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Thromb Haemost 1999; 82(04): 1283-1288
DOI: 10.1055/s-0037-1614376
Review Article
Schattauer GmbH

Phosphorylation of Coagulation Factor XI by a Casein Kinase Released by Activated Human Platelets Increases Its Susceptibility to Activation by Factor XIIa and Thrombin

Kristina Nilsson Ekdahl
1   From the Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, and the Department of Natural Sciences, University of Kalmar, Kalmar, Sweden
2   Department of Natural Sciences, University of Kalmar, Kalmar, Sweden
,
Graciela Elgue
1   From the Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, and the Department of Natural Sciences, University of Kalmar, Kalmar, Sweden
,
Bo Nilsson
1   From the Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, and the Department of Natural Sciences, University of Kalmar, Kalmar, Sweden
› Author Affiliations
Further Information

Publication History

Received 08 March 1999

Accepted after revision 07 May 1999

Publication Date:
08 December 2017 (online)

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Summary

Previous studies suggest that activated platelets facilitate the cleavage of factor XI by both factor XIIa and thrombin. Extracellular phosphorylation is a mechanism by which the function of plasma proteins can be regulated. Phosphorylation is mediated by a casein kinase which is released by activated platelets concomitant with large amounts of ATP and Ca2+. The purpose of this study was to investigate if factor XI is phosphorylated by a platelet casein kinase and whether phosphorylation may affect its activation properties. It was shown that supernatants from platelets which contain platelet casein kinase phosphorylated factor XI. By Western blot analysis it was shown that phosphorylation of factor XI substantially increased its susceptibility to cleavage by factor XIIa, and, to a lesser extent, by thrombin. The generated factor XIa was functionally active in that it cleaved the chromogenic substrate S2366, and in that factor XIa-antithrombin and thrombin-antithrombin complexes were generated when phosphorylated factor XI was added to blood plasma. The present study indicates that platelet-mediated phosphorylation of factor XI enhances the cleavage of factor XI into XIa and that the generated XIa possesses functional activity. Phosphorylation of factor XI might be an essential regulatory mechanism by which platelets mediate amplification of the coagulation cascade.

 

