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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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Submitted August 3, 2007
Accepted September 4, 2007
Determinants of PF4/heparin immunogenicity
Shayela Suvarna, Benjamin Espinasse, Rui Qi, Rauova Lubica, Mortimer Poncz, Douglas B. Cines, Mark R. Wiesner, and Gowthami M. Arepally*
Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC, United States
Department of Civil and Environmental Engineering, Duke University Medical Center, Durham, NC, United States
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: arepa001{at}mc.duke.edu.
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 of 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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