Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.

Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor. Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

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IntroductionCell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosomes were suggested to play an important role in inflammation and were demonstrated to correlate with severity and outcome in sepsis patients. We recently showed that plasma can release nucleosomes from late apoptotic cells. Factor VII-activating protease (FSAP) was identified to be the plasma serine protease responsible for nucleosome release. The aim of this study was to investigate FSAP activation in patients suffering from various inflammatory diseases of increasing severity.MethodsWe developed ELISAs to measure FSAP-C1-inhibitor and FSAP-α2-antiplasmin complexes in plasma. FSAP-inhibitor complexes were measured in the plasma of 20 adult patients undergoing transhiatal esophagectomy, 32 adult patients suffering from severe sepsis and 8 from septic shock and 38 children suffering from meningococcal sepsis.ResultsWe demonstrate plasma FSAP to be activated upon contact with apoptotic and necrotic cells by an assay detecting complexes between FSAP and its target serpins α2-antiplasmin and C1-inhibitor, respectively. By means of that assay we demonstrate FSAP activation in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis. Levels of FSAP-inhibitor complexes correlate with nucleosome levels and correlate with severity and mortality in these patients.ConclusionsThese results suggest FSAP activation to be a sensor for cell death in the circulation and that FSAP activation in sepsis might be involved in nucleosome release, thereby contributing to lethality.

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SummaryIn order to assess the clinical implications of hereditary F XII deficietrcy, all available members of Swiss families with F XII deficiency were investigated. Based on the F XII: C values and the family pedigree, the 74 subjects, aged 8-–82 years, were classified as homozygotes/double heterozygotes for F XII deficiency (n = 18), as obligatory (n = 20) or possibly (n = 25) heterozygotes, respectively, and as norrnals (n = 11). None of the 18 subjects with F XII: C <0.01 U/ml and only one possibly heterozygous woman had an abnormal bleeding tendency, confirming the notion that Hageman trait generally does not result in a hemorrhagic diathesis. Two of the 18 subjects with severe F XII deficiency had suffered from venous thromboembolic disease at age <40 years. One heterozygous woman had a leg ulcer probably due to venous thrombosis. Thus, whereas homozygous F XII deficiency may be associated with an increased risk for venous thromboembolic disease, partial F XII deficiency is not, by itself, a strong risk factor for thrombosis.Where as 17 of the 18 subjects with F xII : C <0.01 U/ml had no detectable F XIL Ag, one cross reacting material-positive F XII deficient subject (F XII:Ag = 0.11 U/ml) was identified. The dysfunctional F XII, present in this subject's plasma and tentatively called F XII Bern, is the fourth abnormal F XII molecule identified so far.

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