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Immunoglobulin G from patients with heparin-induced thrombocytopenia binds
to a complex of heparin and platelet factor 4
JG Kelton, JW Smith, TE Warkentin, CP Hayward, GA Denomme and P Horsewood
Department of Medicine, McMaster University Medical Centre, Hamilton,
Ontario, Canada.
Heparin-induced thrombocytopenia (HIT) is an important complication of
heparin therapy. Although there is general agreement that platelet
activation in vitro by the HIT IgG is mediated by the platelet Fc receptor,
the interaction among the antibody, heparin, and platelet membrane
components is uncertain and debated. In this report, we describe studies
designed to address these interactions. We found, as others have noted,
that a variety of other sulfated polysaccharides could substitute for
heparin in the reaction. Using polysaccharides selected for both size and
charge, we found that reactivity depended on two independent factors: a
certain minimum degree of sulfation per saccharide unit and a certain
minimum size. Hence, highly sulfated but small (< 1,000 daltons)
polysaccharides were not reactive nor were large but poorly sulfated
polysaccharides. The ability of HIT IgG to recognize heparin by itself was
tested by Ouchterlony gel diffusion, ammonium sulfate and polyethylene
glycol precipitation, and equilibrium dialysis. No technique demonstrated
reactivity. However, when platelet releasate was added to heparin and HIT
IgG, a 50-fold increase in binding of radio-labeled heparin to HIT IgG was
observed. The releasate was then depleted of proteins capable of binding to
heparin by immunoaffinity chromatography. Only platelet factor
4-immunodepleted releasate lost its reactivity with HIT IgG and heparin.
Finally, to determine whether the reaction occurred on the surface of
platelets or in the fluid phase, washed platelets were incubated with HIT
IgG or heparin and after a wash step, heparin or HIT IgG was added,
respectively. Reactivity was only noted when platelets were preincubated
with heparin. Consistent with these observations was the demonstration of
the presence of PF4 on platelets using flow cytometry. These studies
indicate that heparin and other large, highly sulfated polysaccharides bind
to PF4 to form a reactive antigen on the platelet surface. HIT IgG then
binds to this complex with activation of platelets through the platelet Fc
receptors.
Volume 83,
Issue 11,
pp. 3232-3239,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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