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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1533-1540
PLENARY PAPER
Characterization of a murine monoclonal antibody that mimics
heparin-induced thrombocytopenia antibodies
G. M. Arepally,
S. Kamei,
K. S. Park,
K. Kamei,
Z. Q. Li,
W. Liu,
D. L. Siegel,
W. Kisiel,
D. B. Cines, and
M. Poncz
From the Cancer Research and Treatment Center and the Department of
Pathology, the University of New Mexico Health Sciences Center,
Albuquerque, NM; the Department of Microbiology, School of Medicine,
Korea University, Seoul, Korea; and the Departments of Pathology and
Laboratory Medicine and Pediatrics, University of Pennsylvania School
of Medicine, Philadelphia, PA.
Antibodies to PF4/heparin can be demonstrated in almost all patients
with heparin-induced thrombocytopenia/thrombosis (HIT/HITT) and in some
persons exposed to heparin who do not have clinical manifestations. The
role of anti-PF4/heparin antibodies in the pathogenesis of HIT/HITT has
been difficult to establish because the antibodies found in serum are
generally polyclonal and polyspecific. To circumvent this problem, we
developed a murine monoclonal antibody (mAb) to human (h) PF4/heparin
complexes. A monoclonal IgG2b antibody (designated KKO)
was identified that bound specifically to hPF4/heparin complexes.
Maximal binding of KKO to hPF4/heparin complexes occurred at similar
molar ratios of PF4:heparin observed for HIT/HITT antibodies. KKO also
bound to hPF4 in association with other glycosaminoglycans. Platelet
activation by KKO required heparin and was abrogated by blockade of
Fc RIIA. In the presence of PF4, KKO bound to endothelial cells, but
not to CHO cells lacking heparan sulfate proteoglycans. Variants of PF4
complexed to heparin were recognized equally well by KKO and HIT/HITT
sera. KKO competes for binding with a subset of HIT/HITT antibodies
that are relatively spared by mutations in the 3rd domain of PF4. The
nucleotide and predicted amino acid sequences of KKO and RTO, a murine
anti-hPF4 mAb that does not require heparin for binding, revealed no
obvious relationship in either the heavy- or the light-chain
immunoglobulin variable regions. These studies suggest that KKO
recapitulates the antigenic and functional specificity of a subset of
HIT/HITT antibodies and may, therefore, provide insight into the
pathogenesis of thrombocytopenia and thrombosis in affected persons.
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