Platelet factor 4 explained

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 alpha-granules of activated platelets 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.^[1] It is usually found in a complex with proteoglycan.

Genomics

The gene for human PF4 is located on human chromosome 4.^[2]

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.^{[1] [3]}

PF4 is chemotactic for neutrophils, fibroblasts and monocytes, and interacts with a splice variant of the chemokine receptor CXCR3, known as CXCR3-B.^[4]

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.^[5] PF4 autoantibodies have also been found in patients with thrombosis and features resembling HIT but no prior administration of heparin.^[6] Antibodies against PF4 have been implicated in cases of thrombosis and thrombocytopenia subsequent to vaccination with the Oxford–AstraZeneca or the Janssen COVID-19 vaccine.^{[7] [8]} This phenomenon has been termed vaccine-induced immune thrombotic thrombocytopenia (VITT).^[9] Changes in the expression of PF4 have also been associated with symptoms of long COVID.^[10]

It is increased in patients with systemic sclerosis that also have interstitial lung disease.^[11]

The human platelet factor 4 kills malaria parasites within erythrocytes by selectively lysing the parasite's digestive vacuole.^[12]

See also

• Platelet-activating factor
• Platelet-derived growth factor

Further reading

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

Notes and References

1. Eisman R, Surrey S, Ramachandran B, Schwartz E, Poncz M . Structural and functional comparison of the genes for human platelet factor 4 and PF4alt . Blood . 76 . 2 . 336–44 . July 1990 . 1695112 . 10.1182/blood.V76.2.336.336 . free .
2. O'Donovan N, Galvin M, Morgan JG . Physical mapping of the CXC chemokine locus on human chromosome 4 . Cytogenetics and Cell Genetics . 84 . 1–2 . 39–42 . 1999 . 10343098 . 10.1159/000015209 . 8087808 .
3. Web site: Entrez Gene: PF4 platelet factor 4 (chemokine (C-X-C motif) ligand 4).
4. 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 . 6 . 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 . The Journal of Experimental Medicine . 197 . 11 . 1537–49 . June 2003 . 12782716 . 2193908 . 10.1084/jem.20021897 .
5. Warkentin TE . Drug-induced immune-mediated thrombocytopenia--from purpura to thrombosis . The New England Journal of Medicine . 356 . 9 . 891–3 . March 2007 . 17329695 . 10.1056/NEJMp068309 .
6. Warkentin TE, Makris M, Jay RM, Kelton JG . A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia . The American Journal of Medicine . 121 . 7 . 632–6 . July 2008 . 18589060 . 10.1016/j.amjmed.2008.03.012 .
7. Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, Wiedmann M, Aamodt AH, Skattør TH, Tjønnfjord GE, Holme PA . 6 . Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination . The New England Journal of Medicine . April 2021 . 384 . 22 . 2124–2130 . 33835768 . 10.1056/NEJMoa2104882 . 0028-4793 . 8112568 . free .
8. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S . Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination . The New England Journal of Medicine . 2092–2101 . April 2021 . 384 . 22 . 33835769 . 10.1056/NEJMoa2104840 . 8095372 . free .
9. Arepally GM, Ortel TL . Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): What We Know and Don't Know . Blood . June 2021 . 34061166 . 10.1182/blood.2021012152 . 8172307 .
10. 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 . 6 . Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection . BMC Medicine . 20 . 1 . 26 . January 2022 . 35027067 . 8758383 . 10.1186/s12916-021-02228-6 . free .
11. Volkmann ER, Tashkin DP, Roth MD, Clements PJ, Khanna D, Furst DE, Mayes M, Charles J, Tseng CH, Elashoff RM, Assassi S . 6 . Changes in plasma CXCL4 levels are associated with improvements in lung function in patients receiving immunosuppressive therapy for systemic sclerosis-related interstitial lung disease . Arthritis Research & Therapy . 18 . 1 . 305 . December 2016 . 28038680 . 5203703 . 10.1186/s13075-016-1203-y . free .
12. 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 . 6 . Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials . Cell Host & Microbe . 12 . 6 . 815–23 . December 2012 . 23245326 . 3638032 . 10.1016/j.chom.2012.10.017 .