Protein binding may explain heparin-induced thrombocytopenia

Krauel K. Blood. 2010;doi:10.1182/blood-2010-08-301424.

Observation that an endogenous protein binds to infectious pathogens may have shed light on why heparin-induced thrombocytopenia can occur early in patients treated with heparin, according to study results.

Researchers from several institutions in Germany conducted a cross-sectional population study of 4,029 individuals. They noted that antibodies specific for complexes of the chemokine platelet Factor IV and the polyanion heparin can lead to heparin-induced thrombocytopenia.

Andreas Greinacher, MD, of the Institute for Immunology and Transfusion Medicine at the Ernst-Moritz-Arndt University in Greifswald, Germany, told HemOnc Today that the findings are “basic science.” Greinacher said antiplatelet Factor IV and heparin immunoglobulin G can be generated by heparin-naive patients as early as day 4 of treatment with heparin. This may induce pre-immunization with antigens that mimic the Factor IV and heparin IgG complexes.

“This is the first example that an endogenous protein binds to pathogens, thereby changing its conformation and now labeling the pathogen as something to be attacked by the immune system,” he said. “The work explains why heparin-induced thrombocytopenia can occur in patients who receive heparin for the first time within 5 days.” Greinacher cited the following evidence for the assumption that bacterial infections may be the cause of these antibodies:

Platelet Factor IV bound charge-dependently to various bacteria.
Human heparin-induced antiplatelet Factor IV/heparin antibodies cross-reacted with platelet Factor IV-coated Staphylococcus aureus and Escherichia coli.
Mice developed antiplatelet Factor IV/heparin antibodies during polymicrobial sepsis without heparin application.

The platelet Factor IV protein may induce antibodies with specificity for platelet Factor IV4/polyanion-complexes after binding to the infecting bacteria. The antibodies may then target a variety of bacteria that are coated with the protein and enhance bacterial phagocytosis in vitro, according to the researchers.

“The absorption and elution experiments by which we purified heparin-induced thrombocytopenia antibodies using platelet Factor IV-coated bacteria may best illustrate our conclusions,” Greinacher said.

When pharmacologic heparin binds to platelets that augment the formation of the protein complexes, it has been observed that the same antigenic epitopes are expressed. The early occurrence of IgG antibodies in patients with heparin-induced thrombocytopenia could be explained by the boosting of preformed B-cells by the platelet Factor IV protein and heparin complexes.

A continuous — and not a dichotomous — distribution of platelet Factor IV/heparin IgM and IgG serum concentrations was observed. This may indicate that pre-immunization to a modified version of the protein may be frequent.

Platelet Factor IV may also play a role in combating bacteria, according to Greinacher. He said heparin-induced thrombocytopenia may be a host defense mechanism that is simply misdirected.

“Platelet Factor IV has a potential biological role in host defense, and heparin-induced thrombocytopenia is a misdirected antibacteria response,” Greinacher said. “I would strongly highlight that this mechanism is what we call an ‘innate-specific immune response.’ This term seems to be a contradiction in itself, but it reflects that platelet Factor IV binding enables the immune system to attack bacteria with IgG antibodies early on, even if the body never had contact with these bacteria. Such a mechanism was not known before.”

Greinacher said the findings may increase understanding about the protein and the risk of other protein clusters that can induce immune responses.

“The impact of recombinantly produced human protein drugs has potentially far-reaching consequences for many biotherapeutics,” Greinacher said.

Follow HemOncToday.com on Twitter.