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Effects of leukocyte-derived cathepsin G on platelet membrane glycoprotein
Ib-IX and IIb-IIIa complexes: a comparison with thrombin
M Molino, M Di Lallo, N Martelli, G de Gaetano and C Cerletti
Instituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri
Sud, Santa Maria Imbaro, Italy.
Cathepsin G is a serine, chymotrypsin-like protease released by activated
polymorphonuclear leukocytes (PMN) that may act as a platelet agonist. The
effect of this enzyme on platelet surface glycoproteins (Gp) Ib and
IIb-IIIa was evaluated by means of a cytofluorimetric assay, using
fluorescein isothiocyanate-labeled monoclonal antibodies (MoAbs) directed
at the alpha chain of Gp Ib (SZ2), at Gp IX or at the complex Gp IIb-IIIa
(P2), and the fibrinogen-receptor-specific MoAb PAC- 1. In human washed
platelets, cathepsin G increased the binding of P2 and PAC-1, decreased the
binding of SZ2, but only slightly affected the binding of anti-Gp IX. SZ2
binding decrease was more rapid in cathepsin G- than in thrombin-stimulated
platelets, whereas the increase of P2 and PAC-1 binding occurred to a
comparable extent with either agonist. In paraformaldehyde (PFA)-fixed and
energy-depleted platelets, no effect on either Gp Ib or Gp IIb-IIIa complex
was observed with thrombin. At variance, cathepsin G was still able to
reduce binding of SZ2, whereas increased binding of P2 or PAC-1 antibodies
was not observed. Triton X-100 permeabilization of cathepsin G-treated,
PFA- fixed platelets did not restore SZ2 binding at variance with thrombin.
Moreover, platelet incubation with cathepsin G resulted in the loss of
ristocetin-induced agglutination in the presence of the von Willebrand
factor and in the appearance of Gp Ib-derived proteolytic products in
supernatants. After dissociation by EDTA pretreatment of surface Gp IIb-
IIIa complexes, cathepsin G still induced increased binding of P2. Aspirin
and an adenosine diphosphate scavenger system had only a slight but not
significant effect on changes in antibody binding induced by cathepsin G.
All these data would indicate that cathepsin G, like thrombin, interacts
with platelet-surface Gp, inducing the exposure of the intracellular pool
of the Gp IIb-IIIa complex with concomitant expression of a functional
fibrinogen receptor. Moreover, it induces a loss of antigenic sites on Gp
Ib, but the mechanism involved, a proteolytic cleavage of Gp Ib, is
substantially different from that of thrombin. These changes, induced by a
product of activated PMN, might reduce the reactivity of platelets to the
subendothelium, while increasing their ability to undergo aggregation and
release reaction.
Volume 82,
Issue 8,
pp. 2442-2451,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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