PMID- 35313081
OWN - NLM
STAT- MEDLINE
DCOM- 20220524
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 20
IP  - 6
DP  - 2022 Jun
TI  - Investigations of the effectiveness of heparin variants as inhibitors of 
      histones.
PG  - 1485-1495
LID - 10.1111/jth.15706 [doi]
AB  - BACKGROUND: Extracellular histones exert cytotoxic and procoagulant effects which 
      contribute to immunothrombosis in vascular diseases such as sepsis. Heparin has 
      been shown to neutralize the pathologic effects of histones in vitro and in 
      animal models. OBJECTIVES: To compare the effectiveness of unfractionated heparin 
      (UFH), low-molecularweight heparin (LMWH), Vasoflux (lacks anticoagulant 
      activity), and fondaparinux in neutralizing the cytotoxic and procoagulant 
      activities of histones METHODS: Binding affinities between heparin variants and 
      histone subunits were determined by Bio-layer Interferometry. The ability of 
      heparin variants to diminish the cytotoxic and procoagulant effects of histones 
      was studied by treating endothelial cells or monocytic THP-1 cells with histones 
      +/- heparin variants. RESULTS: Unfractionated heparin, LMWH, and Vasoflux bind 
      histone subunits with high affinities (K(d) <1 pM-66.7 nM) whereas fondaparinux 
      exhibited a low affinity (K(d) of 3.06 microM-81.1 mM). UFH, LMWH, and Vasoflux 
      neutralize histone-mediated cytotoxicity as well as monocytic procoagulant 
      activity (as assessed by cell surface tissue factor and phosphatidylserine). In 
      contrast, fondaparinux has no effect on these activities. All four heparin 
      variants reverse histone-mediated impairment of APC generation in a 
      dose-dependent manner. CONCLUSIONS: The ability of heparin to neutralize the 
      cytotoxic and procoagulant effects of histones require heparin fragments >1.7 kDa 
      and is independent of the antithrombin-binding pentasaccharide. In contrast, the 
      ability of heparin to neutralize histone-mediated impairment of APC generation is 
      independent of size and anticoagulant activity. These findings suggest that 
      heparin variants may have differential therapeutic potential in vascular diseases 
      associated with elevated levels of histones.
CI  - (c) 2022 International Society on Thrombosis and Haemostasis.
FAU - Sharma, Neha
AU  - Sharma N
AUID- ORCID: 0000-0002-9481-7673
AD  - Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
AD  - Department of Medical Sciences, McMaster University, Hamilton, ON, Canada.
FAU - Haggstrom, Lauren
AU  - Haggstrom L
AD  - Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
FAU - Sohrabipour, Sahar
AU  - Sohrabipour S
AD  - Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
AD  - Department of Medical Sciences, McMaster University, Hamilton, ON, Canada.
FAU - Dwivedi, Dhruva J
AU  - Dwivedi DJ
AD  - Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
AD  - Department of Medical Sciences, McMaster University, Hamilton, ON, Canada.
FAU - Liaw, Patricia C
AU  - Liaw PC
AUID- ORCID: 0000-0002-7783-1393
AD  - Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
AD  - Department of Medical Sciences, McMaster University, Hamilton, ON, Canada.
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220417
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Anticoagulants)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Histones)
RN  - 9005-49-6 (Heparin)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Animals
MH  - Anticoagulants/metabolism/pharmacology
MH  - Endothelial Cells/metabolism
MH  - Fondaparinux
MH  - *Heparin/pharmacology
MH  - Heparin, Low-Molecular-Weight/pharmacology
MH  - Histones/pharmacology
MH  - Humans
MH  - *Vascular Diseases
OTO - NOTNLM
OT  - Vasoflux
OT  - extracellular histones
OT  - fondaparinux
OT  - low-molecular-weight heparin
OT  - unfractionated heparin
EDAT- 2022/03/22 06:00
MHDA- 2022/05/25 06:00
CRDT- 2022/03/21 17:20
PHST- 2022/03/04 00:00 [revised]
PHST- 2021/11/17 00:00 [received]
PHST- 2022/03/16 00:00 [accepted]
PHST- 2022/03/22 06:00 [pubmed]
PHST- 2022/05/25 06:00 [medline]
PHST- 2022/03/21 17:20 [entrez]
AID - S1538-7836(22)00200-8 [pii]
AID - 10.1111/jth.15706 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2022 Jun;20(6):1485-1495. doi: 10.1111/jth.15706. Epub 2022 Apr 
      17.