonal antibodies against the heavy chain of FXII to establish a sandwich enzyme linked immunosorbent assay (ELISA) for quantification of total FXII concentration in human plasma samples. A unique characteristic of this assay is its equal recognition of FXII and inhibitor bound FXII. This is important, as inhibitor complexes of α-FXIIa are formed in vivo as well as during blood sampling and handling. Validation of the assay demonstrated a high sensitivity, with a limit of detection and quantification of 1.2 ng/mL and 2.6 ng/mL respectively. The coefficients of variation for the repeatability and within-laboratory standard deviations were 2.6% and 5.2% respectively. The reference interval determined from healthy volunteers (n=240) was 10.6-43 mg/L., (Copyright © 2013 Elsevier B.V. All rights reserved.)