View source for Platelet factor 4

{{Short description|Protein involved in blood clotting, wound healing and inflammation}}
{{redirect|PF4|SpaceShipTwo PF04|2014 Virgin Galactic crash|USN Tacoma-class patrol frigate|USS Sausalito (PF-4)|Philippine Navy frigate|BRP Rajah Lakandula (PF-4)|JMSDF frigate|JDS Momi (PF-4)|1997 PF4|14967 Madrid|1999 PF4|38245 Marcospontes|PF4 receptor|PF4 receptor}}
{{Infobox gene}}

'''Platelet factor 4''' ('''PF4''') is a small [[cytokine]] belonging to the CXC [[chemokine]] family that is also known as '''chemokine (C-X-C motif) ligand 4''' (CXCL4) . This chemokine is released from [[Platelet alpha-granule|alpha-granules]] of activated [[platelet]]s during platelet aggregation, and promotes blood [[coagulation]] by moderating the effects of [[heparin]]-like molecules. Due to these roles, it is predicted to play a role in [[wound repair]] and [[inflammation]].<ref name="Eisman_1990">{{cite journal | vauthors = Eisman R, Surrey S, Ramachandran B, Schwartz E, Poncz M | title = Structural and functional comparison of the genes for human platelet factor 4 and PF4alt | journal = Blood | volume = 76 | issue = 2 | pages = 336–44 | date = July 1990 | pmid = 1695112 | doi = 10.1182/blood.V76.2.336.336 | doi-access = free }}</ref> It is usually found in a complex with [[proteoglycan]].

== Genomics ==

The [[gene]] for human PF4 is located on human [[chromosome 4]].<ref>{{cite journal | vauthors = O'Donovan N, Galvin M, Morgan JG | title = Physical mapping of the CXC chemokine locus on human chromosome 4 | journal = Cytogenetics and Cell Genetics | volume = 84 | issue = 1–2 | pages = 39–42 | year = 1999 | pmid = 10343098 | doi = 10.1159/000015209 | s2cid = 8087808 }}</ref>

== Function ==

Platelet factor-4 is a 70-amino acid protein that is released from the alpha-granules of activated platelets and binds with high affinity to heparin. Its major physiologic role appears to be neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local [[antithrombin]] activity and promoting coagulation. As a strong chemoattractant for neutrophils and fibroblasts, PF4 probably has a role in inflammation and wound repair.<ref name="Eisman_1990"/><ref>{{cite web | title = Entrez Gene: PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5196}}</ref>

PF4 is chemotactic for [[neutrophil]]s, [[fibroblast]]s and [[monocyte]]s, and interacts with a [[splice variant]] of the chemokine receptor [[CXCR3]], known as CXCR3-B.<ref>{{cite journal | vauthors = Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P | display-authors = 6 | title = An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4 | journal = The Journal of Experimental Medicine | volume = 197 | issue = 11 | pages = 1537–49 | date = June 2003 | pmid = 12782716 | pmc = 2193908 | doi = 10.1084/jem.20021897 }}</ref>

== Clinical significance ==

The heparin:PF4 complex is the antigen in [[heparin-induced thrombocytopenia]] (HIT), an idiosyncratic autoimmune reaction to the administration of the anticoagulant [[heparin]].<ref>{{cite journal | vauthors = Warkentin TE | title = Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis | journal = The New England Journal of Medicine | volume = 356 | issue = 9 | pages = 891–3 | date = March 2007 | pmid = 17329695 | doi = 10.1056/NEJMp068309 }}</ref> PF4 [[autoantibody|autoantibodies]] have also been found in patients with thrombosis and features resembling HIT but no prior administration of heparin.<ref>{{cite journal | vauthors = Warkentin TE, Makris M, Jay RM, Kelton JG | title = A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia | journal = The American Journal of Medicine | volume = 121 | issue = 7 | pages = 632–6 | date = July 2008 | pmid = 18589060 | doi = 10.1016/j.amjmed.2008.03.012 }}</ref> Antibodies against PF4 have been implicated in cases of thrombosis and thrombocytopenia subsequent to vaccination with the [[Oxford–AstraZeneca COVID-19 vaccine|Oxford–AstraZeneca]] or the [[Janssen COVID-19 vaccine]].<ref>{{cite journal | vauthors = Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, Wiedmann M, Aamodt AH, Skattør TH, Tjønnfjord GE, Holme PA | display-authors = 6 | title = Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination | journal = The New England Journal of Medicine | date = April 2021 | volume = 384 | issue = 22 | pages = 2124–2130 | pmid = 33835768 | doi = 10.1056/NEJMoa2104882 |issn=0028-4793 | pmc = 8112568 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S | title = Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination | journal = The New England Journal of Medicine | pages = 2092–2101 | date = April 2021 | volume = 384 | issue = 22 | pmid = 33835769 | doi = 10.1056/NEJMoa2104840 | pmc = 8095372 | doi-access = free }}</ref> This phenomenon has been termed [[Post-vaccination embolic and thrombotic events|vaccine-induced immune thrombotic thrombocytopenia]] (VITT).<ref>{{cite journal | vauthors = Arepally GM, Ortel TL | title = Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): What We Know and Don't Know | journal = Blood | date = June 2021 | pmid = 34061166 | doi = 10.1182/blood.2021012152 | pmc = 8172307 }}</ref> Changes in the expression of PF4 have also been associated with symptoms of [[long COVID]].<ref>{{cite journal | vauthors = Ryan FJ, Hope CM, Masavuli MG, Lynn MA, Mekonnen ZA, Yeow AE, Garcia-Valtanen P, Al-Delfi Z, Gummow J, Ferguson C, O'Connor S, Reddi BA, Hissaria P, Shaw D, Kok-Lim C, Gleadle JM, Beard MR, Barry SC, Grubor-Bauk B, Lynn DJ | display-authors = 6 | title = Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection | journal = BMC Medicine | volume = 20 | issue = 1 | pages = 26 | date = January 2022 | pmid = 35027067 | pmc = 8758383 | doi = 10.1186/s12916-021-02228-6 | doi-access = free }}</ref>

It is increased in patients with [[systemic sclerosis]] that also have [[interstitial lung disease]].<ref>{{cite journal | vauthors = Volkmann ER, Tashkin DP, Roth MD, Clements PJ, Khanna D, Furst DE, Mayes M, Charles J, Tseng CH, Elashoff RM, Assassi S | display-authors = 6 | title = Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease | journal = Arthritis Research & Therapy | volume = 18 | issue = 1 | pages = 305 | date = December 2016 | pmid = 28038680 | pmc = 5203703 | doi = 10.1186/s13075-016-1203-y | doi-access = free }}</ref>

The  human platelet factor 4 kills [[Plasmodium|malaria parasite]]s within [[erythrocyte]]s by selectively lysing the parasite's digestive vacuole.<ref name="pmid23245326">{{cite journal | vauthors = Love MS, Millholland MG, Mishra S, Kulkarni S, Freeman KB, Pan W, Kavash RW, Costanzo MJ, Jo H, Daly TM, Williams DR, Kowalska MA, Bergman LW, Poncz M, DeGrado WF, Sinnis P, Scott RW, Greenbaum DC | display-authors = 6 | title = Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials | journal = Cell Host & Microbe | volume = 12 | issue = 6 | pages = 815–23 | date = December 2012 | pmid = 23245326 | pmc = 3638032 | doi = 10.1016/j.chom.2012.10.017 }}</ref>

