PMID- 15304392
OWN - NLM
STAT- MEDLINE
DCOM- 20050210
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 105
IP  - 1
DP  - 2005 Jan 1
TI  - Ultralarge complexes of PF4 and heparin are central to the pathogenesis of 
      heparin-induced thrombocytopenia.
PG  - 131-8
AB  - Heparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication 
      of heparin therapy caused by antibodies to complexes between unfractionated 
      heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of 
      reactants and initiate antibody-induced platelet activation. We observed that UFH 
      and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a 
      narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. 
      These ULCs were stable and visible by electron microscopy, but they could be 
      dissociated into smaller complexes upon addition of heparin. ULCs formed 
      inefficiently when PF4 was incubated with low-molecular-weight heparin, and none 
      formed with the pentasaccharide fondaparinux sodium. In addition, mutation 
      studies showed that formation of ULCs depended on the presence of PF4 tetramers. 
      The ULCs were more reactive as determined by their capacity to bind to a 
      HITT-like monoclonal antibody and showed greater capacity to promote platelet 
      activation in an antibody- and FcgammaRIIA-dependent manner than were the smaller 
      complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers 
      arrayed in a lattice with several molecules of UFH may play a fundamental role in 
      autoantibody formation, antibody-dependent platelet activation, and the 
      propensity for thrombosis in patients with HITT.
FAU - Rauova, Lubica
AU  - Rauova L
AD  - Division of Hematology, Children's Hospital of Philadelphia, PA, USA.
FAU - Poncz, Mortimer
AU  - Poncz M
FAU - McKenzie, Steven E
AU  - McKenzie SE
FAU - Reilly, Michael P
AU  - Reilly MP
FAU - Arepally, Gowthami
AU  - Arepally G
FAU - Weisel, John W
AU  - Weisel JW
FAU - Nagaswami, Chandrasekaran
AU  - Nagaswami C
FAU - Cines, Douglas B
AU  - Cines DB
FAU - Sachais, Bruce S
AU  - Sachais BS
LA  - eng
GR  - 1 K08 HL04245/HL/NHLBI NIH HHS/United States
GR  - HL54500/HL/NHLBI NIH HHS/United States
GR  - HL68631/HL/NHLBI NIH HHS/United States
GR  - HL69471/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040810
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies, Monoclonal)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal
MH  - Chromatography, High Pressure Liquid
MH  - Heparin/*chemistry/*pharmacology/ultrastructure
MH  - Humans
MH  - Microscopy, Electron, Transmission
MH  - Models, Molecular
MH  - Mutagenesis, Site-Directed
MH  - Platelet Activation/drug effects/immunology
MH  - Platelet Factor 4/*chemistry/genetics/*metabolism/ultrastructure
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Swine
MH  - Thrombocytopenia/*chemically induced/*metabolism
EDAT- 2004/08/12 05:00
MHDA- 2005/02/11 09:00
CRDT- 2004/08/12 05:00
PHST- 2004/08/12 05:00 [pubmed]
PHST- 2005/02/11 09:00 [medline]
PHST- 2004/08/12 05:00 [entrez]
AID - S0006-4971(20)48397-1 [pii]
AID - 10.1182/blood-2004-04-1544 [doi]
PST - ppublish
SO  - Blood. 2005 Jan 1;105(1):131-8. doi: 10.1182/blood-2004-04-1544. Epub 2004 Aug 
      10.