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Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A

Nature Medicine volume 9, pages 1020–1025 (2003)Cite this article

Abstract

High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel–Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1−/− mice produced fewer microparticles after P-sel–Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel–Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel–Ig treatment could become a new approach to sustained control of bleeding in hemophilia.

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Figure 1: Generation of procoagulant activity in human blood by P-sel–Ig is mediated by PSGL-1.
Figure 2: Recruitment of fluorescent microparticles into a growing thrombus.
Figure 3: P-sel–Ig treatment of hemophilia A mice generates procoagulant microparticles and accelerates the onset of clotting.
Figure 4: P-sel–Ig normalized bleeding time in hemophilia A mice.

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Acknowledgements

We thank W. Ruf for advice and control reagents for tissue factor studies, P. Salaj and Z. Vorlová for procuring blood samples from hemophilia A patients, A. Kumar for helpful discussions, S. Saffaripour and K. Thomas for technical assistance, and L. Cowan and T. Takagi for help preparing the manuscript. This work was supported in part by National Institutes of Health, National Heart, Lung and Blood Institute grants HL 54502 (R.P.M.) and HL56949 and 53756 (D.D.W.).

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Author notes

  1. Ingrid Hrachovinová

    Present address: Laboratory of Hemostasis, Institute of Hematology and Blood Transfusion, University Nemocnice 1, 128 20 Praha 2, Czech Republic

Authors and Affiliations

  1. The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ingrid Hrachovinová, Beatrice Cambien, Ali Hafezi-Moghadam & Denisa D Wagner

  2. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, Oklahoma, USA

    János Kappelmayer, Lijun Xia & Rodger P McEver

  3. Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, Oklahoma, USA

    János Kappelmayer, Lijun Xia & Rodger P McEver

  4. Wyeth Research, 87 Cambridge Park Drive, Cambridge, 02140, Massachusetts, USA

    Raymond T Camphausen, Angela Widom & Robert G Schaub

  5. Departments of Genetics and Dermatology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Haig H Kazazian Jr

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Correspondence to Denisa D Wagner.

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R.G.S. is an employee of Wyeth Research. R.T.C. and A.W. were employees of Wyeth Research while the study was performed.

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Hrachovinová, I., Cambien, B., Hafezi-Moghadam, A. et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9, 1020–1025 (2003). https://doi.org/10.1038/nm899

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