Effects of human mast cell tryptase and eosinophil granule proteins on the kinetics of blood clotting.
Hypereosinophilic syndromes are often associated with thrombosis through unclear mechanisms, and mastocytosis has been associated with a variety of bleeding disorders. The present studies were aimed at defining the roles and interactions of eosinophil and mast cell constituents on the kinetics of blood clotting as measured by thromboelastograms. Eosinophil granule proteins and purified eosinophil peroxidase markedly reduced the anticoagulant properties of the mast cell tryptase/heparin complex. Moreover, eosinophil peroxidase by itself functioned as a powerful procoagulant and also inhibited the anticoagulant actions of heparin in a chromogenic assay for antithrombin III/factor Xa activity. The anticoagulant activity of the tryptase/heparin complex was attributable exclusively to the associated heparin and not to the intrinsic enzymatic activity of tryptase. Eosinophil granule proteins also strongly inhibited the enzymatic activity of tryptase in the presence of hydrogen peroxide, thus implicating a critical role for eosinophil peroxidase. We conclude that eosinophil granule proteins and eosinophil peroxidase both function as powerful procoagulants and also inhibit the anticoagulant and enzymatic activities of mast cell tryptase. The present results thus provide a mechanistic rationale for the well-established link between certain eosinophilic inflammatory disorders and hypercoagulant states. They also suggest that eosinophils may play an important role in neutralizing the anticoagulant activity of mast cell tryptase/heparin in various diseases.
Samoszuk
Michael
M
Pathology Department, University of California-Irvine, UCI Medical Building 10, Route 40, 101 The City Drive, Orange, CA 92868-3298, USA. msamoszu@uci.edu
Corwin
Mark
M
Hazen
Stanley L
SL
D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000209:etiology; D001798:Blood Proteins / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000201:enzymology / Q000502:physiology; D015951:Factor Xa / Q000032:analysis; D006493:Heparin / Q000494:pharmacology; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D008407:Mast Cells / Q000201:enzymology* / Q000502:physiology; D009195:Peroxidase / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012260:Ribonucleases; D012697:Serine Endopeptidases / Q000494:pharmacology*; D013916:Thrombelastography; D053802:Tryptases
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D047091:Eosinophil Granule Proteins; D011480:Protease Inhibitors; D000990:Antithrombin III; D006493:Heparin; D006861:Hydrogen Peroxide; D009195:Peroxidase; D012260:Ribonucleases; D012697:Serine Endopeptidases; D053802:Tryptases; D015951:Factor Xa; D019763:Heparin Lyase