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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3250-3259
Defining an Antigenic Epitope on Platelet Factor 4 Associated With
Heparin-Induced Thrombocytopenia
L. Ziporen,
Z.Q. Li,
K.S. Park,
P. Sabnekar,
W.Y. Liu,
G. Arepally,
Y. Shoenfeld,
T. Kieber-Emmons,
D.B. Cines, and
M. Poncz
From Tel-Aviv University, Sackler School of Medicine and Sheba
Medical Center, Institute for Autoimmune Diseases, Tel-Aviv, Israel;
the Division of Hematology, Children's Hospital of Philadelphia,
Philadelphia, PA; Korea University, the Department of Microbiology,
School of Medicine, Seoul, Korea; and the University of
Pennsylvania School of Medicine, the Departments of Pediatrics,
Pathology and Laboratory Medicine, and Biochemistry,
Philadelphia.
Heparin-induced thrombocytopenia (HIT) is a potentially serious
complication of heparin therapy. Antibodies to platelet factor 4 (PF4)/heparin complexes have been implicated in the pathogenesis of
this disorder, but the antigenic epitope(s) on the protein have not
been defined. To address this issue, we studied the binding of HIT
antibodies to a series of recombinant proteins containing either point
mutations in PF4 or chimeras containing various domains of PF4 and the
related protein, neutrophil activating peptide-2 (NAP-2). Serum samples
from 50 patients with a positive 14C-serotonin release
assay (14C-SRA) and a clinical diagnosis of HIT and 20 normal controls were studied. HIT antibodies reacted strongly with
wild-type (WT) PF4/heparin complexes, but reacted little, if at all,
with NAP-2/heparin complexes (optical density
[OD]405 = 2.5 and 0.2, respectively). Alanine substitutions at three of the four lysine residues implicated in heparin binding, K62, K65, and K66, had little effect on recognition by HIT antibodies (OD405 = 2.2, 2.8, and 2.0, respectively), whereas an alanine substitution at position K61 led to
reduced, but still significant binding (OD405 = 1.0).
Similar studies involving chimeras between PF4 and NAP-2 localized a
major antigenic site to the region between the third and fourth
cysteine residues for more than half of the sera tested. This site
appears to involve a series of amino acids immediately after the third
cysteine residue beginning with P37. Thus our studies suggest that
whereas the C-terminal lysine residues of PF4 are important for heparin
binding, they do not comprise a critical antigenic site for most HIT
antibodies. Rather, we propose that maintaining a region near the third
cysteine residue of PF4, distal from the proposed heparin-binding
domain, is required to form the epitope recognized by many HIT
antibodies.
© 1998 by The American Society of Hematology.
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