PMID- 21126754
OWN - NLM
STAT- MEDLINE
DCOM- 20110629
LR  - 20161125
IS  - 1879-2472 (Electronic)
IS  - 0049-3848 (Linking)
VI  - 127
IP  - 2
DP  - 2011 Feb
TI  - Heparin affinity of factor VIIa: implications on the physiological inhibition by 
      antithrombin and clearance of recombinant factor VIIa.
PG  - 154-60
LID - 10.1016/j.thromres.2010.11.008 [doi]
AB  - Factor VIIa (FVIIa), a trypsin-like serine protease, plays an essential role in 
      haemostasis by initiating the coagulation in complex with its cofactor, tissue 
      factor (TF). The TF pathway inhibitor is the main physiological inhibitor of 
      FVIIa-TF complex, but FVIIa can also be inhibited by antithrombin, although 
      little is known about this process. Functional analyses by second order kinetic 
      determination and identification of FVIIa-antithrombin complex by 
      electrophoresis, evaluating the effect of different cofactors: pentasaccharide, 
      low molecular weight heparin (LMWH) and unfractionated heparin (UFH), confirmed 
      that any activation of antithrombin significantly enhanced the inhibition of 
      FVIIa. The analysis of the binding of FVIIa to heparin by surface plasmon 
      resonance identified a high affinity interaction under physiologic conditions 
      (K(D)=3.38 muM, with 0.15M of ionic strength) strongly dependent on Ca(2+) and 
      ionic strength. This interaction was verified in cell models, indicating that 
      FVIIa also binds to the surface of endothelial cells with similar requirements. 
      Structural modeling suggests the presence of a potential exosite II in FVIIa. 
      However, the binding of heparin did not display significant changes on both the 
      intrinsic fluorescence and the associated functional consequences of FVIIa. These 
      results indicate that FVIIa binds to exposed glycosaminglycans of the endothelium 
      through an exosite II, structurally similar to that reported for thrombin and 
      suggested for FIXa. This binding may favor its inhibition by antithrombin in the 
      absence of TF, contributing to the physiological control of this protease. This 
      process may also play an important role in the clearance of recombinant FVIIa 
      administered to patients.
CI  - Copyright A(c) 2010 Elsevier Ltd. All rights reserved.
FAU - Martinez-Martinez, I
AU  - Martinez-Martinez I
AD  - University of Murcia, Centro Regional de Hemodonacion, Spain.
FAU - Ordonez, A
AU  - Ordonez A
FAU - Pedersen, S
AU  - Pedersen S
FAU - de la Morena-Barrio, M E
AU  - de la Morena-Barrio ME
FAU - Navarro-Fernandez, J
AU  - Navarro-Fernandez J
FAU - Kristensen, S R
AU  - Kristensen SR
FAU - Minano, A
AU  - Minano A
FAU - Padilla, J
AU  - Padilla J
FAU - Vicente, V
AU  - Vicente V
FAU - Corral, J
AU  - Corral J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101203
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Antithrombins)
RN  - 0 (Recombinant Proteins)
RN  - 9005-49-6 (Heparin)
RN  - AC71R787OV (recombinant FVIIa)
RN  - EC 3.4.21.21 (Factor VIIa)
SB  - IM
MH  - Animals
MH  - Antithrombins/metabolism/*pharmacology
MH  - Cell Line, Tumor
MH  - Endothelial Cells/drug effects/metabolism
MH  - Factor VIIa/antagonists & inhibitors/*chemistry/metabolism
MH  - Heparin/*chemistry/pharmacology
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Molecular
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry/metabolism
MH  - Surface Plasmon Resonance
EDAT- 2010/12/04 06:00
MHDA- 2011/06/30 06:00
CRDT- 2010/12/04 06:00
PHST- 2010/06/28 00:00 [received]
PHST- 2010/11/02 00:00 [revised]
PHST- 2010/11/08 00:00 [accepted]
PHST- 2010/12/04 06:00 [entrez]
PHST- 2010/12/04 06:00 [pubmed]
PHST- 2011/06/30 06:00 [medline]
AID - S0049-3848(10)00604-3 [pii]
AID - 10.1016/j.thromres.2010.11.008 [doi]
PST - ppublish
SO  - Thromb Res. 2011 Feb;127(2):154-60. doi: 10.1016/j.thromres.2010.11.008. Epub 
      2010 Dec 3.