Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia

• Published in: Blood 2011-01, Vol.117 (4), p.1370-1378
• Main Authors: Krauel, Krystin, Pötschke, Christian, Weber, Claudia, Kessler, Wolfram, Fürll, Birgitt, Ittermann, Till, Maier, Stefan, Hammerschmidt, Sven, Bröker, Barbara M., Greinacher, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - metabolism; Bacteria - immunology; Bacteria - metabolism; Bacterial Adhesion; Biological and medical sciences; Blood; Chemokines; Cross Reactions - immunology; Defense mechanisms; Drugs; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; Escherichia coli - immunology; Escherichia coli - metabolism; Female; Hematologic and hematopoietic diseases; Heparin; Humans; Immunodominant Epitopes - immunology; Immunoglobulin G; Immunoglobulin M; Infection; Listeria monocytogenes - immunology; Listeria monocytogenes - metabolism; Lymphocytes B; Medical sciences; Mice; Mice, Inbred C57BL; Mimicry; Neisseria meningitidis - immunology; Neisseria meningitidis - metabolism; Phagocytosis; Platelet diseases and coagulopathies; platelet factor 4; Platelet Factor 4 - metabolism; Platelets; Polyanions; Population studies; Protein Binding; Sepsis; Side effects; Staphylococcus aureus; Staphylococcus aureus - immunology; Staphylococcus aureus - metabolism; Streptococcus pneumoniae - immunology; Streptococcus pneumoniae - metabolism; Thrombocytopenia; Thrombocytopenia - chemically induced; Thrombocytopenia - immunology; Thrombocytopenia - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-08-301424

A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism.