Pf4, also known as Platelet factor 4 or chemokine (C-X-C motif) ligand 4 (CXCL4), is a highly cationic tetrameric protein and an abundant chemokine released from platelet α -granules on activation. It is central to blood coagulation and also involved in innate and adaptive immunity when platelets respond to infections [1,2,3,7]. PF4 binds and activates the thrombopoietin receptor c -Mpl on platelets, leading to the activation of the JAK2-STAT3/5 pathway and platelet aggregation [2].

PF4 is implicated in several thrombotic disorders. It combines with heparin to form an antigen that can produce IgG antibodies, participating in heparin-induced thrombocytopenia (HIT) [3]. In vaccine-induced immune thrombotic thrombocytopenia (VITT), antibodies to PF4 form immune complexes, activating platelets and neutrophils through Fc receptors [2,3,4,5,6,8,9]. The electrostatic interaction between PF4 and negatively charged molecules is crucial in VITT progression, similar to HIT [3,9]. Different types of anti-PF4 antibodies have been proposed, with type 2 (heparin-dependent, platelet-activating) and type 3 (heparin-independent, platelet-activating) associated with severe prothrombotic disorders [4].

In conclusion, Pf4 is vital in platelet activation and coagulation processes. Its role in HIT and VITT has been well-studied, highlighting the importance of understanding Pf4-related immune responses for the diagnosis and treatment of these thrombotic disorders. The research on Pf4 provides insights into the pathogenesis of immune-associated thrombosis and potential therapeutic directions [1,2,3,4,5,6,7,8,9].

References:

1. Warkentin, Theodore E. 2022. Platelet-activating anti-PF4 disorders: An overview. In Seminars in hematology, 59, 59-71. doi:10.1053/j.seminhematol.2022.02.005. https://pubmed.ncbi.nlm.nih.gov/35512902/

2. Buka, Richard J, Montague, Samantha J, Moran, Luis A, Watson, Steve P, Nicolson, Phillip L R. . PF4 activates the c-Mpl-Jak2 pathway in platelets. In Blood, 143, 64-69. doi:10.1182/blood.2023020872. https://pubmed.ncbi.nlm.nih.gov/37883794/

3. Liu, Zhiyan, Li, Longtu, Zhang, Hanxu, Xiang, Qian, Cui, Yimin. 2023. Platelet factor 4(PF4) and its multiple roles in diseases. In Blood reviews, 64, 101155. doi:10.1016/j.blre.2023.101155. https://pubmed.ncbi.nlm.nih.gov/38008700/

4. Greinacher, Andreas, Warkentin, Theodore E. . Thrombotic anti-PF4 immune disorders: HIT, VITT, and beyond. In Hematology. American Society of Hematology. Education Program, 2023, 1-10. doi:10.1182/hematology.2023000503. https://pubmed.ncbi.nlm.nih.gov/38066843/

5. Ngo, Anh T P, Bochenek, Veronica, Gollomp, Kandace. 2023. The immunology of PF4 polyanion interactions. In Current opinion in hematology, 30, 219-229. doi:10.1097/MOH.0000000000000782. https://pubmed.ncbi.nlm.nih.gov/37603711/

6. Yang, Chieh, Wang, Irene, Chitkara, Akshit, Patel, Rushin, Kubba, Samir V. 2024. Anti-PF4 antibodies and their relationship with COVID infection. In Hematology, transfusion and cell therapy, 46, 516-523. doi:10.1016/j.htct.2023.11.012. https://pubmed.ncbi.nlm.nih.gov/38388299/

7. Cai, Zheng, Greene, Mark I, Zhu, Zhiqiang, Zhang, Hongtao. 2020. Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19. In Antibodies (Basel, Switzerland), 9, . doi:10.3390/antib9040052. https://pubmed.ncbi.nlm.nih.gov/33050376/

8. Zhang, Yi, Bissola, Anna-Lise, Treverton, Jared, Arnold, Addi, Nazy, Ishac. 2024. Vaccine-Induced Immune Thrombotic Thrombocytopenia: Clinicopathologic Features and New Perspectives on Anti-PF4 Antibody-Mediated Disorders. In Journal of clinical medicine, 13, . doi:10.3390/jcm13041012. https://pubmed.ncbi.nlm.nih.gov/38398325/

9. Liu, Zhi-Yan, Sun, Min-Xue, Hua, Man-Qi, Xiang, Qian, Cui, Yi-Min. 2023. New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF. In Frontiers in immunology, 14, 1098665. doi:10.3389/fimmu.2023.1098665. https://pubmed.ncbi.nlm.nih.gov/36926331/