Journal article
Platelet factor 4 enhances generation of activated protein C in vitro and in vivo
Blood, Vol.102(1), pp.146-151
07/01/2003
DOI: 10.1182/blood-2002-11-3529
PMID: 12609838
Abstract
AbstractPlatelet factor 4 (PF4), an abundant platelet α-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 to 100 μg PF4 was up to 5-fold higher than baseline for human umbilical vein endothelial cells, 10-fold higher 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 ng/mL and 39 ± 2 ng/mL, respectively (P < .001). The activated partial thromboplastin time (APTT; baseline, 28 seconds) increased maximally by 27 ± 6 seconds in PF4-treated animals and by 9 ± 1 seconds in control animals at 30 minutes (P < .001). PF4-dependent increases in circulating APC and APTT persisted more than 2-fold greater than that of control's from 10 through 120 minutes (P ≤ .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 physiologic role in enhancing APC generation. (Blood. 2003;102:146-151)
Details
- Title: Subtitle
- Platelet factor 4 enhances generation of activated protein C in vitro and in vivo
- Creators
- Arne Slungaard - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IAJose A Fernandez - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IAJohn H Griffin - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IANigel S Key - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IAJanel R Long - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IADonald J Piegors - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IASteven R Lentz - From the Department of Medicine, Section of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and the Department of Internal Medicine, University of Iowa, Iowa City, and Veterans Affairs Medical Center, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.102(1), pp.146-151
- DOI
- 10.1182/blood-2002-11-3529
- PMID
- 12609838
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 07/01/2003
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094338102771
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