Human Neutrophil Elastase Alters Human _-Thrombin Function: Limited Proteolysis Near the y-Cleavage Site Results in Decreased Fibrinogen Clotting and Platelet-Stimulatory Activity

Author(s): Walz, D., Garry, K., Fenton, J.

Journal/Book: Blood. 1987; 69: 813-819.

Abstract: During blood coagulation. polymorphonuclear leukocytes release elastase in amounts that can exceed 100 nmol/L. We therefore studied the interaction between human leukocyte elastase and human ?-thrombin. EIastase cleaved the thrombin B chain /Ala 150-Asn 151) near the ?-cleavage site, resulting in two fragments held together by noncovalent interactions. The NH2-terminal fragment IFI). mol wt ~18,000. was disulfide-linked to the thrombin A chain. The COOH-terminal fragment (Fll), mol wt ~13,000, contained the active-site serine and formed a covalent bond with antithrombin III. Heparin accelerated proteolysia of ?-thrombin by elastase. Proteolyzed ?-thrombin (T.) retained full amidolytic activity; however, the concentration of T. causing 50% maximal platelet aggregation and adenosine triphoaphate (ATP) release was 7.9 nmol/L (1.1 nmol/L for ?-thrombin and 220 nmol/L for ?-thrombin). Fibrinogen clotting activity of T. and ?-thrombin was 32% and 1% that of ?-thrombin, respectively. Elastase released during the coagulation process may modulate thrombin activity. In addition, elastase-modified thrombin may be a useful probe of the structure and function of the ?-cleavage region.

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