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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2427-2433
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Human single chain antibodies against heparin: selection,
characterization, and effect on coagulation
Els M. A. van de Westerlo,
Toon F. C. M. Smetsers,
Michel
A. B. A. Dennissen,
Robert J. Linhardt,
Jacques H. Veerkamp,
Goos N. P. van
Muijen, and
Toin H. van
Kuppevelt
From the Department of Biochemistry and the Department
of Pathology, University Medical Center Nijmegen, The Netherlands, and
the Division of Medicinal and Natural Products Chemistry, Department of
Chemistry, University of Iowa, Iowa City.
Heparin, located in mast cells and basophilic granulocytes, is
widely used as an anticoagulant. It belongs to a class of linear polysaccharides called glycosaminoglycans (GAGs). Using phage display
technology, we have selected 19 unique human antiheparin antibodies.
Some antibodies react almost exclusively with heparin, others also
react with the structurally related heparan sulfate, and some with
chondroitin sulfate. In all cases, sulfate groups are essential for
binding. For activity of some antibodies, O-sulfation is more important
than N-sulfation. Antibodies are reactive with heparin in mast cells.
Each antibody showed a defined staining pattern on cryosections of rat
kidney, pancreas, and testis. Enzymatic digestion with glycosidases on
tissue sections further indicated that the antibodies are specific for
GAGs. All antibodies recognize a unique epitope. The effect of the
antibodies on heparin as an anticoagulant was also studied. There were
3 antibodies that were very effective inhibitors of heparin action in
the activated partial thromboplastin time (APTT) clotting assay, and
their effect was related to the amount of heparin bound. Some
antibodies reacted strongly with the pentasaccharide, which interacts
with antithrombin III. The human antibodies selected represent unique
tools to study the structure, location, and function of heparin and
related GAGs, and some may be used as blocking agents.
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