PMID- 31604180
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20210514
IS  - 1878-0180 (Electronic)
IS  - 1878-0180 (Linking)
VI  - 102
DP  - 2020 Feb
TI  - Biorelevant polyanions stabilize fibrin against mechanical and proteolytic 
      decomposition: Effects of polymer size and electric charge.
PG  - 103459
LID - S1751-6161(19)30759-3 [pii]
LID - 10.1016/j.jmbbm.2019.103459 [doi]
AB  - The release of neutrophil extracellular traps (NETs) containing DNA and histones 
      is an essential mechanism in the neutrophil-mediated innate immunity. In thrombi 
      the polyanionic DNA confers mechanical and lytic resistance to fibrin and 
      heparins interfere with the effects of NET components. Heparins are polyanions 
      used not only as therapeutic agents, but they are also released by mast cells at 
      entry sites of pathogens. Platelets and microorganisms release a different type 
      of polyanions (polyphosphates) of various size (in the range 60-1000 phosphate 
      monomers). With the current study we aimed to evaluate if the stability of fibrin 
      is influenced by the type of polyanion, its molecular size or relative electric 
      charge. Fibrin structure was approached with scanning electron microscopy (SEM) 
      and pressure-driven permeation. An oscillation rheometer was used to investigate 
      viscoelastic properties. Kinetic turbidimetric assays for the generation and 
      dissolution of composite fibrin clots containing unfractionated heparin (UFH), 
      and its partially or fully desulfated derivatives, as well as low 
      molecular-weight heparin (LMWH), pentasaccharide (S5), and polyphosphates 
      composed of 45 (P45), 100 (P100) or 700 (P700) monomers at average. The smaller 
      polyanions P45, P100, LMWH, and S5 accelerated, whereas P700 and UFH retarded 
      clot formation. All polyanions altered the fibrin structure: SEM and clot 
      permeation showed thicker fibers with smaller (LMWH, S5, P700) or larger (UFH, 
      P100) pores. All polyanions stabilized the clots mechanically, but the smaller 
      P45, P100 and LMWH decreased the deformability of fibrin, whereas the large UFH 
      and P700 increased the maximal bearable deformation of clots. Despite the 
      size-dependent structural changes, all heparins caused a 10-15% prolongation of 
      lysis-times with plasmin, and UFH-effects depended on sulfation patterns. The 
      20-35% prolongation of lysis-times caused by all polyphosphates was a 
      kringle-dependent phenomenon, and was dampened in the presence of 
      6-aminohexanoate blocking the lysine-binding sites of plasmin. In summary, we 
      found that polyanions of different chemical structure stabilize fibrin clots via 
      size-dependent modulation of fibrin structure and kringle-dependent inhibition of 
      plasmin-mediated fibrinolysis.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Komorowicz, Erzsebet
AU  - Komorowicz E
AD  - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
FAU - Balazs, Nora
AU  - Balazs N
AD  - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
FAU - Tanka-Salamon, Anna
AU  - Tanka-Salamon A
AD  - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
FAU - Varga, Zoltan
AU  - Varga Z
AD  - Department of Biological Nanochemsitry, Institute of Materials and Environmental 
      Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 
      Budapest, Hungary.
FAU - Szabo, Laszlo
AU  - Szabo L
AD  - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
FAU - Bota, Attila
AU  - Bota A
AD  - Department of Biological Nanochemsitry, Institute of Materials and Environmental 
      Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 
      Budapest, Hungary.
FAU - Longstaff, Colin
AU  - Longstaff C
AD  - Biotherapeutics, Haemostasis Section, National Institute for Biological Standards 
      and Control, South Mimms, Potters Bar, UK.
FAU - Kolev, Krasimir
AU  - Kolev K
AD  - Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary. 
      Electronic address: Krasimir.Kolev@eok.sote.hu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190928
PL  - Netherlands
TA  - J Mech Behav Biomed Mater
JT  - Journal of the mechanical behavior of biomedical materials
JID - 101322406
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Polyelectrolytes)
RN  - 0 (Polymers)
RN  - 0 (polyanions)
RN  - 9001-31-4 (Fibrin)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - *Fibrin
MH  - *Heparin
MH  - Heparin, Low-Molecular-Weight
MH  - Polyelectrolytes
MH  - Polymers
OTO - NOTNLM
OT  - Fibrin
OT  - Fibrinolysis
OT  - Heparin
OT  - Plasmin
OT  - Polyphosphate
COIS- Declaration of competing interest The authors declare that the research was 
      conducted in the absence of any commercial or financial relationships that could 
      be construed as a potential conflict of interest.
EDAT- 2019/10/12 06:00
MHDA- 2021/05/15 06:00
CRDT- 2019/10/12 06:00
PHST- 2019/05/30 00:00 [received]
PHST- 2019/09/27 00:00 [revised]
PHST- 2019/09/28 00:00 [accepted]
PHST- 2019/10/12 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2019/10/12 06:00 [entrez]
AID - S1751-6161(19)30759-3 [pii]
AID - 10.1016/j.jmbbm.2019.103459 [doi]
PST - ppublish
SO  - J Mech Behav Biomed Mater. 2020 Feb;102:103459. doi: 10.1016/j.jmbbm.2019.103459. 
      Epub 2019 Sep 28.