SEARCH:   Advanced

Blood, 15 November 2004, Vol. 104, No. 10, pp. 3173-3180. Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-11-3994. This Article Full Text (PDF) All Versions of this Article: 2003-11-3994v1 104/10/3173    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Eslin, D. E Articles by Kowalska, M A Search for Related Content PubMed PubMed Citation Articles by Eslin, D. E Articles by Kowalska, M A Social Bookmarking                   What's this? Submitted November 21, 2003 Accepted January 26, 2004 Transgenic Mice Studies Demonstrate a Role for Platelet Factor 4 in Thrombosis: Dissociation between Anticoagulant and Antithrombotic Effect of Heparin Don E Eslin, Chunyan Zhang, Kathleen J Samuels, Lubica Rauova, Li Zhai, Stefan Niewiarowski, Douglas B Cines, Mortimer Poncz, and M A Kowalska* Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; University of Pennsylvania School of Medicine, Philadelphia, PA, USA Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA Temple University School of Medicine, Philadelphia, PA, USA University of Pennsylvania School of Medicine, Philadelphia, PA, USA * Corresponding author; email: kowalska{at}email.chop.edu. The platelet-specific chemokine Platelet Factor 4 (PF4) is released in large amounts at sites of vascular injury. PF4 binds to heparin with high affinity, but its in vivo biological role has not been defined. We studied the role of PF4 in thrombosis using heterozygote and homozygote PF4 knockout mice (mPF4+/- and mPF4-/-, respectively) and transgenic mice over-expressing human PF4 (hPF4+). None of these lines had an overt bleeding diathesis, but in a FeCl3 carotid artery thrombosis model, all showed impaired thrombus formation. This defect in thrombus formation in the mPF4-/- animals was corrected by infusing hPF4 over a narrow concentration range. The thrombotic defect in the mPF4+/- and mPF4-/- animals was particularly sensitive to infusions of the negatively-charged anticoagulant heparin. However, the same amount of heparin paradoxically normalized thrombus formation in the hPF4+ animals, although these animals were anticoagulated systemically. Upon infusion of the positively-charged protein, protamine sulfate, the reverse was observed with mPF4+/- and mPF4-/- animals having improved thrombosis, while hPF4+ animals having worsened thrombus formation. These studies support an important role for PF4 in thrombosis, and show that neutralization of PF4 is an important component of heparin's anticoagulant effect. The mechanisms underlying these observations of PF4 biology and their clinical implications remain to be determined. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. P. Lambert, Y. Wang, K. H. Bdeir, Y. Nguyen, M. A. Kowalska, and M. Poncz Platelet factor 4 regulates megakaryopoiesis through low-density lipoprotein receptor-related protein 1 (LRP1) on megakaryocytes Blood, September 10, 2009; 114(11): 2290 - 2298. [Abstract] [Full Text] [PDF] R. Blue, M. A. Kowalska, J. Hirsch, M. Murcia, C. A. Janczak, A. Harrington, M. Jirouskova, J. Li, R. Fuentes, M. A. Thornton, et al. Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel {alpha}IIb-specific {alpha}IIb{beta}3 antagonist Blood, July 2, 2009; 114(1): 195 - 201. [Abstract] [Full Text] [PDF] H. Wang, W. Zhang, R. Tang, R. P. Hebbel, M. A. Kowalska, C. Zhang, J. D. Marth, M. Fukuda, C. Zhu, and Y. Huo Core2 1-6-N-Glucosaminyltransferase-I Deficiency Protects Injured Arteries From Neointima Formation in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1053 - 1059. [Abstract] [Full Text] [PDF] R. J. S. Preston, S. Tran, J. A. Johnson, F. N. Ainle, S. Harmon, B. White, O. P. Smith, P. V. Jenkins, B. Dahlback, and J. S. O'Donnell Platelet Factor 4 Impairs the Anticoagulant Activity of Activated Protein C J. Biol. Chem., February 27, 2009; 284(9): 5869 - 5875. [Abstract] [Full Text] [PDF] S. Kapa and Q. Qian 84-Year-Old Woman With Hemodialysis-Associated Shortness of Breath Mayo Clin. Proc., February 1, 2009; 84(2): 187 - 190. [Full Text] [PDF] R. Flaumenhaft Platelet proteoglycans packing it in Blood, April 1, 2008; 111(7): 3308 - 3309. [Full Text] [PDF] D. S. Woulfe, J. K. Lilliendahl, S. August, L. Rauova, M. A. Kowalska, M. Abrink, G. Pejler, J. G. White, and B. P. Schick Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice Blood, April 1, 2008; 111(7): 3458 - 3467. [Abstract] [Full Text] [PDF] S. Suvarna, B. Espinasse, R. Qi, R. Lubica, M. Poncz, D. B. Cines, M. R. Wiesner, and G. M. Arepally Determinants of PF4/heparin immunogenicity Blood, December 15, 2007; 110(13): 4253 - 4260. [Abstract] [Full Text] [PDF] R. J. Westrick, M. E. Winn, and D. T. Eitzman Murine Models of Vascular Thrombosis Arterioscler Thromb Vasc Biol, October 1, 2007; 27(10): 2079 - 2093. [Abstract] [Full Text] [PDF] M. A. Kowalska, S. A. Mahmud, M. P. Lambert, M. Poncz, and A. Slungaard Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge Blood, September 15, 2007; 110(6): 1903 - 1905. [Abstract] [Full Text] [PDF] M. P. Lambert, L. Rauova, M. Bailey, M. C. Sola-Visner, M. A. Kowalska, and M. Poncz Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications Blood, August 15, 2007; 110(4): 1153 - 1160. [Abstract] [Full Text] [PDF] S. Struyf, M. D. Burdick, E. Peeters, K. Van den Broeck, C. Dillen, P. Proost, J. Van Damme, and R. M. Strieter Platelet Factor-4 Variant Chemokine CXCL4L1 Inhibits Melanoma and Lung Carcinoma Growth and Metastasis by Preventing Angiogenesis Cancer Res., June 15, 2007; 67(12): 5940 - 5948. [Abstract] [Full Text] [PDF] A. A. Amelot, M. Tagzirt, G. Ducouret, R. L. Kuen, and B. F. Le Bonniec Platelet Factor 4 (CXCL4) Seals Blood Clots by Altering the Structure of Fibrin J. Biol. Chem., January 5, 2007; 282(1): 710 - 720. [Abstract] [Full Text] [PDF] L. Rauova, L. Zhai, M. A. Kowalska, G. M. Arepally, D. B. Cines, and M. Poncz Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications Blood, March 15, 2006; 107(6): 2346 - 2353. [Abstract] [Full Text] [PDF] H. Yarovoi, A. T. Nurden, R. R. Montgomery, P. Nurden, and M. Poncz Intracellular interaction of von Willebrand factor and factor VIII depends on cellular context: lessons from platelet-expressed factor VIII Blood, June 15, 2005; 105(12): 4674 - 4676. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020