PMID- 18262226
OWN - NLM
STAT- MEDLINE
DCOM- 20080915
LR  - 20181201
IS  - 0049-3848 (Print)
IS  - 0049-3848 (Linking)
VI  - 122
IP  - 2
DP  - 2008
TI  - Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the 
      differing immunogenicities of unfractionated heparin, low-molecular-weight 
      heparin, and fondaparinux in different clinical settings.
PG  - 211-20
LID - 10.1016/j.thromres.2007.11.007 [doi]
AB  - INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is caused by 
      platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin 
      complexes. The frequency of HIT is highly variable in different clinical 
      settings, and is more frequent with unfractionated heparin (UFH) than with 
      low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT 
      antibodies activate platelets similarly well with LMWH as with UFH. An important 
      difference between UFH, LMWH, and fondaparinux is their widely differing plasma 
      concentrations. We aimed to provide a model that included anticoagulant 
      concentrations and PF4 availability as risk factors influencing the 
      anti-PF4/heparin immune response. MATERIALS AND METHODS: By photon correlation 
      spectroscopy we determined the concentrations at which UFH, LMWH, and 
      fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and 
      LMWH were calculated based on ex vivo pharmacokinetic data, with information on 
      fondaparinux and PF4 concentrations taken from the literature. RESULTS AND 
      CONCLUSIONS: The main features of our model are: optimal complex formation occurs 
      at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH 
      concentrations are too high for optimal complex formation; in contrast, 
      concentrations of fondaparinux are usually below the optimal stoichiometric 
      range. Thus, immunization should occur more often in situations with major rather 
      than minor platelet activation, and--for a given degree of platelet activation 
      (PF4 availability)--as: prophylactic-dose UFH>therapeutic-dose 
      UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model 
      provides a framework for explaining empirical observations that LMWH induces less 
      anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies 
      are more often found in patients undergoing major surgery than in medical 
      patients.
FAU - Greinacher, A
AU  - Greinacher A
AD  - Institut fur Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universitat 
      Greifswald, Greifswald. Germany. greinach@uni-greifswald.de
FAU - Alban, S
AU  - Alban S
FAU - Omer-Adam, M A
AU  - Omer-Adam MA
FAU - Weitschies, W
AU  - Weitschies W
FAU - Warkentin, T E
AU  - Warkentin TE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080208
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Anticoagulants)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 0 (Polysaccharides)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - 9005-49-6 (Heparin)
RN  - J177FOW5JL (Fondaparinux)
SB  - IM
MH  - Anticoagulants/*pharmacology
MH  - Blood Platelets/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Fondaparinux
MH  - Heparin/*pharmacology
MH  - Heparin, Low-Molecular-Weight/chemistry
MH  - Humans
MH  - Immune System
MH  - Models, Biological
MH  - Photons
MH  - Platelet Activation
MH  - Platelet Factor 4/metabolism
MH  - Polysaccharides/chemistry/*pharmacology
MH  - Risk Factors
MH  - Thrombocytopenia/*chemically induced/*pathology
EDAT- 2008/02/12 09:00
MHDA- 2008/09/16 09:00
CRDT- 2008/02/12 09:00
PHST- 2007/06/05 00:00 [received]
PHST- 2007/09/28 00:00 [revised]
PHST- 2007/11/18 00:00 [accepted]
PHST- 2008/02/12 09:00 [pubmed]
PHST- 2008/09/16 09:00 [medline]
PHST- 2008/02/12 09:00 [entrez]
AID - S0049-3848(07)00447-1 [pii]
AID - 10.1016/j.thromres.2007.11.007 [doi]
PST - ppublish
SO  - Thromb Res. 2008;122(2):211-20. doi: 10.1016/j.thromres.2007.11.007. Epub 2008 
      Feb 8.