PMID- 21048158
OWN - NLM
STAT- MEDLINE
DCOM- 20110404
LR  - 20210206
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 6
DP  - 2011 Feb 10
TI  - Development of a recombinant antithrombin variant as a potent antidote to 
      fondaparinux and other heparin derivatives.
PG  - 2054-60
LID - 10.1182/blood-2010-06-288522 [doi]
AB  - Heparin derivative-based therapy has evolved from unfractionated heparin (UFH) to 
      low-molecular-weight heparins (LMWHs) and now fondaparinux, a synthetic 
      pentasaccharide. Contrary to UFH or LMWHs, fondaparinux is not neutralized by 
      protamine sulfate, and no antidote is available to counteract bleeding disorders 
      associated with overdosing. To make the use of fondaparinux safer, we developed 
      an antithrombin (AT) variant as a potent antidote to heparin derivatives. This 
      variant (AT-N135Q-Pro394) combines 2 mutations: substitution of Asn135 by a Gln 
      to remove a glycosylation site and increase affinity for heparins, and the 
      insertion of a Pro between Arg393 and Ser394 to abolish its anticoagulant 
      activity. As expected, AT-N135Q-Pro394 anticoagulant activity was almost 
      abolished, and it exhibited a 3-fold increase in fondaparinux affinity. 
      AT-N135Q-Pro394 was shown to reverse fondaparinux overdosing in vitro in a 
      dose-dependent manner through a competitive process with plasma AT for 
      fondaparinux binding. This antidote effect was also observed in vivo: 
      administration of AT-N135Q-Pro394 in 2.5-fold molar excess versus plasma AT 
      neutralized 86% of the anti-Xa activity within 5 minutes in mice treated with 
      fondaparinux. These results clearly demonstrate that AT-N135Q-Pro394 can reverse 
      the anticoagulant activity of fondaparinux and thus could be used as an antidote 
      for this drug.
FAU - Bianchini, Elsa P
AU  - Bianchini EP
AD  - Universite Paris-Sud, Laboratoire d'hematologie, Chatenay-Malabry, France. 
      elsa.bianchini@u-psud.fr
FAU - Fazavana, Judicael
AU  - Fazavana J
FAU - Picard, Veronique
AU  - Picard V
FAU - Borgel, Delphine
AU  - Borgel D
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
DEP - 20101103
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Anticoagulants)
RN  - 0 (Antidotes)
RN  - 0 (Antithrombin Proteins)
RN  - 0 (Antithrombins)
RN  - 0 (Heparin Antagonists)
RN  - 0 (Polysaccharides)
RN  - 0 (Recombinant Proteins)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Anticoagulants/*antagonists & inhibitors/toxicity
MH  - Antidotes/*pharmacology
MH  - Antithrombin Proteins/*genetics/*pharmacology
MH  - Antithrombins/*pharmacology
MH  - Drug Design
MH  - Female
MH  - Fondaparinux
MH  - HEK293 Cells
MH  - Hemorrhage/chemically induced/drug therapy
MH  - Heparin Antagonists/*pharmacology
MH  - Humans
MH  - Mice
MH  - Polysaccharides/*antagonists & inhibitors/toxicity
MH  - Recombinant Proteins/genetics/pharmacology
EDAT- 2010/11/05 06:00
MHDA- 2011/04/05 06:00
CRDT- 2010/11/05 06:00
PHST- 2010/11/05 06:00 [entrez]
PHST- 2010/11/05 06:00 [pubmed]
PHST- 2011/04/05 06:00 [medline]
AID - S0006-4971(20)60324-X [pii]
AID - 10.1182/blood-2010-06-288522 [doi]
PST - ppublish
SO  - Blood. 2011 Feb 10;117(6):2054-60. doi: 10.1182/blood-2010-06-288522. Epub 2010 
      Nov 3.