PMID- 30135185
OWN - NLM
STAT- MEDLINE
DCOM- 20190404
LR  - 20220701
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 2
IP  - 16
DP  - 2018 Aug 28
TI  - Comparison of reversal activity and mechanism of action of UHRA, andexanet, and 
      PER977 on heparin and oral FXa inhibitors.
PG  - 2104-2114
LID - 10.1182/bloodadvances.2016003616 [doi]
AB  - Anticoagulants such as unfractionated heparin (UFH), low-molecular-weight 
      heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting 
      thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of 
      thromboembolic disorders. However, anticoagulant-associated bleeding is a concern 
      that demands monitoring and neutralization. Protamine, the UFH antidote, has 
      limitations, while there is no antidote available for certain direct FXa 
      inhibitors. Improved antidotes in development include UHRA (Universal Heparin 
      Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a 
      recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag 
      (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The 
      binding affinities of these antidotes for their presumed anticoagulant targets 
      have not been compared. Here, isothermal titration calorimetry (ITC) was used to 
      determine the affinity of each antidote for its putative targets. Clotting and 
      chromogenic FXa assays were used to characterize neutralization activity, and 
      electron microscopy was used to visualize the effect of each antidote on clot 
      morphology in the absence or presence of anticoagulant. ITC confirmed binding of 
      UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and 
      to the antithrombin-enoxaparin complex. PER977 was found to bind heparins weakly, 
      but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at 
      or below the micromolar level was found to correlate with neutralization 
      activity, while no reversal activity was observed for the PER977/anticoagulant 
      systems. Standard metrics of clot structure were found to correlate weakly with 
      PER977's activity. This is the first study comparing 3 antidotes in development, 
      with each exerting activity through a distinct mechanism.
CI  - (c) 2018 by The American Society of Hematology.
FAU - Kalathottukaren, Manu T
AU  - Kalathottukaren MT
AD  - Centre for Blood Research.
AD  - Department of Pathology and Laboratory Medicine, and.
FAU - Creagh, A Louise
AU  - Creagh AL
AD  - Centre for Blood Research.
AD  - Michael Smith Laboratories, Department of Chemical and Biological Engineering, 
      University of British Columbia, Vancouver, BC, Canada.
FAU - Abbina, Srinivas
AU  - Abbina S
AD  - Centre for Blood Research.
AD  - Department of Pathology and Laboratory Medicine, and.
FAU - Lu, Genmin
AU  - Lu G
AD  - Portola Pharmaceuticals, Inc., South San Francisco, CA; and.
FAU - Karbarz, Mark J
AU  - Karbarz MJ
AD  - Portola Pharmaceuticals, Inc., South San Francisco, CA; and.
FAU - Pandey, Anjali
AU  - Pandey A
AD  - Portola Pharmaceuticals, Inc., South San Francisco, CA; and.
FAU - Conley, Pamela B
AU  - Conley PB
AD  - Portola Pharmaceuticals, Inc., South San Francisco, CA; and.
FAU - Kizhakkedathu, Jayachandran N
AU  - Kizhakkedathu JN
AD  - Centre for Blood Research.
AD  - Department of Pathology and Laboratory Medicine, and.
AD  - Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.
FAU - Haynes, Charles
AU  - Haynes C
AD  - Centre for Blood Research.
AD  - Michael Smith Laboratories, Department of Chemical and Biological Engineering, 
      University of British Columbia, Vancouver, BC, Canada.
LA  - eng
GR  - CIHR/Canada
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Dendrimers)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (PRT064445)
RN  - 0 (Piperazines)
RN  - 0 (Recombinant Proteins)
RN  - 9005-49-6 (Heparin)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.4.21.6 (Factor Xa)
RN  - U2R67KV65Q (PER977)
SB  - IM
MH  - Administration, Oral
MH  - Arginine/*analogs & derivatives/pharmacology
MH  - Blood Coagulation/*drug effects
MH  - Dendrimers/*pharmacology
MH  - Factor Xa/*pharmacology
MH  - Factor Xa Inhibitors/*pharmacology
MH  - Heparin/*pharmacology
MH  - Humans
MH  - Piperazines/*pharmacology
MH  - Recombinant Proteins/*pharmacology
PMC - PMC6113616
COIS- Conflict-of-interest disclosure: J.N.K. and C.H. hold patents for the use of UHRA 
      compounds as antidotes for heparin-based anticoagulants and for treating other 
      blood disorders. G.L., M.J.K., A.P. and P.B.C. are employed by Portola 
      Pharmaceuticals, Inc. The remaining authors declare no competing financial 
      interests.
EDAT- 2018/08/24 06:00
MHDA- 2019/04/05 06:00
PMCR- 2018/08/22
CRDT- 2018/08/24 06:00
PHST- 2016/12/09 00:00 [received]
PHST- 2018/07/27 00:00 [accepted]
PHST- 2018/08/24 06:00 [entrez]
PHST- 2018/08/24 06:00 [pubmed]
PHST- 2019/04/05 06:00 [medline]
PHST- 2018/08/22 00:00 [pmc-release]
AID - bloodadvances.2016003616 [pii]
AID - 2016/003616 [pii]
AID - 10.1182/bloodadvances.2016003616 [doi]
PST - ppublish
SO  - Blood Adv. 2018 Aug 28;2(16):2104-2114. doi: 10.1182/bloodadvances.2016003616.