PMID- 17285619
OWN - NLM
STAT- MEDLINE
DCOM- 20070405
LR  - 20070215
IS  - 0733-2459 (Print)
IS  - 0733-2459 (Linking)
VI  - 22
IP  - 1
DP  - 2007 Feb
TI  - Heparin-induced thrombocytopenia: an autoimmune disorder regulated through 
      dynamic autoantigen assembly/disassembly.
PG  - 31-6
AB  - Heparin-induced thrombocytopenia (HIT) is the most common drug-induced, 
      antibody-mediated cause of thrombocytopenia and thrombosis. HIT is caused by IgG 
      antibodies that bind to epitopes on platelet factor 4 (PF4) released from 
      activated platelets that develop when it forms complexes with heparin. 
      Anti-PF4/antibodies develop in over 50% of patients undergoing surgery involving 
      cardiopulmonary bypass (CPB), an incidence 20-fold higher than HIT. Why might 
      this occur? Binding of HIT IgG occurs only over a narrow molar ratio of 
      reactants, being optimal at 1 mol PF4 tetramer to 1 mol unfractionated heparin 
      (UFH). At these ratios, PF4 and UFH form ultralarge (>670 kD) complexes that bind 
      multiple IgG molecules/complex, are highly antigenic, and promote platelet 
      activation. Low molecular weight heparin (LMWH), which is less antigenic, forms 
      ultralarge complexes less efficiently and largely at supratherapeutic 
      concentrations. In transgenic mice that vary in expression of human PF4 on their 
      platelets, antigenic complexes form between PF4 and endogenous chondroitin 
      sulfate. Binding of HIT IgG to platelets and induction of thrombocytopenia in 
      vivo is proportional to PF4 expression. Heparin prolongs the duration and 
      exacerbates the severity of the thrombocytopenia. High doses of heparin, as used 
      in CPB, or protamine, which competes with PF4 for heparin, disrupts antigen 
      formation and prevents thrombocytopenia induced by HIT antibody. These studies 
      may help explain the disparity between the incidence of antibody formation and 
      clinical disease and may help identify patients at risk for HIT (high platelet 
      PF4). They also demonstrate that this autoimmune disease can be modulated at the 
      level of autoantigen formation and point to rational means to intervene proximal 
      to thrombin generation.
CI  - Copyright (c) 2007 Wiley-Liss, Inc.
FAU - Cines, Douglas B
AU  - Cines DB
AD  - Department of Pathology and Laboratory Medicine, University of Pennsylvania, and 
      Division of Hematology, Children's Hospital of Philadelphia 19104, USA. 
      dcines@mail.med.upenn.edu
FAU - Rauova, Lubica
AU  - Rauova L
FAU - Arepally, Gowthami
AU  - Arepally G
FAU - Reilly, Michael P
AU  - Reilly MP
FAU - McKenzie, Steven E
AU  - McKenzie SE
FAU - Sachais, Bruce S
AU  - Sachais BS
FAU - Poncz, Mortimer
AU  - Poncz M
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - J Clin Apher
JT  - Journal of clinical apheresis
JID - 8216305
RN  - 0 (Autoantigens)
RN  - 0 (Immunoglobulin G)
RN  - 37270-94-3 (Platelet Factor 4)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Animals
MH  - Autoantigens/*immunology
MH  - Autoimmune Diseases
MH  - Heparin/*adverse effects
MH  - Humans
MH  - Immunoglobulin G
MH  - Mice
MH  - Platelet Factor 4/immunology
MH  - Thrombocytopenia/*chemically induced/etiology/immunology
RF  - 34
EDAT- 2007/02/08 09:00
MHDA- 2007/04/06 09:00
CRDT- 2007/02/08 09:00
PHST- 2007/02/08 09:00 [pubmed]
PHST- 2007/04/06 09:00 [medline]
PHST- 2007/02/08 09:00 [entrez]
AID - 10.1002/jca.20109 [doi]
PST - ppublish
SO  - J Clin Apher. 2007 Feb;22(1):31-6. doi: 10.1002/jca.20109.