|
|
 Previous Article | Table of Contents | Next Article 
Rapid Activation of Protein C by Factor Xa and Thrombin in the
Presence of Polyanionic Compounds
Alireza R. Rezaie
From the Cardiovascular Biology Research Program, Oklahoma Medical
Research Foundation, Oklahoma City, OK.
A recent study indicated that negatively charged substances such as
heparin and dextran sulfate accelerate thrombin activation of
coagulation factor XI by a template mechanism. Because the serine
proteinase of the natural anticoagulant pathway, activated protein C,
can bind heparin, it was reasonable to think that these compounds may
also bind protein C (PC) and accelerate its activation by thrombin or
other heparin binding plasma serine proteinases by a similar mechanism.
To test this, PC activation by thrombin and factor Xa (fXa) was studied
in the presence of these polysaccharides. With thrombin in the absence
of thrombomodulin (TM), these polysaccharides markedly reduced the
Km for PC and Gla-domainless PC (GDPC) activation in the
presence of Ca2+. With TM containing chondroitin sulfate,
heparin did not influence PC activation by thrombin, but with TM
lacking chondroitin sulfate, the characteristic high-affinity PC
interaction at low Ca2+ (~50 to 100 µmol/L) was
largely eliminated by heparin. In EDTA, heparin enhanced thrombin
activation of GDPC by reducing the Km, but it inhibited PC
activation by increasing the Km. PC activation in EDTA was
insensitive to the presence of heparin if the exosite 2 mutant,
R93,97,101A thrombin, was used for activation. These results suggest
that, when the Gla-domain of PC is not fully stabilized by
Ca2+, it interacts with the anion binding exosite 2 of
thrombin and that heparin binding to this site prevents this
interaction. Additional studies indicated that, in the presence of
phospholipid vesicles, heparin and dextran sulfate dramatically
accelerate PC activation by fXa by also reducing the Km.
Interestingly, on phospholipids containing 40%
phosphatidylethanolamine, the activation rate of near physiological PC
concentrations (~80 nmol/L) by fXa in the presence of dextran sulfate
was nearly comparable to that observed by the thrombin-TM complex. The
biochemical and potential therapeutical ramifications of these findings
are discussed.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4572-4580
© 1998 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
W. Li, X. Zheng, J.-M. Gu, G. L. Ferrell, M. Brady, N. L. Esmon, and C. T. Esmon
Extraembryonic expression of EPCR is essential for embryonic viability
Blood,
October 15, 2005;
106(8):
2716 - 2722.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. R. Rezaie and L. Yang
Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin
PNAS,
October 14, 2003;
100(21):
12051 - 12056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Yang, C. Manithody, T. D. Walston, S. T. Cooper, and A. R. Rezaie
Thrombomodulin Enhances the Reactivity of Thrombin with Protein C Inhibitor by Providing Both a Binding Site for the Serpin and Allosterically Modulating the Activity of Thrombin
J. Biol. Chem.,
September 26, 2003;
278(39):
37465 - 37470.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. A. Simmelink, P. G. de Groot, R. H. W. M. Derksen, J. A. Fernandez, and J. H. Griffin
Oral anticoagulation reduces activated protein C less than protein C and other vitamin K-dependent clotting factors
Blood,
December 1, 2002;
100(12):
4232 - 4233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B Isermann, S. Hendrickson, K Hutley, M Wing, and H Weiler
Tissue-restricted expression of thrombomodulin in the placenta rescues thrombomodulin-deficient mice from early lethality and reveals a secondary developmental block
Development,
January 3, 2001;
128(6):
827 - 838.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. O. Villoutreix, A. M. Blom, and B. Dahlback
Structural prediction and analysis of endothelial cell protein C/activated protein C receptor
Protein Eng. Des. Sel.,
October 1, 1999;
12(10):
833 - 840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Macko, L. A. Killewich, J. A. Fernandez, D. K. Cox, A. Gruber, and J. H. Griffin
Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans
Stroke,
March 1, 1999;
30(3):
542 - 545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Bates and J. I. Weitz
Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin
Cardiovasc Res,
February 1, 1999;
41(2):
418 - 432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. R. Rezaie
Calcium Enhances Heparin Catalysis of the Antithrombin-Factor Xa Reaction by a Template Mechanism. EVIDENCE THAT CALCIUM ALLEVIATES Gla DOMAIN ANTAGONISM OF HEPARIN BINDING TO FACTOR Xa
J. Biol. Chem.,
July 3, 1998;
273(27):
16824 - 16827.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
