| Autor: |
Suvarna S; Division of Hematology, Duke University Medical Center, Durham, NC 27710, USA., Espinasse B, Qi R, Lubica R, Poncz M, Cines DB, Wiesner MR, Arepally GM |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2007 Dec 15; Vol. 110 (13), pp. 4253-60. Date of Electronic Publication: 2007 Sep 11. |
| DOI: |
10.1182/blood-2007-08-105098 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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