PMID- 22905983
OWN - NLM
STAT- MEDLINE
DCOM- 20130228
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7933 (Print)
IS  - 1538-7836 (Linking)
VI  - 10
IP  - 10
DP  - 2012 Oct
TI  - Low molecular weight heparin inhibits plasma thrombin generation via direct 
      targeting of factor IXa: contribution of the serpin-independent mechanism.
PG  - 2086-98
LID - 10.1111/j.1538-7836.2012.04892.x [doi]
AB  - 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.
CI  - (c) 2012 International Society on Thrombosis and Haemostasis.
FAU - Buyue, Y
AU  - Buyue Y
AD  - Department of Pathology, University of Wisconsin-Madison, Madison, WI, USA.
FAU - Misenheimer, T M
AU  - Misenheimer TM
FAU - Sheehan, J P
AU  - Sheehan JP
LA  - eng
GR  - R01 HL080452/HL/NHLBI NIH HHS/United States
GR  - HL080452/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Anticoagulants)
RN  - 0 (Antithrombin Proteins)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Polysaccharides)
RN  - 0 (Recombinant Proteins)
RN  - 0 (antithrombin III-protease complex)
RN  - 9000-94-6 (Antithrombin III)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.21.22 (Factor IXa)
RN  - EC 3.4.21.5 (Thrombin)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
CIN - J Thromb Haemost. 2013 Mar;11(3):564. PMID: 23289967
CIN - J Thromb Haemost. 2013 Mar;11(3):565-6. PMID: 23332108
MH  - Anticoagulants/metabolism/*pharmacology
MH  - Antithrombin III/metabolism
MH  - Antithrombin Proteins/*metabolism
MH  - Binding Sites
MH  - Blood Coagulation/*drug effects
MH  - Blotting, Western
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Factor IXa/*adverse effects/genetics/metabolism
MH  - Fondaparinux
MH  - Heparin, Low-Molecular-Weight/metabolism/*pharmacology
MH  - Humans
MH  - Kinetics
MH  - Mutation
MH  - Peptide Hydrolases/metabolism
MH  - Polysaccharides/metabolism/*pharmacology
MH  - Recombinant Proteins/metabolism
MH  - Thrombin/*metabolism
MH  - Thromboplastin/metabolism
PMC - PMC3463736
MID - NIHMS402668
EDAT- 2012/08/22 06:00
MHDA- 2013/03/01 06:00
PMCR- 2013/10/01
CRDT- 2012/08/22 06:00
PHST- 2012/08/22 06:00 [entrez]
PHST- 2012/08/22 06:00 [pubmed]
PHST- 2013/03/01 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - S1538-7836(22)06512-6 [pii]
AID - 10.1111/j.1538-7836.2012.04892.x [doi]
PST - ppublish
SO  - J Thromb Haemost. 2012 Oct;10(10):2086-98. doi: 10.1111/j.1538-7836.2012.04892.x.