PMID- 19572069
OWN - NLM
STAT- MEDLINE
DCOM- 20090914
LR  - 20090702
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 102
IP  - 1
DP  - 2009 Jul
TI  - Anticoagulant mechanisms of covalent antithrombin-heparin investigated by 
      thrombelastography. Comparison with unfractionated heparin and 
      low-molecular-weight heparin.
PG  - 62-8
LID - 10.1160/TH08-11-0769 [doi]
AB  - We have developed an antithrombin-heparin covalent complex (ATH) which inhibits 
      coagulation enzymes by two mechanisms: directly, or by catalytic activation of 
      plasma antithrombin (AT). Anticoagulation by ATH was compared to unfractionated 
      heparin (UFH) or low-molecular-weight heparin (LMWH) using a blood-based, tissue 
      factor (TF)-activated thrombelastography (TEG) assay. Simplified TEG assays with 
      plasma or purified plasma components were used to determine the contribution of 
      the direct and catalytic mechanisms to ATH efficacy. Low anti-Xa concentrations 
      of UFH inhibited clot formation significantly more than equivalent concentrations 
      of ATH or LMWH in blood and plasma. ATH had reduced ability to catalyse 
      AT-mediated thrombin (IIa) inhibition compared to UFH. However, at high anti-Xa 
      concentrations, ATH had similar anticoagulant activity to UFH. ATH and 
      non-covalent AT+UFH directly inhibited clotting to a similar degree in 
      AT-deficient plasma. IIa-ATH complexes, which are limited to catalytic 
      inhibition, displayed impaired anticoagulation compared to free ATH, and the 
      magnitude of this effect increased significantly as anticoagulant concentration 
      increased. Kinetic experiments indicated that the rate of reaction of AT with IIa 
      is lower when catalysed by ATH versus UFH. In conclusion, at low anti-Xa doses 
      catalytic inhibition is the primary mechanism of ATH anticoagulation, and the 
      catalytic potential of ATH is reduced relative to UFH. However, the direct 
      inhibitory activity of ATH is comparable to non-covalent AT+UFH, and at high 
      anti-Xa doses the direct inhibitory activity of ATH may play a larger role in 
      anticoagulation.
FAU - Atkinson, Helen M
AU  - Atkinson HM
AD  - Henderson Research Centre, Hamilton, ON, Canada.
FAU - Mewhort-Buist, Tracy A
AU  - Mewhort-Buist TA
FAU - Berry, Leslie R
AU  - Berry LR
FAU - Chan, Anthony K C
AU  - Chan AK
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Anticoagulants)
RN  - 0 (Antithrombins)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 9001-32-5 (Fibrinogen)
SB  - IM
MH  - Anticoagulants/*metabolism/pharmacology
MH  - Antithrombins/*metabolism/pharmacology
MH  - Blood Coagulation/*drug effects
MH  - Catalysis
MH  - Dose-Response Relationship, Drug
MH  - Fibrinogen/metabolism
MH  - Heparin, Low-Molecular-Weight/*metabolism/pharmacology
MH  - Humans
MH  - Plasma
MH  - Thrombelastography/*drug effects
EDAT- 2009/07/03 09:00
MHDA- 2009/09/15 06:00
CRDT- 2009/07/03 09:00
PHST- 2009/07/03 09:00 [entrez]
PHST- 2009/07/03 09:00 [pubmed]
PHST- 2009/09/15 06:00 [medline]
AID - TH08-11-0769 [pii]
AID - 10.1160/TH08-11-0769 [doi]
PST - ppublish
SO  - Thromb Haemost. 2009 Jul;102(1):62-8. doi: 10.1160/TH08-11-0769.