Effect of HIT Components on the Development of Breast Cancer Cells

Chen, Liyu; Apte, Gurunath; Lindenbauer, Annerose; Frant, Marion; Nguyen, Thi-Huong

doi:10.3390/life11080832

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…This explains how the body generates platelet-activating anti-PF4 antibodies in COVID-19 patients, as detected recently [ 12 , 13 ]. Furthermore, PF4 has a high affinity to polyanions on many cell surfaces [ 34 ] such as monocytes, neutrophils, endothelial [ 31 ], and even cancer cells [ 50 , 51 ]. Thus, PF4/virus particles have a high potential to mediate and even activate platelets and other cells while PF4-antibodies are known to activate human platelets, monocytes, and neutrophils [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

The Binding of the SARS-CoV-2 Spike Protein to Platelet Factor 4: A Proposed Mechanism for the Generation of Pathogenic Antibodies

Nguyen,

Chen,

Khan

et al. 2024

Biomolecules

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Pathogenic platelet factor 4 (PF4) antibodies contributed to the abnormal coagulation profiles in COVID-19 and vaccinated patients. However, the mechanism of what triggers the body to produce these antibodies has not yet been clarified. Similar patterns and many comparable features between the COVID-19 virus and heparin-induced thrombocytopenia (HIT) have been reported. Previously, we identified a new mechanism of autoimmunity in HIT in which PF4-antibodies self-clustered PF4 and exposed binding epitopes for other pathogenic PF4/heparin antibodies. Here, we first proved that the SARS-CoV-2 spike protein (SP) also binds to PF4. The binding was evidenced by the increase in mass and optical intensity as observed through quartz crystal microbalance and immunosorbent assay, while the switching of the surface zeta potential caused by protein interactions and binding affinity of PF4-SP were evaluated by dynamic light scattering and isothermal spectral shift analysis. Based on our results, we proposed a mechanism for the generation of PF4 antibodies in COVID-19 patients and suggested a reconsideration of current diagnostic assays for the better detection of PF4/SP antibodies. We further validated the changes in zeta potential and interaction affinity between PF4 and SP and found that their binding mechanism differs from ACE2–SP binding. Importantly, the PF4/SP complexes facilitate the binding of anti-PF4/Heparin antibodies. Our findings offer a fresh perspective on PF4 engagement with the SARS-CoV-2 SP, illuminating the role of PF4/SP complexes in severe thrombotic events.

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Section: Discussionmentioning

confidence: 99%

The Binding of the SARS-CoV-2 Spike Protein to Platelet Factor 4: A Proposed Mechanism for the Generation of Pathogenic Antibodies

Nguyen,

Chen,

Khan

et al. 2024

Biomolecules

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“…Platelets were isolated from whole blood as previously described. 49 To test if FIT occurs, we incubated platelets with PF4, Fondaparinux, and KKO and perform experiments under both stirring-based heparin-induced platelet aggregation (HIPA) platform and at the static condition. 13 As a control, unfractionated heparin (UFH) was also tested at concentrations up to 667 μg/mL.…”

Section: Methodsmentioning

confidence: 99%

When Will Fondaparinux Induce Thrombocytopenia?

et al. 2022

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The pentasaccharide Fondaparinux, a synthetic selective factor Xa inhibitor, is one of the safest anticoagulants in the heparin family that is recommended as an alternative drug for patients with hypersensitivity to other drugs such as heparin-induced thrombocytopenia (HIT). However, some observations of Fondaparinux-induced thrombocytopenia (FIT) have been reported while others claimed that FIT does not occur in patients with fondaparinux therapy, indicating that the mechanism of FIT remains controversial. Here, we utilized different methodologies including dynamic light scattering, immunosorbent and platelet aggregation assays, confocal laser scanning microscopy, and flow cytometry to gain insights into FIT. We found that at a certain concentration, Fondaparinux formed sufficient large and stable complexes with PF4 that facilitated binding of the HIT-like monoclonal KKO antibody and enhanced platelet aggregation and activation. We proposed a model to describe the role of Fondaparinux concentration in the formation of complexes with platelet factor 4 and how it promotes the binding of KKO. Our results clarify controversial observations of FIT in patients as each contains a dissimilar PF4:Fondaparinux concentration ratio.

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“…We recently found that HIT components affect the development of breast cancer cell line MDA-MB-231, especially, HIT-mimicked Abs showed different effects as compared to non-HIT Abs. 45 Additionally, previous studies showed that PF4 bound monocytes, 46 human umbilical vein endothelial cells, 47 or platelets 43 allowed better binding of HIT antibodies than non-HIT ones. The negatively charged polyanions such as glycosaminoglycans (GAGs) on these cells bind to the highly positive charged PF4 that induces changes in the structure of an endogenous protein thereby expressing epitopes for HIT antibodies.…”

Section: Introductionmentioning

confidence: 99%