PMID- 23494009
OWN - NLM
STAT- MEDLINE
DCOM- 20140130
LR  - 20130604
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 109
IP  - 6
DP  - 2013 Jun
TI  - Covalently linking heparin to antithrombin enhances prothrombinase inhibition on 
      activated platelets.
PG  - 1016-24
LID - 10.1160/TH12-10-0766 [doi]
AB  - Factor (F)Xa within the prothrombinase complex is protected from inhibition by 
      unfractionated heparin (UFH), enoxaparin and fondaparinux. We have developed a 
      covalent antithrombin-heparin complex (ATH) with enhanced anticoagulant activity. 
      We have also demonstrated that ATH is superior at inhibiting coagulation factors 
      when assembled on artificial surfaces. The objective of the present study is to 
      determine the ability of ATH vs AT+UFH to inhibit FXa within the prothrombinase 
      complex when the enzyme complex is assembled on the more native platelet system. 
      Discontinuous inhibition assays were performed to determine final k2-values for 
      inhibition of FXa, FXa within the platelet-prothrombinase, or FXa within 
      prothrombinase devoid of various components. Thrombin generation and plasma 
      clotting was also assayed in the presence of resting/activated platelets +/- 
      inhibitors. Protection of FXa was not observed for ATH, whereas a moderate 60% 
      protection was observed for AT+UFH. ATH inhibited platelet-prothrombinase ~4-fold 
      faster than AT+UFH. Relative to intact prothrombinase, ratesfor FXa inhibition by 
      AT+UFH in prothrombinase complexes devoid of either prothrombin (II)/activated 
      platelets/FVa were higher. However, inhibition by AT+UFH of prothrombinase devoid 
      of FII yielded slightly lower rates compared to free FXa inhibition. Thrombin 
      generation and plasma clotting was enhanced with activated platelets, while 
      inhibition was better by ATH compared to AT+UFH, thus suggesting an overall 
      enhanced anticoagulant activity of ATH against platelet-bound prothrombinase 
      complexes.
FAU - Stevic, Ivan
AU  - Stevic I
AD  - Thrombosis and Atherosclerosis Research Institute (TaARI), DBCVSRI, Hamilton 
      General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
FAU - Chan, Howard H W
AU  - Chan HH
FAU - Chander, Ankush
AU  - Chander A
FAU - Berry, Leslie R
AU  - Berry LR
FAU - Chan, Anthony K C
AU  - Chan AK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130314
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Anticoagulants)
RN  - 0 (Antithrombins)
RN  - 0 (Enzyme Inhibitors)
RN  - 9005-49-6 (Heparin)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.21.6 (Factor Xa)
SB  - IM
MH  - Anticoagulants/chemistry
MH  - Antithrombins/*chemistry
MH  - Blood Coagulation
MH  - Blood Platelets/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Factor Xa/chemistry
MH  - Flow Cytometry
MH  - Heparin/*chemistry
MH  - Humans
MH  - Nephelometry and Turbidimetry
MH  - *Platelet Activation
MH  - Protein Binding
MH  - Thromboplastin/*antagonists & inhibitors/chemistry
EDAT- 2013/03/16 06:00
MHDA- 2014/01/31 06:00
CRDT- 2013/03/16 06:00
PHST- 2012/10/23 00:00 [received]
PHST- 2013/02/21 00:00 [accepted]
PHST- 2013/03/16 06:00 [entrez]
PHST- 2013/03/16 06:00 [pubmed]
PHST- 2014/01/31 06:00 [medline]
AID - 12-10-0766 [pii]
AID - 10.1160/TH12-10-0766 [doi]
PST - ppublish
SO  - Thromb Haemost. 2013 Jun;109(6):1016-24. doi: 10.1160/TH12-10-0766. Epub 2013 Mar 
      14.