== See also ==
* [[Platelet-activating factor]]
* [[Platelet-derived growth factor]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Bikfalvi A, Gimenez-Gallego G | title = The control of angiogenesis and tumor invasion by platelet factor-4 and platelet factor-4-derived molecules | journal = Seminars in Thrombosis and Hemostasis | volume = 30 | issue = 1 | pages = 137–44 | date = February 2004 | pmid = 15034805 | doi = 10.1055/s-2004-822978 | s2cid = 260320397 }}
* {{cite journal | vauthors = Maurer AM, Zhou B, Han ZC | title = Roles of platelet factor 4 in hematopoiesis and angiogenesis | journal = Growth Factors | volume = 24 | issue = 4 | pages = 242–52 | date = December 2006 | pmid = 17381065 | doi = 10.1080/08977190600988225 | s2cid = 36468865 }}
* {{cite journal | vauthors = Deuel TF, Keim PS, Farmer M, Heinrikson RL | title = Amino acid sequence of human platelet factor 4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 6 | pages = 2256–8 | date = June 1977 | pmid = 267922 | pmc = 432148 | doi = 10.1073/pnas.74.6.2256 | bibcode = 1977PNAS...74.2256D | doi-access = free }}
* {{cite journal | vauthors = Walz DA, Wu VY, de Lamo R, Dene H, McCoy LE | title = Primary structure of human platelet factor 4 | journal = Thrombosis Research | volume = 11 | issue = 6 | pages = 893–8 | date = December 1977 | pmid = 601757 | doi = 10.1016/0049-3848(77)90117-7 }}
* {{cite journal | vauthors = Nath N, Lowery CT, Niewiarowski S | title = Antigenic and antiheparin properties of human platelet factor 4 (PF4) | journal = Blood | volume = 45 | issue = 4 | pages = 537–50 | date = April 1975 | pmid = 803847 | doi = 10.1182/blood.V45.4.537.537 | doi-access = free }}
* {{cite journal | vauthors = Hermodson M, Schmer G, Kurachi K | title = Isolation, crystallization, and primary amino acid sequence of human platelet factor 4 | journal = The Journal of Biological Chemistry | volume = 252 | issue = 18 | pages = 6276–9 | date = September 1977 | doi = 10.1016/S0021-9258(17)39951-9 | pmid = 893407 | doi-access = free }}
* {{cite journal | vauthors = Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ | display-authors = 6 | title = Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides | journal = Science | volume = 247 | issue = 4938 | pages = 77–9 | date = January 1990 | pmid = 1688470 | doi = 10.1126/science.1688470 | bibcode = 1990Sci...247...77M }}
* {{cite journal | vauthors = Han ZC, Bellucci S, Tenza D, Caen JP | title = Negative regulation of human megakaryocytopoiesis by human platelet factor 4 and beta thromboglobulin: comparative analysis in bone marrow cultures from normal individuals and patients with essential thrombocythaemia and immune thrombocytopenic purpura | journal = British Journal of Haematology | volume = 74 | issue = 4 | pages = 395–401 | date = April 1990 | pmid = 2140694 | doi = 10.1111/j.1365-2141.1990.tb06325.x | s2cid = 24529258 }}
* {{cite journal | vauthors = Poncz M, Surrey S, LaRocco P, Weiss MJ, Rappaport EF, Conway TM, Schwartz E | title = Cloning and characterization of platelet factor 4 cDNA derived from a human erythroleukemic cell line | journal = Blood | volume = 69 | issue = 1 | pages = 219–23 | date = January 1987 | pmid = 3098319 | doi = 10.1182/blood.V69.1.219.219 | name-list-style = vanc | doi-access = free }}
* {{cite journal | vauthors = Griffin CA, Emanuel BS, LaRocco P, Schwartz E, Poncz M | title = Human platelet factor 4 gene is mapped to 4q12----q21 | journal = Cytogenetics and Cell Genetics | volume = 45 | issue = 2 | pages = 67–9 | year = 1987 | pmid = 3622011 | doi = 10.1159/000132431 }}
* {{cite journal | vauthors = Senior RM, Griffin GL, Huang JS, Walz DA, Deuel TF | title = Chemotactic activity of platelet alpha granule proteins for fibroblasts | journal = The Journal of Cell Biology | volume = 96 | issue = 2 | pages = 382–5 | date = February 1983 | pmid = 6187750 | pmc = 2112304 | doi = 10.1083/jcb.96.2.382 }}
* {{cite journal | vauthors = Morgan FJ, Begg GS, Chesterman CN | title = Complete covalent structure of human platelet factor 4 | journal = Thrombosis and Haemostasis | volume = 42 | issue = 5 | pages = 1652–60 | date = February 1980 | pmid = 6445090 }}
* {{cite journal | vauthors = Deuel TF, Senior RM, Chang D, Griffin GL, Heinrikson RL, Kaiser ET | title = Platelet factor 4 is chemotactic for neutrophils and monocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 7 | pages = 4584–7 | date = July 1981 | pmid = 6945600 | pmc = 319837 | doi = 10.1073/pnas.78.7.4584 | bibcode = 1981PNAS...78.4584D | doi-access = free }}
* {{cite journal | vauthors = Brown KJ, Parish CR | title = Histidine-rich glycoprotein and platelet factor 4 mask heparan sulfate proteoglycans recognized by acidic and basic fibroblast growth factor | journal = Biochemistry | volume = 33 | issue = 46 | pages = 13918–27 | date = November 1994 | pmid = 7524669 | doi = 10.1021/bi00250a047 }}
* {{cite journal | vauthors = Mayo KH, Roongta V, Ilyina E, Milius R, Barker S, Quinlan C, La Rosa G, Daly TJ | display-authors = 6 | title = NMR solution structure of the 32-kDa platelet factor 4 ELR-motif N-terminal chimera: a symmetric tetramer | journal = Biochemistry | volume = 34 | issue = 36 | pages = 11399–409 | date = September 1995 | pmid = 7547867 | doi = 10.1021/bi00036a012 }}
* {{cite journal | vauthors = Barker S, Mayo KH | title = Quarternary structure amplification of protein folding differences observed in 'native' platelet factor-4 | journal = FEBS Letters | volume = 357 | issue = 3 | pages = 301–4 | date = January 1995 | pmid = 7835432 | doi = 10.1016/0014-5793(94)01384-D | s2cid = 12222261 | doi-access = free | bibcode = 1995FEBSL.357..301B }}
* {{cite journal | vauthors = Zhang X, Chen L, Bancroft DP, Lai CK, Maione TE | title = Crystal structure of recombinant human platelet factor 4 | journal = Biochemistry | volume = 33 | issue = 27 | pages = 8361–6 | date = July 1994 | pmid = 8031770 | doi = 10.1021/bi00193a025 }}
* {{cite journal | vauthors = Horne MK | title = The effect of secreted heparin-binding proteins on heparin binding to platelets | journal = Thrombosis Research | volume = 70 | issue = 1 | pages = 91–8 | date = April 1993 | pmid = 8511754 | doi = 10.1016/0049-3848(93)90226-E }}
* {{cite journal | vauthors = Kolset SO, Mann DM, Uhlin-Hansen L, Winberg JO, Ruoslahti E | title = Serglycin-binding proteins in activated macrophages and platelets | journal = Journal of Leukocyte Biology | volume = 59 | issue = 4 | pages = 545–54 | date = April 1996 | pmid = 8613703 | doi = 10.1002/jlb.59.4.545 | name-list-style = vanc | s2cid = 23125881 }}
{{refend}}

== External links ==
* {{MeshName|Platelet+factor+4}}

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{{Coagulation cascade}}
{{Chemokines}}
{{Proteoglycans}}
{{Chemokine receptor modulators}}
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[[Category:Cytokines]]
[[Category:Proteoglycans]]