HIT-antibodies promote their own antigen

Greinacher, Andreas; Krauel, Krystin; Jensch, Inga

doi:10.1182/blood-2012-06-430694

Cited by 4 publications

(3 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we have shown that polyanions like heparin force two PF4 tetramers together 18 , hereby inducing a conformational change in PF4 (refs 5 , 40 ), which is consistent with X-ray structure analysis of PF4/fondaparinux complexes 19 . The conformational change of PF4, which is required for binding of group-2 ABS, results in the release of energy 5 .…”

Section: Discussionsupporting

confidence: 88%

“…Sachais et al 20 reported that KKO is able to cluster PF4 tetramers using precipitation of complexes of radiolabeled PF4 and KKO. Although we did not observe binding of KKO to PF4 alone in the fluid phase, their findings led to our hypothesis 40 that group-3 ABS can cluster PF4 similar to heparin, which subsequently allows group-2 ABS to bind to PF4/group-3 complexes.…”

Section: Discussioncontrasting

confidence: 73%

See 1 more Smart Citation

Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

et al. 2017

Self Cite

View full text Add to dashboard Cite

Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60–100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 73%

Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…37 Following this concept, sera causing platelet activation in the presence of nucleic acids might contain antibodies that, like KKO, can cross-link PF4 molecules. In this case, the negative charge of nucleic acids would initiate antigen formation by allowing close approximation of PF4 molecules, which would be sufficient for further oligomerization of PF4 by such anti-PF4/heparin antibodies.…”

Section: Discussionmentioning

confidence: 99%

Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4

Jaax

Krauel

Marschall

et al. 2013

Blood

Self Cite

138

116

View full text Add to dashboard Cite

Key Points• PF4 binds to nucleic acids and thereby exposes the epitope to which anti-PF4/ heparin antibodies bind.• PF4/aptamer complexes can induce an immune response resembling heparin-induced thrombocytopenia.The tight electrostatic binding of the chemokine platelet factor 4 (PF4) to polyanions induces heparin-induced thrombocytopenia, a prothrombotic adverse drug reaction caused by immunoglobulin G directed against PF4/polyanion complexes. This study demonstrates that nucleic acids, including aptamers, also bind to PF4 and enhance PF4 binding to platelets. Systematic assessment of RNA and DNA constructs, as well as 4 aptamers of different lengths and secondary structures, revealed that increasing length and double-stranded segments of nucleic acids augment complex formation with PF4, while single nucleotides or single-stranded polyA or polyC constructs do not. Aptamers were shown by circular dichroism spectroscopy to induce structural changes in PF4 that resemble those induced by heparin. Moreover, heparin-induced anti-human-PF4/ heparin antibodies cross-reacted with human PF4/nucleic acid and PF4/aptamer complexes, as shown by an enzyme immunoassay and a functional platelet activation assay. Finally, administration of PF4/44mer-DNA protein C aptamer complexes in mice induced anti-PF4/aptamer antibodies, which cross-reacted with murine PF4/heparin complexes. These data indicate that the formation of anti-PF4/heparin antibodies in postoperative patients may be augmented by PF4/nucleic acid complexes. Moreover, administration of therapeutic aptamers has the potential to induce anti-PF4/polyanion antibodies and a prothrombotic diathesis. (Blood. 2013;122(2):272-281) IntroductionThe chemokine platelet factor 4 (PF4) is released from platelet a-granules during platelet activation 1 and binds, due to its high positive charge, to many negatively charged polyanions, including heparin. PF4 forms large multimolecular complexes with heparin that are highly immunogenic. 2,3 The resulting immunoglobulin G (IgG) antibodies are the cause of heparin-induced thrombocytopenia (HIT), a prothrombotic adverse drug effect. 4 In HIT, multimolecular complexes composed of PF4, heparin, and anti-PF4/heparin IgG cross-link platelet FcgIIa receptors, 5 triggering platelet activation, microparticle formation, and thrombin generation, with ;50% of affected patients developing thrombosis. 6 Recently, we showed that PF4 binds to polyanions on the surface of bacteria, thereby forming multimolecular complexes that are recognized by human anti-PF4/heparin antibodies. More specifically, we identified the PF4 binding site on gram-negative bacteria as the phosphate groups of lipid A. 7 Based on this observation, we hypothesized that nucleic acids might also form multimolecular complexes with PF4 because they also expose multiple negatively charged phosphate groups. This idea was fostered by previous findings that salmon sperm DNA could substitute heparin in HIT-IgG-induced platelet activation. 8Plasma levels of extracellular nucleic acids are re...

show abstract

Bleeding, Heparin-induced thrombocytopenia, and Other adverse reactions

Green

2020

The Heparins

View full text Add to dashboard Cite

HIT-antibodies promote their own antigen

Cited by 4 publications

References 10 publications

Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4

Bleeding, Heparin-induced thrombocytopenia, and Other adverse reactions

Contact Info

Product

Resources

About