PMID- 22318669
OWN - NLM
STAT- MEDLINE
DCOM- 20120813
LR  - 20211021
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 107
IP  - 4
DP  - 2012 Apr
TI  - Disruption of PF4/H multimolecular complex formation with a minimally 
      anticoagulant heparin (ODSH).
PG  - 717-25
LID - 10.1160/TH11-11-0795 [doi]
AB  - Recent studies have shown that ultra-large complexes (ULCs) of platelet factor 4 
      (PF4) and heparin (H) play an essential role in the pathogenesis of 
      heparin-induced thrombocytopenia (HIT), an immune-mediated disorder caused by 
      PF4/H antibodies. Because antigenic PF4/H ULCs assemble through non-specific 
      electrostatic interactions, we reasoned that disruption of charge-based 
      interactions can modulate the immune response to antigen. We tested a minimally 
      anticoagulant compound (2-O, 3-O desulfated heparin, ODSH) with preserved charge 
      to disrupt PF4/H complex formation and immunogenicity. We show that ODSH disrupts 
      complexes when added to pre-formed PF4/H ULCs and prevents ULC formation when 
      incubated simultaneously with PF4 and UFH. In other studies, we show that excess 
      ODSH reduces HIT antibody (Ab) binding in immunoassays and that PF4/ODSH 
      complexes do not cross-react with HIT Abs. When ODSH and unfractionated heparin 
      (UFH) are mixed at equimolar concentrations, we show that there is a negligible 
      effect on amount of protamine required for heparin neutralisation and reduced 
      immunogenicity of PF4/UFH in the presence of ODSH. Taken together, these studies 
      suggest that ODSH can be used concurrently with UFH to disrupt PF4/H charge 
      interactions and provides a novel strategy to reduce antibody mediated 
      complications in HIT.
FAU - Joglekar, M V
AU  - Joglekar MV
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Quintana Diez, P M
AU  - Quintana Diez PM
FAU - Marcus, S
AU  - Marcus S
FAU - Qi, R
AU  - Qi R
FAU - Espinasse, B
AU  - Espinasse B
FAU - Wiesner, M R
AU  - Wiesner MR
FAU - Pempe, E
AU  - Pempe E
FAU - Liu, J
AU  - Liu J
FAU - Monroe, D M
AU  - Monroe DM
FAU - Arepally, G M
AU  - Arepally GM
LA  - eng
GR  - R21 AI074775/AI/NIAID NIH HHS/United States
GR  - HL081395/HL/NHLBI NIH HHS/United States
GR  - R01 AI050050/AI/NIAID NIH HHS/United States
GR  - RD83241301/RD/ORD VA/United States
GR  - AI050050/AI/NIAID NIH HHS/United States
GR  - R01 HL094463/HL/NHLBI NIH HHS/United States
GR  - HL094463/HL/NHLBI NIH HHS/United States
GR  - R01 HL081395/HL/NHLBI NIH HHS/United States
GR  - AI074775/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120208
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Anticoagulants)
RN  - 0 (N-desulfated,2-O,3-O-desulfated heparin)
RN  - 0 (Protamines)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
CIN - Thromb Haemost. 2012 Apr;107(4):602. PMID: 22371221
MH  - Animals
MH  - Anticoagulants/pharmacology
MH  - Binding Sites
MH  - Biophysics/methods
MH  - Cattle
MH  - Dose-Response Relationship, Drug
MH  - Heparin/analogs & derivatives/chemistry/metabolism/pharmacology/*therapeutic use
MH  - Humans
MH  - Immunoassay/methods
MH  - Kinetics
MH  - Platelet Factor 4/*metabolism
MH  - Protamines/metabolism
MH  - Thrombin/metabolism
MH  - Thrombocytopenia/metabolism
PMC - PMC4441624
MID - NIHMS690726
EDAT- 2012/02/10 06:00
MHDA- 2012/08/14 06:00
PMCR- 2015/05/22
CRDT- 2012/02/10 06:00
PHST- 2011/11/16 00:00 [received]
PHST- 2011/12/24 00:00 [accepted]
PHST- 2012/02/10 06:00 [entrez]
PHST- 2012/02/10 06:00 [pubmed]
PHST- 2012/08/14 06:00 [medline]
PHST- 2015/05/22 00:00 [pmc-release]
AID - 11-11-0795 [pii]
AID - 10.1160/TH11-11-0795 [doi]
PST - ppublish
SO  - Thromb Haemost. 2012 Apr;107(4):717-25. doi: 10.1160/TH11-11-0795. Epub 2012 Feb 
      8.