By a News Reporter-Staff News Editor at Biotech Week -- Data detailed on Drugs and Therapies have been presented. According to news originating from Lowell, Massachusetts, by NewsRx correspondents, research stated, "Heparin-treated patients often develop antibodies, but only a subset cause heparin-induced thrombocytopenia. In a single-molecule assay, a pathogenic monoclonal antibody bound more strongly to cross-linked platelet factor 4 than a non-pathogenic antibody."
Our news journalists obtained a quote from the research from the University of Massachusetts, "Oligomerization of platelet factor 4 may enhance binding of pathogenic antibodies. A molecular basis for specificity of pathogenic antibodies in heparin-induced thrombocytopenia is provided. Heparin-induced thrombocytopenia (HIT) is a thrombotic complication of heparin therapy mediated by antibodies to complexes between platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans. However, only a fraction of patients with anti-PF4-heparin antibodies develop HIT, implying that only a subset of these antibodies is pathogenic. The basis for the pathogenic potential of anti-PF4-heparin antibodies remains unclear. To elucidate the intrinsic PF4-binding properties of HIT-like monoclonal antibody (KKO) versus non-pathogenic antibody (RTO) at the single-molecule level, we utilized optical trap-based force spectroscopy to measure the strength and probability of binding of surface-attached antibodies with oligomeric PF4 to simulate interactions on cells. To mimic the effect of heparin in bringing PF4 complexes into proximity, we chemically cross-linked PF4 tetramers using glutaraldehyde. Analysis of the force histograms revealed that KKO-PF4 interactions had approximate to 10-fold faster on-rates than RTO-PF4, and apparent equilibrium dissociation constants differed approximate to 10-fold with similar force-free off-rates (k(off) = 0.0031 and 0.0029 s(-1)). Qualitatively similar results were obtained for KKO and RTO interacting with PF4-heparin complexes. In contrast to WT PF4, KKO and RTO showed lower and similar binding probabilities to cross-linked PF4(K50E), which forms few if any oligomers. Thus, formation of stable PF4 polymers results in much stronger interactions with the pathogenic antibody without a significant effect on the binding of the non-pathogenic antibody."
According to the news editors, the research concluded: "These results suggest a fundamental difference in the antigen-binding mechanisms between model pathogenic and non-pathogenic anti-PF4 antibodies that might underlie their distinct pathophysiological behaviors."
For more information on this research see: Distinct Specificity and Single-molecule Kinetics Characterize the Interaction of Pathogenic and Non-pathogenic Antibodies against Platelet Factor 4-Heparin Complexes with Platelet Factor 4. Journal of Biological Chemistry, 2013;288(46):33060-33070. Journal of Biological Chemistry can be contacted at: Amer Soc Biochemistry Molecular Biology Inc, 9650 Rockville Pike, Bethesda, MD 20814-3996, USA. (American Society for Biochemistry and Molecular Biology - www.asbmb.org; Journal of Biological Chemistry - www.jbc.org/)
The news correspondents report that additional information may be obtained from R.I. Litvinov, University of Massachusetts, Dept. of Chem, Lowell, MA 01854, United States. Additional authors for this research include S.V. Yarovoi, L. Rauova, V. Barsegov, B.S. Sachais, A.H. Rux, J.L. Hinds, G.M. Arepally, D.B. Cines and J.W. Weisel (see also Drugs and Therapies).
Keywords for this news article include: Antibodies, Lowell, Heparin, Immunology, Massachusetts, United States, Blood Proteins, Immunoglobulins, Thrombocytopenia, Drugs and Therapies, Hematologic Diseases, Blood Platelet Disorders, North and Central America
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