https://orcid.org/0000-0001-7942-3273
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ABSTRACT
Introduction
Fcγ-receptors (FcγR) are membrane receptors expressed on a variety of immune cells, specialized in recognition of the Fc part of immunoglobulin G (IgG) antibodies. FcγRIIA-dependent platelet activation in platelet factor 4 (PF4) antibody-related disorders have gained major attention, when these antibodies were identified as the cause of the adverse vaccination event termed vaccine-induced immune thrombocytopenia and thrombosis (VITT) during the COVID-19 vaccination campaign. With the recognition of anti-PF4 antibodies as cause for severe spontaneous and sometimes recurrent thromboses independent of vaccination, their clinical relevance extended far beyond heparin-induced thrombocytopenia (HIT) and VITT.
Areas covered
Patients developing these disorders show life-threatening thromboses, and the outcome is highly dependent on effective treatment. This narrative literature review summarizes treatment options for HIT and VITT that are currently available for clinical application and provides the perspective toward new developments.
Expert opinion
Nearly all these novel approaches are based on in vitro, preclinical observations, or case reports with only limited implementation in clinical practice. The therapeutic potential of these approaches still needs to be proven in larger cohort studies to ensure treatment efficacy and long-term patient safety.
Article highlights
Anticoagulation is a mainstay of treatment in HIT and VITT, but some patients require additional treatment.
Besides anticoagulation, danaparoid inhibits PF4/heparin-complex-formation and PF4-binding to anti-PF4 antibodies.
Additional therapeutic strategies include: therapeutic plasma exchange to lower anti-PF4 antibody plasma concentration; modulation of Fc-receptor function, e.g. by intravenous immunoglobulins (IVIGs), and downstream signaling, e.g. by Bruton Tyrosin Kinase inhibition.
Potential novel approaches in preclinical development are partially cleaved anti-PF4 monoclonal antibodies against PF4/heparin complexes, PF4, or FcγRIIa and FcRn; and designed ankyrin repeat proteins (DARPins) blocking FcγRIIa.
List of abbreviations
| 12-LOX | = | 12[S]-lipoxygenase |
| aPTT | = | activated partial thromboplastin time |
| BTK | = | Bruton tyrosine kinase |
| CLEC-2 | = | C-type lectin-like receptor 2 |
| DAG | = | diacetyl glycerol |
| DARPins | = | Designed ankyrin repeat proteins |
| DOACs | = | direct oral anticoagulants |
| DTI | = | direct thrombin-inhibitor |
| EndoS | = | endo-β-N-acetylglucosaminidases of Streptococcus pyogenes |
| FcRn | = | neonate Fc receptor |
| FcγR | = | Fcγ-receptors |
| FXa | = | factor Xa |
| GPIIb/IIIa | = | glycoprotein IIb/IIIa |
| GPVI | = | glycoprotein VI |
| HIT | = | heparin-induced thrombocytopenia |
| ICU | = | intensive care unit |
| IdeS | = | IgG-degrading enzyme of Streptococcus pyogenes |
| Ig | = | immunoglobulin |
| IP3 | = | inositol triphosphate |
| ITAMs | = | immunoreceptor tyrosine-based activation motifs |
| IVIGs | = | intravenous immunoglobulins |
| LMWH | = | low molecular weight heparin |
| mAb | = | monoclonal antibodies |
| ODSH | = | 2-O,3-O-desulfated heparin |
| PF4 | = | platelet factor 4 |
| PI3 | = | phosphoinositid-3 |
| PIP2 | = | phosphatidylinositol-(4,5)-bisphosphate |
| PIP3 | = | phosphatidylinositol-(3,4,5)-triphosphate |
| PKC | = | protein kinase C |
| PLCγ | = | phosphoinositide phospholipase Cγ |
| SFKs | = | Src family kinases |
| Syk | = | spleen tyrosine kinase |
| TF | = | tissue factor |
| TPE | = | therapeutic plasma exchange |
| UFH | = | unfractionated heparin |
| VITT | = | vaccine-induced immune thrombocytopenia and thrombosis |
| VKAs | = | vitamin K antagonists |
Declaration of interests
A Greinacher reports grants and nonfinancial support from Aspen, Boehringer Ingelheim, MSD, Bristol Myers Squibb (BMS), Paringenix, Bayer Healthcare, Gore, Inc., Rovi, Sagent, Biomarin/Prosensa, personal fees from Aspen, Boehringer Ingelheim, MSD, Macopharma, BMS, Chromatec, Werfen (Instrumentation Laboratory), and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, GTH e.V.
All other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Acknowledgments
L Schönborn was supported within the Gerhard-Domagk-Research-Program by the University Medicine Greifswald and by the American Society of Hematology with a Global Research Award. Figures in this article were created with BioRender.com.
Author contributions
Conceptualization, L Müller and A Greinacher; resources, L Schönborn and A Greinacher; writing – original draft preparation, L Müller and V A S Dabbiru; writing – review and editing, L Schönborn and A Greinacher; visualization, V A S Dabbiru; supervision, A Greinacher; project administration, A Greinacher; funding acquisition, A Greinacher and L Schönborn.
All authors have read and agreed to the published version of the manuscript.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary Material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2024.2328241