PMID- 20216984
OWN - NLM
STAT- MEDLINE
DCOM- 20101005
LR  - 20101007
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 103
IP  - 5
DP  - 2010 May
TI  - Covalent antithrombin-heparin effect on thrombin-thrombomodulin and activated 
      protein C reaction with factor V/Va.
PG  - 910-9
LID - 10.1160/TH09-07-0473 [doi]
AB  - Thrombomodulin (TM), which variably contains a chondroitin sulfate (+/-CS), forms 
      an anticoagulant complex with thrombin (IIa). IIa-TM(+/-CS) converts protein C 
      (PC) into activated PC (APC), which then inactivates activated factors V (FVa) 
      and VIII (FVIIIa). This reduces prothrombinase and tenase complexes that generate 
      IIa. Heparin (H) increases the rate of IIa-TM inhibition by antithrombin (AT) and 
      enhances FV cleavage by APC. Our novel covalent AT-H (ATH) product, has superior 
      anticoagulant activity compared to AT + unfractionated H (UFH). We studied 
      mechanisms by which ATH versus AT + UFH inhibits IIa-TM(+/-CS), and ATH 
      influences on APC cleavage of FV/FVa compared to UFH. Findings would determine 
      how these reactions moderate ATH's overall effects as an anticoagulant. 
      Discontinuous second order rate inhibition assays of IIa-TM(+/-CS) inhibition by 
      AT + UFH or ATH were performed in presence or absence of human umbilical vein 
      endothelial cells (HUVECs). FV/FVa cleavage by APC in the presence of UFH or ATH 
      was analysed by Western blots. ATH increased IIa-TM(+/-CS) inhibition to a 
      greater degree than AT + UFH, both on plastic and HUVEC surfaces. Unlike UFH, ATH 
      did not accelerate FV cleavage by APC, but ATH did enhance FVa cleavage relative 
      to UFH. Increased IIa-TM inhibition by ATH downregulates PC activation. However, 
      ATH does accelerate downstream inactivation of FVa, which increases its potency 
      for IIa generation inhibition compared to UFH. This trend holds true in the 
      presence of APC's cofactor, protein S. Overall, ATH may have a balanced function 
      towards inhibiting or accelerating PC pathway activities.
FAU - Van Walderveen, Maria Christina
AU  - Van Walderveen MC
AD  - David Braley Research Institute, Hamilton, Ontario, Canada.
FAU - Berry, Leslie Roy
AU  - Berry LR
FAU - Atkinson, Helen Mary
AU  - Atkinson HM
FAU - Chan, Anthony Kam Chuen
AU  - Chan AK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100309
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Anticoagulants)
RN  - 0 (Antithrombins)
RN  - 0 (Protein C)
RN  - 0 (Thrombomodulin)
RN  - 9001-24-5 (Factor V)
RN  - 9001-26-7 (Prothrombin)
RN  - 9002-04-4 (Factor IIa)
RN  - 9005-49-6 (Heparin)
RN  - 9007-28-7 (Chondroitin Sulfates)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Anticoagulants/therapeutic use
MH  - Antithrombins/chemical synthesis/*pharmacology/therapeutic use
MH  - Blood Coagulation/drug effects
MH  - Cells, Cultured
MH  - Chondroitin Sulfates/metabolism
MH  - Endothelial Cells/drug effects/*metabolism/pathology
MH  - Enzyme Activation/drug effects
MH  - Factor V/metabolism
MH  - Heparin/chemical synthesis/*pharmacology/therapeutic use
MH  - Humans
MH  - Protein Binding
MH  - Protein C/metabolism
MH  - Prothrombin/metabolism
MH  - Thrombin/*antagonists & inhibitors
MH  - Thrombomodulin/metabolism
EDAT- 2010/03/11 06:00
MHDA- 2010/10/06 06:00
CRDT- 2010/03/11 06:00
PHST- 2009/07/22 00:00 [received]
PHST- 2009/12/19 00:00 [accepted]
PHST- 2010/03/11 06:00 [entrez]
PHST- 2010/03/11 06:00 [pubmed]
PHST- 2010/10/06 06:00 [medline]
AID - 09-07-0473 [pii]
AID - 10.1160/TH09-07-0473 [doi]
PST - ppublish
SO  - Thromb Haemost. 2010 May;103(5):910-9. doi: 10.1160/TH09-07-0473. Epub 2010 Mar 
      9.