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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-11-3529. This Article Full Text (PDF) All Versions of this Article: 2002-11-3529v1 102/1/146    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 Slungaard, A. Articles by Lentz, S. R Search for Related Content PubMed PubMed Citation Articles by Slungaard, A. Articles by Lentz, S. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted November 26, 2002 Accepted February 14, 2003 Platelet factor 4 enhances generation of activated protein C in vitro and in vivo Arne Slungaard*, Jose A Fernandez, John H Griffin, Nigel S Key, Janel R Long, Donald J Piegors, and Steven R Lentz Department of Medicine, University of Minnesota, Minneapolis, MN, USA Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, USA Department of Internal Medicine, University of Iowa and VA Medical Center, Iowa City, IA, USA * Corresponding author; email: slung001{at}tc.umn.edu. Platelet factor 4 (PF4), an abundant platelet alpha-granule protein, accelerates in vitro generation of activated protein C (APC) by soluble thrombin/thrombomodulin (TM) complexes up to 25-fold. To test the hypothesis that PF4 similarly stimulates endothelium-associated TM, we assessed the influence of human PF4 on thrombin-dependent APC generation by cultured endothelial monolayers. APC generated in the presence of 1-100 µg PF4 was up to 5-fold over baseline for human umbilical vein endothelial cells, 10-fold for microvascular endothelial cells, and unaltered for blood outgrowth endothelial cells. In an in vivo model, cynomolgus monkeys (n=6, each serving as its own control) were infused with either PF4 (7.5 mg/kg) or vehicle buffer, then with human thrombin (1.0 µg/kg/min) for 10 minutes. Circulating APC levels (baseline 3 ng/ml) peaked at 10 minutes when PF4-treated and vehicle-treated animals had APC levels of 67±5 and 39±2 ng/ml, respectively (p < 0.001). The APTT (baseline 28 seconds) increased maximally by 27±6 seconds in PF4-treated animals and by 9±1 seconds in control animals at 30 min (p < 0.001). PF4-dependent increases in circulating APC and APTT persisted >2-fold that of control from 10 through 120 min (p 0.04). All APTT prolongations were essentially reversed by monoclonal antibody C3, which blocks APC activity. Thus, physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC generation both in vitro by cultured endothelial cells and in vivo in a primate thrombin infusion model. These findings suggest that PF4 may play a previously unsuspected physiological role to enhance APC generation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Platelets are anticoagulants? Charles T. Esmon Blood 2003 102: 3. [Full Text] [PDF] This article has been cited by other articles: 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. 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