  • References

  • 1 Bouma BN, Griffin JH. Human coagulation factor XI: Purification properties and mechanism of activation by activated factor XII. J Biol Chem 1977; 252: 6432-7.
    PubMedGoogle Scholar
  • 2 Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. J Biol Chem 1991; 266: 7353-8.
    PubMedGoogle Scholar
  • 3 Osterud B, Bouma BN, Griffin JH. Human blood coagulation factor IX. J Biol Chem 1978; 253: 5946-51.
    PubMedGoogle Scholar
  • 4 Brunneé T, La Porta C, Reddigari SR, Salerno VM, Kaplan AP, Silverberg M. Activation of factor XI in plasma is dependent on factor XII. Blood 1993; 81: 580-6.
    PubMedGoogle Scholar
  • 5 Gailani D, Broze GJJ. Factor XII-independent activation of factor XI in plasma: effects of sulfatides on tissue factor-induced coagulation. Blood 1993; 82: 813-9.
    PubMedGoogle Scholar
  • 6 Gailani D, Broze GJJ. Factor XI activation in a revised model of blood coagulation. Science 1993; 253: 909-12.
    PubMedGoogle Scholar
  • 7 Minnema MC, Pajkrt D, Wuillemin WA, Roen D, Bleeker WK, Levi M, van Deventer SJH, Hack CE, ten Cate H. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood 1998; 92: 3294-3301.
    PubMedGoogle Scholar
  • 8 Walsh PN. The effects of collagen and kaolin on the intrinsic coagulant activity of platelets: Evidence for an alternative pathway in intrinsic coagulation not requiring factor XII. Br J Haematol 1972; 22: 393-405.
    CrossrefPubMedGoogle Scholar
  • 9 Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999; 19: 170-7.
    CrossrefPubMedGoogle Scholar
  • 10 Walsh PN, Griffin JN. Contributions of human platelets to the proteolytic activation of blood coagulation factors XII and XI. Blood 1981; 57: 106-18.
    PubMedGoogle Scholar
  • 11 Nilsson Ekdahl K, Nilsson B. Phosphorylation of complement component C3 and C3 fragments by a human platelet protein kinase. Inhibition of factor I mediated cleavage of C3b. J Immunol 1995; 154: 6502-10.
    PubMedGoogle Scholar
  • 12 Holmsen H. Activation of human platelets in vitro. Nordic Meeting on Platelet Storage and Transfusion. Biochemistry, physiology and practice. Bergen, Norway: 1992. Chapter 1 11-38.
    Google Scholar
  • 13 Nilsson Ekdahl K, Rönnblom L, Sturfeldt G, Nilsson B. Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus. Covariations with platelet activation and possible association with thrombosis. Arth Rheum 1997; 40: 2178-86.
    CrossrefPubMedGoogle Scholar
  • 14 Storm KE, Artursson G, Nilsson UR. Purification and characterization of porcine C3. Studies of the biologically active protein and its split products. Vet Immunol Immunopathol 1992; 34: 47-61.
    CrossrefPubMedGoogle Scholar
  • 15 Gong J, Larsson R, Nilsson Ekdahl K, Mollnes TE, Nilsson UR, Nilsson B. Tubing loops as a model for cardiopulmonary bypass circuits: Both the biomaterial and the blood-gas interfaces induce complement activation in an in vitro model. J Clin Immunol 1996; 16: 223-30.
    PubMedGoogle Scholar
  • 16 Mustard JF, Perry DW, Ardlie NG, Packham MA. Preparation of suspensions of washed platelets from humans. Br J Haematol 1972; 22: 193-204.
    CrossrefPubMedGoogle Scholar
  • 17 Naik UP, Kornecki E, Ehrlich YH. Phosphorylation and dephosphorylation of human platelet surface proteins by an ecto-protein kinase/phosphatase system. Biochim Biophys Acta 1991; 1092: 256-64.
    CrossrefPubMedGoogle Scholar
  • 18 Nilsson Ekdahl K, Nilsson B. Alterations in C3 functions caused by phosphorylation by a casein kinase released from activated human platelets. J Immunol 1999; 162: 7426-33.
    PubMedGoogle Scholar
  • 19 Inagaki M, Kawamoto S, Itoh H, Saitoh M, Hagiwara M, Takahashi J, Hidaka H. Naphatlenesulfonamides as calmodulin antagonists and protein kinase inhibitors. Mol Pharmacol 1986; 29: 577-81.
    PubMedGoogle Scholar
  • 20 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-5.
    CrossrefPubMedGoogle Scholar
  • 21 Scott CF, Sinha D, Seaman FS, Walsh PN, Colman RW. Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay. Blood 1984; 63: 42-50.
    PubMedGoogle Scholar
  • 22 Hojima Y, Pierce JV, Pisano J. Hageman factor fragment inhibitor in corn seeds: Purification and characterization. Thromb Res 1980; 20: 149-62.
    CrossrefPubMedGoogle Scholar
  • 23 Sanchez J, Elgue G, Riesenfeld J, Olsson P. Studies of adsorption, activation and inhibition of Factor XII on immobilized heparin. Thromb Res 1998; 89: 41-50.
    CrossrefPubMedGoogle Scholar
  • 24 Hong J, Nilsson Ekdahl K, Reynolds H, Larsson R, Nilsson B. A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin. Biomaterials 1999; 20: 603-11.
    CrossrefPubMedGoogle Scholar
  • 25 Nilsson Ekdahl K, Nilsson B. Phosphorylation of plasma proteins with emphasis on complement component C3. Mol Immunol 1999; 36: 233-40.
    CrossrefPubMedGoogle Scholar
  • 26 Korc-Grodzicki B, Tauber-Finkelstein M, Shaltiel S. Platelet stimulation releases a cAMP-dependent protein kinase that specifically phosphorylates a plasma protein. Proc Natl Acad Sci, USA 1988; 85: 7541-5.
    CrossrefPubMedGoogle Scholar
  • 27 Kalafatis M, Rand MD, Jenny RJ, Ehrlich YH, Mann KG. Phosphorylation of factor Va and factor VIIIa by activated platelets. Blood 1993; 81: 704-19.
    PubMedGoogle Scholar
  • 28 Kalafatis M. Identification and partial characterization of factor Va heavy chain kinase from human platelets. J Biol Chem 1998; 273: 8459-66.
    CrossrefPubMedGoogle Scholar
  • 29 Blombäck B, Blombäck M, Edman P, Hessel B. Amino-acid sequence and the occurrence of phosphorus in human fibrinopeptides. Nature 1962; 193: 883-4.
    CrossrefPubMedGoogle Scholar
  • 30 Rand MD, Kalafatis M, Mann KG. Platelet coagulation factor Va: the major secretory platelet phosphoprotein. Blood 1994; 83: 2180-90.
    PubMedGoogle Scholar
  • 31 Mehringer JH, Weigel CJ, Tollefsen DM. Cyclic AMP-dependent protein kinase phosphorylates serine378 in vitronectin. Biochem Biophys Res Commun 1991; 179: 655-60.
    CrossrefPubMedGoogle Scholar
  • 32 Martin SC. Phosphorylation of complement factor C3 in vivo. Biochem J 1989; 261: 1051-4.
    CrossrefPubMedGoogle Scholar