PMID- 26709038
OWN - NLM
STAT- MEDLINE
DCOM- 20161024
LR  - 20181113
IS  - 1879-2472 (Electronic)
IS  - 0049-3848 (Print)
IS  - 0049-3848 (Linking)
VI  - 138
DP  - 2016 Feb
TI  - In vitro and in vivo characterization of a reversible synthetic heparin analog.
PG  - 121-129
LID - S0049-3848(15)30222-X [pii]
LID - 10.1016/j.thromres.2015.12.007 [doi]
AB  - BACKGROUND: The global supply of unfractionated heparin (UFH) and all 
      commercially available low molecular weight heparins (LMWH) remain dependent on 
      animal sources, such as porcine intestine or bovine lung. Recent experience has 
      shown that contamination of the supply chain (with over-sulfated chondroitin 
      sulfates) can result in lethal toxicity. Fondaparinux is currently the only 
      commercially available synthetic analog of heparin. We recently described a new 
      class of chemoenzymatically synthesized heparin analogs. One of these compounds 
      (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with 
      repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the 
      ability to bind protamine. OBJECTIVE/METHODS: We sought to further characterize 
      this new compound in vitro using biochemical and global coagulation assays and in 
      vivo using thrombosis and hemostasis assays. RESULTS: The anticoagulant 
      activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and 
      plasma-based thrombin generation assays were roughly equivalent with a 50% 
      reduction in peak thrombin generation occurring at approximately 325nM. When 
      protamine was titrated against a fixed concentration of S12-mer in plasma or 
      blood, the S12-mer displayed a significant restitution of thrombin generation and 
      clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent 
      as Enoxaparin, with similar bleeding profiles. CONCLUSIONS: These data show that 
      the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa 
      inhibition, while displaying significant reversibility with protamine. Taken 
      together with the ability to ensure purity and homogeneity from batch to batch, 
      the S12-mer is a promising new synthetic heparin analog with a potentially 
      enhanced safety profile.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Whelihan, Matthew F
AU  - Whelihan MF
AD  - Department of Medicine, The University of North Carolina at Chapel Hill, Chapel 
      Hill, NC, United States; McAllister Heart Institute, The University of North 
      Carolina at Chapel Hill, Chapel Hill, NC, United States.
FAU - Cooley, Brian
AU  - Cooley B
AD  - Department of Pathology and Laboratory Medicine, The University of North Carolina 
      at Chapel Hill, Chapel Hill, NC, United States; McAllister Heart Institute, The 
      University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
FAU - Xu, Yongmei
AU  - Xu Y
AD  - Division of Chemical Biology and Medicinal Chemistry, Eshelman School of 
      Pharmacy, The University of North Carolina at Chapel Hill, NC, United States.
FAU - Pawlinski, Rafal
AU  - Pawlinski R
AD  - Department of Medicine, The University of North Carolina at Chapel Hill, Chapel 
      Hill, NC, United States; McAllister Heart Institute, The University of North 
      Carolina at Chapel Hill, Chapel Hill, NC, United States.
FAU - Liu, Jian
AU  - Liu J
AD  - Division of Chemical Biology and Medicinal Chemistry, Eshelman School of 
      Pharmacy, The University of North Carolina at Chapel Hill, NC, United States.
FAU - Key, Nigel S
AU  - Key NS
AD  - Department of Medicine, The University of North Carolina at Chapel Hill, Chapel 
      Hill, NC, United States; Department of Pathology and Laboratory Medicine, The 
      University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; 
      McAllister Heart Institute, The University of North Carolina at Chapel Hill, 
      Chapel Hill, NC, United States. Electronic address: Nigel_key@med.unc.edu.
LA  - eng
GR  - R01 HL094463/HL/NHLBI NIH HHS/United States
GR  - T32 HL007149/HL/NHLBI NIH HHS/United States
GR  - U01 GM102137/GM/NIGMS NIH HHS/United States
GR  - R01-HL094463/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20151210
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Anticoagulants)
RN  - 0 (Enoxaparin)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Heparin Antagonists)
RN  - 0 (Protamines)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.4.21.6 (Factor Xa)
SB  - IM
MH  - Animals
MH  - Anticoagulants/pharmacology
MH  - Blood Coagulation/*drug effects
MH  - Enoxaparin/pharmacology
MH  - Factor Xa/metabolism
MH  - Factor Xa Inhibitors/*chemistry/*pharmacology
MH  - Heparin/*analogs & derivatives/*pharmacology
MH  - Heparin Antagonists/pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Protamines/pharmacology
MH  - Thrombin/metabolism
PMC - PMC4751072
MID - NIHMS746630
COIS- Conflicts of Interest Disclosure MFW, NSK, BC and RP have no conflicts of 
      interest to declare.
EDAT- 2015/12/29 06:00
MHDA- 2016/10/25 06:00
PMCR- 2017/02/01
CRDT- 2015/12/29 06:00
PHST- 2015/09/23 00:00 [received]
PHST- 2015/12/01 00:00 [revised]
PHST- 2015/12/09 00:00 [accepted]
PHST- 2015/12/29 06:00 [entrez]
PHST- 2015/12/29 06:00 [pubmed]
PHST- 2016/10/25 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - S0049-3848(15)30222-X [pii]
AID - 10.1016/j.thromres.2015.12.007 [doi]
PST - ppublish
SO  - Thromb Res. 2016 Feb;138:121-129. doi: 10.1016/j.thromres.2015.12.007. Epub 2015 
      Dec 10.