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The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21)

Sanjay Khandelwal, Grace M. Lee, C. Garren Hester, Mortimer Poncz, Steven E. McKenzie, Bruce S. Sachais, Lubica Rauova, Garnett Kelsoe, Douglas B. Cines, Michael Frank and Gowthami M. Arepally

Key Points

  • PF4/heparin ultra-large complexes activate complement and bind preferentially to B cells via CR2 (CD21).

  • Complement-fixed PF4/heparin complexes can be detected on circulating B cells in patients receiving heparin therapy.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

Heparin-induced thrombocytopenia is a prothrombotic disorder caused by antibodies to platelet factor 4 (PF4)/heparin complexes. The mechanism that incites such prevalent anti-PF4/heparin antibody production in more than 50% of patients exposed to heparin in some clinical settings is poorly understood. To investigate early events associated with antigen exposure, we first examined the interaction of PF4/heparin complexes with cells circulating in whole blood. In healthy donors, PF4/heparin complexes bind preferentially to B cells (>90% of B cells bind to PF4/heparin in vitro) relative to neutrophils, monocytes, or T cells. Binding of PF4 to B cells is heparin dependent, and PF4/heparin complexes are found on circulating B cells from some, but not all, patients receiving heparin. Given the high proportion of B cells that bind PF4/heparin, we investigated complement as a mechanism for noncognate antigen recognition. Complement is activated by PF4/heparin complexes, co-localizes with antigen on B cells from healthy donors, and is present on antigen-positive B cells in patients receiving heparin. Binding of PF4/heparin complexes to B cells is mediated through the interaction between complement and complement receptor 2 (CR2 [CD21]). To the best of our knowledge, these are the first studies to demonstrate complement activation by PF4/heparin complexes, opsonization of PF4/heparin to B cells via CD21, and the presence of complement activation fragments on circulating B cells in some patients receiving heparin. Given the critical contribution of complement to humoral immunity, our observations provide new mechanistic insights into the immunogenicity of PF4/heparin complexes.

  • Submitted April 6, 2016.
  • Accepted July 7, 2016.
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