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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1230-1236
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Defining a second epitope for heparin-induced
thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like
monoclonal antibody
Zhong Q. Li,
Weiyi Liu,
Kwang S. Park,
Brue S. Sachais,
Gowthani M. Arepally,
Douglas B. Cines, and
Mortimer Poncz
From the Departments of Pathology and Laboratory
Medicine and Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia; Korea University, Department of Microbiology, School of
Medicine, Seoul; and University of New Mexico Health Sciences Center,
the Cancer Research and Treatment Center and Department of Pathology,
Albuquerque.
Heparin-induced thrombocytopenia/thrombosis (HIT/T) is
a common complication of heparin therapy that is caused by antibodies to platelet factor 4 (PF4) complexed with heparin. The immune response
is polyclonal and polyspecific, ie, more than one neoepitope on PF4 is
recognized by HIT/T antibodies. One such epitope has been previously
identified; it involves the domain between the third and fourth
cysteine residues in PF4 (site 1). However, the binding sites for other
HIT/T antibodies remain to be defined. To explore this issue, the
binding site of KKO, an HIT/T-like murine monoclonal antibody,
was defined. KKO shares a binding site with many HIT/T antibodies on
PF4/heparin, but does not bind to site 1 or recognize mouse
PF4/heparin. Therefore, the binding of KKO to a series of mouse/human
PF4 chimeras complexed with heparin was examined. KKO recognizes a site
that requires both the N terminus of PF4 and Pro34, which immediately
precedes the third cysteine. Both regions lie on the surface of the PF4
tetramer in sufficient proximity (within 0.74 nm) to form a
contiguous antigenic determinant. The 10 of 14 HIT/T sera that
require the N terminus of PF4 for antigen recognition also require
Pro34 to bind. This epitope, termed site 2, lies adjacent to site 1 in the crystal structure of the PF4 tetramer. Yet sites 1 and 2 can be
recognized by distinct populations of antibodies. These studies further
help to define a portion of the PF4 tetramer to which self-reactive
antibodies develop in patients exposed to heparin.
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