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High molecular weight kininogen: localization in the unstimulated and
activated platelet and activation by a platelet calpain(s)
AH Schmaier, PM Smith, AD Purdon, JG White and RW Colman
High mol wt kininogen (HMWK), the major cofactor-substrate of the contact
phase of coagulation, is contained within and secreted by platelets.
Studies have been performed to localize platelet HMWK in both the
unstimulated and activated platelet and to ascertain the effect of platelet
enzymes on HMWK itself. On platelet subcellular fractionation, platelet
HMWK was localized to alpha-granules, and platelets from a patient with a
deficiency of these granules (gray platelet syndrome) had 28% normal
platelet HMWK. Platelet HMWK, in addition to being secreted from the
platelet, was also localized to the surface of the platelet when activated.
Using a competitive enzyme- linked immunosorbent assay for HMWK as an
indirect antibody consumption assay, the external membrane of
thrombin-activated platelets as well as the releasate from these stimulated
platelets had 17 ng HMWK antigen/10(8) platelets available, whereas
unstimulated platelets and their supernatant had only 4.9 and 4.2 ng
HMWK/10(8) platelets present, respectively. The anti-HMWK antibody
consumption by activated normal platelets was specific for
membrane-expressed platelet HMWK, since activated platelets from a patient
with total kininogen deficiency did not adsorb the anti-HMWK antibody.
Enzymes in the cytosolic fraction of platelets cleaved 125I-HMWK (mol wt
120,000) into a mol wt 100,000 polypeptide as well as smaller products at
mol wt 74,000, mol wt 62,000, mol wt 47,000, and a few components below mol
wt 45,000. No cleavage products were observed when DFP and leupeptin were
present. The cleavage of HMWK was specifically prevented by inhibitors of
calcium-activated cysteine proteases (leupeptin, N-ethylmaleimide,
iodoacetamide, and EDTA) but not by inhibitors of serine proteases (DFP,
benzamidine, soybean trypsin inhibitor, or aprotinin). Platelet cytosol
increased the coagulant activity of exogenous purified HMWK with maximum
HMWK coagulant activity (35-fold) occurring within ten minutes of exposure
to platelet cytosol. Treatment of platelet cytosol with leupeptin prevented
the increase in the coagulant activity of exogenous HMWK. These studies
indicate that activated platelets express platelet HMWK on their external
membrane and platelet enzymes can cleave and increase the coagulant
activity of exogenous HMWK.
Volume 67,
Issue 1,
pp. 119-130,
01/01/1986
Copyright © 1986 by The American Society of Hematology
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