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 Blood, 15 December 2007, Vol. 110, No. 13, pp. 4253-4260.
Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-08-105098.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Determinants of PF4/heparin immunogenicity

Shayela Suvarna1, Benjamin Espinasse2, Rui Qi1, Rauova Lubica3, Mortimer Poncz3,4, Douglas B. Cines4, Mark R. Wiesner2, and Gowthami M. Arepally1

1 Division of Hematology and 2 Department of Civil and Environmental Engineering, Duke University Medical Center, Durham, NC; 3 Department of Pediatrics, Children's Hospital of Philadelphia, PA; and 4 Department of Pathology, The University of Pennsylvania School of Medicine, Philadelphia

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that occurs with variable frequency in patients exposed to heparin. HIT antibodies preferentially recognize large macromolecular complexes formed between PF4 and heparin over a narrow range of molar ratios, but the biophysical properties of complexes that initiate antibody production are unknown. To identify structural determinants underlying PF4/heparin immunogenicity, we characterized the in vitro interactions of murine PF4 (mPF4) and heparin with respect to light absorption, size, and surface charge (zeta potential). We show that PF4/heparin macromolecular assembly occurs through colloidal interactions, wherein heparin facilitates the growth of complexes through charge neutralization. The size of PF4/heparin macromolecules is governed by the molar ratios of the reactants. Maximal complex size occurs at molar ratios of PF4/heparin at which surface charge is neutral. When mice are immunized with complexes that differ in size and/or zeta potential, antibody formation varies inversely with heparin concentration and is most robust in animals immunized with complexes displaying a net positive zeta-potential. These studies suggest that the clinical heterogeneity in the HIT immune response may be due in part to requirements for specific biophysical parameters of the PF4/heparin complexes that occur in settings of intense platelet activation and PF4 release.


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