Heparin enhances uptake of platelet factor 4/heparin complexes by monocytes and macrophages.

Journal Article (Journal Article)

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies to a self-antigen, platelet factor (4) and heparin. The reasons why antibodies form to PF4/heparin, but not to PF4 bound to other cellular glycosaminoglycans are poorly understood. OBJECTIVE: To investigate differences in cellular responses to cell-bound PF4 and PF4/heparin complexes, we studied the internalization of each by peripheral blood-derived monocytes, dendritic cells and neutrophils. METHODS AND RESULTS: Using unlabeled and fluorescently-labeled antigen and/or labeled monoclonal antibody to PF4/heparin complexes (KKO), we show that PF4/heparin complexes are taken up by monocytes in a heparin-dependent manner and are internalized by human monocytes and dendritic cells, but not by neutrophils. Complexes of PF4/low-molecular-weight heparin and complexes composed of heparin and murine PF4, protamine or lysozyme are internalized similarly, suggesting a common endocytic pathway. Uptake of complexes is mediated by macropinocytosis, as shown by inhibition using cytochalasin D and amiloride. Internalized complexes are transported intact to late endosomes, as indicated by co-staining of vesicles with KKO and lysosomal associated membrane protein-2 (LAMP-2). Lastly, we show that cellular uptake is accompanied by expression of MHCII and CD83 co-stimulatory molecules. CONCLUSIONS: Taken together, these studies establish a distinct role for heparin in enhancing antigen uptake and activation of the initial steps in the cellular immune response to PF4-containing complexes.

Full Text

Duke Authors

Cited Authors

  • Joglekar, M; Khandelwal, S; Cines, DB; Poncz, M; Rauova, L; Arepally, GM

Published Date

  • August 2015

Published In

Volume / Issue

  • 13 / 8

Start / End Page

  • 1416 - 1427

PubMed ID

  • 25960020

Pubmed Central ID

  • PMC4516590

Electronic International Standard Serial Number (EISSN)

  • 1538-7836

Digital Object Identifier (DOI)

  • 10.1111/jth.13003


  • eng

Conference Location

  • England