Document Detail


Low molecular weight heparin inhibits plasma thrombin generation via direct targeting of factor IXa: contribution of the serpin-independent mechanism.
MedLine Citation:
PMID:  22905983     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Although heparin possesses multiple mechanisms of action, enhanced factor Xa inhibition by antithrombin is accepted as the predominant therapeutic mechanism. The contribution of FIXa inhibition to heparin activity in human plasma remains incompletely defined.
OBJECTIVES: To determine the relevance of FIXa as a therapeutic target for heparins, particularly serpin-independent inhibition of intrinsic tenase (FIXa-FVIIIa) activity.
PATIENTS/METHODS: Thrombin generation was detected by fluorogenic substrate cleavage. The inhibitory potencies (EC(50) s) of low molecular weight heparin (LMWH), super-sulfated LMWH (ssLMWH), fondaparinux and unfractionated heparin (UFH) were determined by plotting concentration vs. relative velocity index (ratio ± heparin). Inhibition was compared under FIX-dependent and FIX-independent conditions (0.2 or 4 pm tissue factor [TF], respectively) in normal plasma, and in mock-depleted or antithrombin/FIX-depleted plasma supplemented with recombinant FIX.
RESULTS: UFH and fondaparinux demonstrated similar potency under FIX-dependent and FIX-independent conditions, whereas LMWH (2.9-fold) and ssLMWH (5.1-fold) demonstrated increased potency with limiting TF. UFH (62-fold) and fondaparinux (42-fold) demonstrated markedly increased EC(50) values in antithrombin-depleted plasma, whereas LMWH (9.4-fold) and ssLMWH (two-fold) were less affected, with an EC(50) within the therapeutic range for LMWH. The molecular target for LMWH/ssLMWH was confirmed by supplementing FIX/antithrombin-depleted plasma with 90 nm recombinant FIX possessing mutations in the heparin-binding exosite. Mutated FIX demonstrated resistance to inhibition of thrombin generation by LMWH and ssLMWH that paralleled the effect of these mutations on intrinsic tenase inhibition.
CONCLUSIONS: Therapeutic LMWH concentrations inhibit plasma thrombin generation via antithrombin-independent interaction with the FIXa heparin-binding exosite.
Authors:
Y Buyue; T M Misenheimer; J P Sheehan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  10     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-02-28     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  2086-98     Citation Subset:  IM    
Copyright Information:
© 2012 International Society on Thrombosis and Haemostasis.
Affiliation:
Department of Pathology, University of Wisconsin-Madison, Madison, WI, USA.
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MeSH Terms
Descriptor/Qualifier:
Anticoagulants / metabolism,  pharmacology*
Antithrombin III / metabolism
Antithrombin Proteins / metabolism*
Binding Sites
Blood Coagulation / drug effects*
Blotting, Western
Dose-Response Relationship, Drug
Down-Regulation
Factor IXa / adverse effects*,  genetics,  metabolism
Heparin, Low-Molecular-Weight / metabolism,  pharmacology*
Humans
Kinetics
Mutation
Peptide Hydrolases / metabolism
Polysaccharides / metabolism,  pharmacology*
Recombinant Proteins / metabolism
Thrombin / metabolism*
Thromboplastin / metabolism
Grant Support
ID/Acronym/Agency:
HL080452/HL/NHLBI NIH HHS; R01 HL080452/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Antithrombin Proteins; 0/Heparin, Low-Molecular-Weight; 0/Polysaccharides; 0/Recombinant Proteins; 0/antithrombin III-protease complex; 9000-94-6/Antithrombin III; 9035-58-9/Thromboplastin; EC 3.4.-/Peptide Hydrolases; EC 3.4.21.22/Factor IXa; EC 3.4.21.5/Thrombin; J177FOW5JL/fondaparinux
Comments/Corrections
Comment In:
J Thromb Haemost. 2013 Mar;11(3):565-6   [PMID:  23332108 ]
J Thromb Haemost. 2013 Mar;11(3):564   [PMID:  23289967 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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