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Heparin-independent, PF4-dependent binding of HIT antibodies to platelets: implications for HIT pathogenesis. Blood 2015 Jan 01;125(1):155-61

Date

10/25/2014

Pubmed ID

25342714

Pubmed Central ID

PMC4281824

DOI

10.1182/blood-2014-06-580894

Scopus ID

2-s2.0-84920555104   42 Citations

Abstract

Antibodies specific for platelet factor 4 (PF4)/heparin complexes are the hallmark of heparin-induced thrombocytopenia and thrombosis (HIT), but many antibody-positive patients have normal platelet counts. The basis for this is not fully understood, but it is believed that antibodies testing positive in the serotonin release assay (SRA) are the most likely to cause disease. We addressed this issue by characterizing PF4-dependent binding of HIT antibodies to intact platelets and found that most antibodies testing positive in the SRA, but none of those testing negative, bind to and activate platelets when PF4 is present without any requirement for heparin (P < .0001). Binding of SRA-positive antibodies to platelets was inhibited by chondroitinase ABC digestion (P < .05) and by the addition of chondroitin-4-sulfate (CS) or heparin in excess quantities. The findings suggest that although all HIT antibodies recognize PF4 in a complex with heparin, only a subset of these antibodies recognize more subtle epitopes induced in PF4 when it binds to CS, the major platelet glycosaminoglycan. Antibodies having this property could explain "delayed HIT" seen in some individuals after discontinuation of heparin and the high risk for thrombosis that persists for weeks in patients recovered from HIT.

Author List

Padmanabhan A, Jones CG, Bougie DW, Curtis BR, McFarland JG, Wang D, Aster RH

Authors

Richard H. Aster MD Professor in the Medicine department at Medical College of Wisconsin
Brian Curtis PhD Director in the Platelet & Neutrophil Immunology Laboratory department at BloodCenter of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antibodies
Blood Platelets
Chondroitin Sulfates
Enzyme-Linked Immunosorbent Assay
Epitopes
Glycosaminoglycans
Heparin
Humans
Immunoglobulin G
P-Selectin
Platelet Activation
Platelet Factor 4
Polysaccharide-Lyases
Protein Binding
Serotonin
Thrombocytopenia
Thrombosis
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5