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

• Published in: Blood Vol. 128; no. 14; pp. 1789 - 1799
• Main Authors: Khandelwal, Sanjay, Lee, Grace M., Hester, C. Garren, Poncz, Mortimer, McKenzie, Steven E., Sachais, Bruce S., Rauova, Lubica, Kelsoe, Garnett, Cines, Douglas B., Frank, Michael, Arepally, Gowthami M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.10.2016; American Society of Hematology
• Series: Platelets and Thrombopoiesis
• Subjects: Antigens - metabolism; B-Lymphocytes - metabolism; Complement System Proteins - metabolism; Heparin - adverse effects; Heparin - therapeutic use; Humans; Models, Biological; Platelet Factor 4 - metabolism; Plenary Paper; Protamines - metabolism; Protein Binding; Receptors, Complement 3d - metabolism; Thrombocytopenia - blood; Thrombocytopenia - chemically induced; Thrombocytopenia - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-04-709634

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. •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.