fibrin and Anaphylaxis

Tetramer-forming tryptase (hTryptase-β) was recently discovered to have a prominent role in preventing the internal accumulation of life-threatening fibrin deposits and fibrin-platelet clots. The anticoagulant activity of hTryptase-β is an explanation for the presence of hemorrhagic disorders in some patients with anaphylaxis or mastocytosis. The fragments of hFibrinogen formed by the proteolysis of this prominent protein by hTryptase-β could be used as biomarkers in the blood and/or urine for the identification and monitoring of patients with mast cell-dependent disorders. Recombinant hTryptase-β has potential to be used in clinical settings where it is desirable to inhibit blood coagulation.

Topics: Anaphylaxis; Blood Coagulation; Fibrin; Fibrinogen; Gene Expression Regulation, Neoplastic; Histamine; Humans; Isoenzymes; Mast Cells; Mastocytosis; Protein Multimerization; Signal Transduction; Skin; Thrombin; Tryptases

The mouse and human TPSB2 and TPSAB1 genes encode tetramer-forming tryptases stored in the secretory granules of mast cells (MCs) ionically bound to heparin-containing serglycin proteoglycans. In mice these genes encode mouse MC protease-6 (mMCP-6) and mMCP-7. The corresponding human genes encode a family of serine proteases that collectively are called hTryptase-β. We previously showed that the α chain of fibrinogen is a preferred substrate of mMCP-7. We now show that this plasma protein also is highly susceptible to degradation by hTryptase-β· and mMCP-6·heparin complexes and that Lys(575) is a preferred cleavage site in the protein α chain. Because cutaneous mouse MCs store substantial amounts of mMCP-6·heparin complexes in their secretory granules, the passive cutaneous anaphylaxis reaction was induced in the skin of mMCP-6(+)/mMCP-7(-) and mMCP-6(-)/mMCP-7(-) C57BL/6 mice. In support of the in vitro data, fibrin deposits were markedly increased in the skin of the double-deficient mice 6 h after IgE-sensitized animals were given the relevant antigen. Fibrinogen is a major constituent of the edema fluid that accumulates in tissues when MCs degranulate. Our discovery that mouse and human tetramer-forming tryptases destroy fibrinogen before this circulating protein can be converted to fibrin changes the paradigm of how MCs hinder fibrin deposition and blood coagulation internally. Because of the adverse consequences of fibrin deposits in tissues, our data explain why mice and humans lack a circulating protease inhibitor that rapidly inactivates MC tryptases and why mammals have two genes that encode tetramer-forming serine proteases that preferentially degrade fibrinogen.

Topics: Anaphylaxis; Animals; Blood Coagulation; Edema; Fibrin; Fibrinogen; Heparin; Humans; Immunoglobulin E; Mast Cells; Mice; Mice, Knockout; Proteolysis; Secretory Vesicles; Skin; Thrombin; Tryptases

The new morphologic findings reviewed here substantially alter prevalent conceptions of delayed hypersensitivity as a simple cutaneous infiltration of lymphocytes and macrophages. By assigning an integral role of basophils, mast cells, the microvasculature, and the clotting system, the findings have far-reaching implications for an understanding of these clinically important reactions. Morphologic observations, of course, represent only a first step, a foundation on which subsequent immunologic, physiologic, and biochemical experiments can build. Much further work will be required to interrelate these new findings and to integrate them with older observations into a coherent sequence of events which can explain the pathogenesis of cell-mediated reactions. A preliminary attempt in this direction, based on present, rather incomplete information, is presented in Figure 8 as a basis for further investigation.

Topics: Anaphylaxis; Basophils; Blood Coagulation; Cytoplasmic Granules; Edema; Female; Fibrin; Humans; Hypersensitivity, Delayed; Male; Mast Cells; Mitosis; Models, Biological; Skin

Intravascular fibrin formation could not be detected in various phase of IgE mediated anaphylactic shock of rats, either by using an isotope technique or testing the plasma samples by the ethanol gelation test.

Topics: Anaphylaxis; Animals; Blood Coagulation; Ellagic Acid; Erythrocyte Aggregation; Fibrin; Fibrinogen; Heparin; Intestine, Small; Kidney; Liver; Lung; Male; Rats; Serum Albumin, Radio-Iodinated; Spleen; Thrombin

Topics: Adolescent; Anaphylaxis; Biopsy; Child, Preschool; Fibrin; gamma-Globulins; Humans; Kidney; Kidney Glomerulus; Microscopy, Electron; Microscopy, Fluorescence; Purpura

Topics: Agar; Anaphylaxis; Animals; Epinephrine; Female; Fibrin; Fluorescent Antibody Technique; Kidney; Microscopy; Microscopy, Electron; Microscopy, Fluorescence; Purpura; Rats; Shwartzman Phenomenon

Topics: Anaphylaxis; Animals; Blood Coagulation Disorders; Fibrin; Fibrinogen; Fibrinolysis; Kidney Glomerulus; Liver; Rabbits; Spleen

Topics: Anaphylaxis; Antigens; Fibrin; Humans; Hypersensitivity; Immune System Diseases

Topics: Anaphylaxis; Capillary Permeability; Fibrin; Humans; Hypersensitivity; Peptones; Serum; Shock

Topics: Anaphylaxis; Animals; Blood; Dogs; Fibrin; Fibrinolysis; Hypersensitivity; Immune System Diseases; Peptones; Shock