Platelet factor 4 triggers thrombo‐inflammation by bridging innate and adaptive immunity

Abstract

Platelet factor 4 (PF4, synonym: CXCL4) is an evolutionary old chemokine with proposed roles in hemostasis and antimicrobial defense. In addition, PF4 has attracted considerable attention as a crucial mediator of one of the most prothrombotic adverse drug effects affecting blood cells, heparin‐induced thrombocytopenia (HIT). Interest in PF4 substantially increased in 2021 when it was identified as the target antigen in the life‐threatening adverse effect, vaccine‐induced immune thrombotic thrombocytopenia (VITT). We address the concept that a major biological function of PF4—a strongly cationic chemokine—is to bind to negatively‐charged prokaryotic microorganisms, resulting in structural changes in PF4 that trigger a danger signal recognized by the adaptive immune system. Application of biophysical tools has provided substantial insights into the molecular mechanisms by which PF4 becomes immunogenic, providing insights into a new mechanism of autoimmunity. Binding of autoantibodies with high affinity induces conformational change(s) in the endogenous protein, which are then recognized as foreign antigen, as exemplified by the prothrombotic disorders, autoimmune HIT and VITT. The final part of our review summarizes current assays for HIT and VITT, explaining how structural aspects of anti‐PF4 pathobiology relate to assay design and performance characteristics. Currently, functional (platelet activation) assays using washed platelets detect HIT antibodies when heparin is added, and VITT antibodies when PF4 is added. Solid‐phase PF4‐dependent immunoassays using microtiter plates are sensitive for both HIT and VITT antibodies, while rapid immunoassays, in which the PF4/heparin antigen is coated on beads, are sensitive and specific for HIT, but not for VITT antibodies.

New, Old, and Shared Antibody Specificities in Autoimmune Diseases

“…CXCL4 is a chemokine that can bind heparin and, on rare occasions, antibodies are induced (even in previously healthy individuals) that are specific to CXCL4-heparin complexes. These latter antibodies play a key role in heparin-induced thrombocytopenia (HIT), a rare condition in which they massively activate platelets, inducing dangerous thrombosis [ 23 ]. Since vasculitis and thrombosis are present in SSc, this paper addresses whether antibodies to CXCL4 in SSc are only directed to CXCL4 or also recognize complexes formed by CXCL4 and heparin.…”

Serum Plasminogen Activator Inhibitor-1, α 1-Acid Glycoprotein, C-Reactive Protein, and Platelet Factor 4 Levels—Promising Molecules That Can Complete the “Puzzle” of the Biochemical Milieu in Severe Burns: Preliminary Results of a Cohort Prospective Study

“…Hence, there is a powerful procoagulant effect [37,38]. The same cationic characteristic explains why PF4 binds to microorganisms (that have a negatively charged surface); this results in conformational changes in PF4 that is recognized as a foreign antigen by the immune system [38]. So, it is quite explicable why important amounts of PF4 are released from activated platelets, in infection.…”

“…The result is the facilitation of platelet aggregation and edification of a thrombus. Hence, there is a powerful procoagulant effect [37,38]. The same cationic characteristic explains why PF4 binds to microorganisms (that have a negatively charged surface); this results in conformational changes in PF4 that is recognized as a foreign antigen by the immune system [38].…”

“…PF4 is a small protein produced by activated platelets and dendritic cells [34][35][36]. PF4 levels increase in trauma and infections [37,38]. Being a cationic chemokine, PF4 binds to glycosaminoglycans (GAGs) on the surface of endothelial cells and on the surface of platelets.…”

“…So, it is quite explicable why important amounts of PF4 are released from activated platelets, in infection. The same mechanism (binding to autoantibody-conformational changes in PF4 that is marked as non-self protein) is involved in autoimmune heparin-induced thrombocytopenia (HIT) and in vaccine-induced immune thrombotic thrombocytopenia (VITT) [38].…”