PF4 activates the c-Mpl-Jak2 pathway in platelets
© 2024 by American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
ABSTRACT: Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:143 |
|---|---|
| Enthalten in: |
Blood - 143(2024), 1 vom: 04. Jan., Seite 64-69 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Buka, Richard J [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 06.01.2024 Date Revised 24.03.2024 published: Print CommentIn: Blood. 2024 Jan 4;143(1):7-9. - PMID 38175681 Citation Status MEDLINE |
|---|
| doi: |
10.1182/blood.2023020872 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363758852 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363758852 | ||
| 003 | DE-627 | ||
| 005 | 20240324234834.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood.2023020872 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1344.xml |
| 035 | |a (DE-627)NLM363758852 | ||
| 035 | |a (NLM)37883794 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Buka, Richard J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PF4 activates the c-Mpl-Jak2 pathway in platelets |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.01.2024 | ||
| 500 | |a Date Revised 24.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Blood. 2024 Jan 4;143(1):7-9. - PMID 38175681 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 by American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
| 520 | |a ABSTRACT: Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antigen-Antibody Complex |2 NLM | |
| 650 | 7 | |a Heparin |2 NLM | |
| 650 | 7 | |a 9005-49-6 |2 NLM | |
| 650 | 7 | |a Immunologic Factors |2 NLM | |
| 650 | 7 | |a Janus Kinase 2 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Platelet Factor 4 |2 NLM | |
| 650 | 7 | |a 37270-94-3 |2 NLM | |
| 650 | 7 | |a Receptors, Thrombopoietin |2 NLM | |
| 650 | 7 | |a JAK2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a PF4 protein, human |2 NLM | |
| 650 | 7 | |a MPL protein, human |2 NLM | |
| 650 | 7 | |a 143641-95-6 |2 NLM | |
| 700 | 1 | |a Montague, Samantha J |e verfasserin |4 aut | |
| 700 | 1 | |a Moran, Luis A |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Eleyna M |e verfasserin |4 aut | |
| 700 | 1 | |a Slater, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Watson, Steve P |e verfasserin |4 aut | |
| 700 | 1 | |a Nicolson, Phillip L R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 143(2024), 1 vom: 04. Jan., Seite 64-69 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
| 773 | 1 | 8 | |g volume:143 |g year:2024 |g number:1 |g day:04 |g month:01 |g pages:64-69 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2023020872 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 143 |j 2024 |e 1 |b 04 |c 01 |h 64-69 | ||