Skip to main content
SpringerLink
Log in
Book cover

Hughes Syndrome pp 427–438Cite as

The Influence of Antiphospholipid Antibodies on the Protein C Pathway

  • Chapter

  • 734 Accesses

Concluding Remarks

aPL are a heterogeneous population of antibodies directed against different phospholipid binding proteins. It is not clear which mechanism is responsible for the thrombogenic activity of all aPL. There is, however, an attractive hypothesis that suggests that aPL selectively inhibit one of the dominant natural anticoagulant pathways, the protein C pathway. Most attention has been focused on the induction of an acquired APC resistance, probably due to interference of the antibodies with binding of protein C or S to negatively charged phospholipids It is questionable whether in aPL-related thrombosis, an acquired APC resistance is responsible for both arterial and venous events. Although exogenous APC could prevent arterial thrombosis in a number of animal models, deficiencies in the protein C axis are correlated with venous thrombosis and not with arterial thrombosis. A safe conclusion is that interference of the protein C pathway can explain a large part of the venous complications in patients with APS. The observations that suggest a correlation between antibodies against EPCR and pregnancy morbidity warrant further studies.

Keywords

  • Systemic Lupus Erythematosus
  • Lupus Anticoagulant
  • Anticoagulant Pathway
  • Endothelial Cell Protein
  • Hughes Syndrome

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (Canada)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (Canada)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992;12:135–145.

    PubMed  CAS  Google Scholar 

  2. Dahlback B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol 2004;79:109–116.

    PubMed  Google Scholar 

  3. Gresele P, Momi S, Berrettini M, et al. Activated human protein C prevents thrombin induced thromboembolism in mice. J Clin Invest 1998;101:667–676.

    PubMed  CAS  Google Scholar 

  4. Taylor FB, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987;9:918–925.

    Google Scholar 

  5. Hughes GRV. Hughes’ syndrome: the antiphospholipid syndrome. A historical view. Lupus 1998;7:S1–S7.

    CrossRef  PubMed  Google Scholar 

  6. De Groot PG, Oosting JD, Derksen RHWM. Antiphospholipid antibodies: specificity and pathophysiology. Baillieres Clin Haematol 1993;6:691–709.

    PubMed  Google Scholar 

  7. Arnout J, Vermylen J. Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. Thromb Haemost 2003;1:931–942.

    CrossRef  CAS  Google Scholar 

  8. Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin catalyzed activation of protein C. Proc Natl Acad Sci U S A 1981;78:2249–2252.

    CrossRef  PubMed  CAS  Google Scholar 

  9. Bajzar L, Morser J, Nesheim ME. TAFI or plasma procarboxypeptidase B couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996;27:16603–16608.

    Google Scholar 

  10. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.

    CrossRef  PubMed  CAS  Google Scholar 

  11. Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 2004. Epub ahead of print.

    Google Scholar 

  12. Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia, part 1.Thromb Haemost 1996;76:651–662.

    CAS  Google Scholar 

  13. Gruber A, Griffin JH. Direct detection of activated protein C in blood from human subjects. Blood 1992;79:2340–2348.

    PubMed  CAS  Google Scholar 

  14. Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization. J Biol Chem 1983;258:163–168.

    PubMed  CAS  Google Scholar 

  15. Di Scipio RG, Davie EW. Characterization of protein S, a γ-carboxyglutamic acid containing protein from bovine and human plasma. Biochemistry 1979;18:899–904.

    CrossRef  Google Scholar 

  16. Walker FJ. Regulation of vitamin K dependent protein S. Inactivation by thrombin. J Biol Chem 1984;259:10335–10339.

    PubMed  CAS  Google Scholar 

  17. Dahlback B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant pathway. Thromb Haemost 1991;66:49–61.

    PubMed  CAS  Google Scholar 

  18. Esmon CT, Owen WG. The discovery of thrombomodulin. Thromb Haemost 2004;2:209–213.

    CrossRef  CAS  Google Scholar 

  19. Lohi O, Urban S, Freeman M. Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by mammalian rhomboids. Curr Biol 2004;14:236–241.

    CrossRef  PubMed  CAS  Google Scholar 

  20. Fukudome K, Esmon CT. Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). The structural and functional conservation in human, bovine, and murine EPCR. J Biol Chem 1995;270:5571–5577.

    CrossRef  PubMed  CAS  Google Scholar 

  21. Dahlback B, Carlsson M, Svennson PJ. Familiar thrombophilia due to a previous unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004–1008.

    CrossRef  PubMed  CAS  Google Scholar 

  22. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–67.

    CrossRef  PubMed  CAS  Google Scholar 

  23. Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002;22:530–538.

    CrossRef  PubMed  CAS  Google Scholar 

  24. Rosing J, Tans G. Coagulation factor V: an old star shines again. Thromb Haemost 1997;78:427–433.

    PubMed  CAS  Google Scholar 

  25. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990;87:4120–4124.

    CrossRef  PubMed  CAS  Google Scholar 

  26. Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991;66:629–632.

    PubMed  CAS  Google Scholar 

  27. Willems GM, Janssen MP, Pelsers MM, et al. Role of divalency in the high-affinity binding of anticardiolipin antibody-beta 2-glycoprotein I complexes to lipid membranes. Biochemistry 1996;35:13833–13842.

    CrossRef  PubMed  CAS  Google Scholar 

  28. de Laat HB, Derksen RHWM, Urbanus RT, Roest M, de Groot PG. β2-glycoprotein I dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 2004;105:1540–1545

    CrossRef  PubMed  CAS  Google Scholar 

  29. Takeuchi R, Atsumi T, Ieko M, et al. Coagulation and fibrinolytic activities in 2 siblings with beta(2)-glycoprotein I deficiency. Blood 2000;96:1594–1595.

    PubMed  CAS  Google Scholar 

  30. Sheng Y, Reddel SW, Herzog H, et al. Impaired thrombin generation in beta 2-glycoprotein I null mice. J Biol Chem 2001;276:13817–13821.

    PubMed  CAS  Google Scholar 

  31. Oosting JD, Derksen RHWM, Bobbink IWG, Hackeng T, Bouma BN, de Groot PG. Antiphospholipid antibodies are directed to a combination of phospholipids with prothrombin, protein C or protein S. An explanation for their pathogenic mechanism? Blood 1993;81:2618–2625.

    PubMed  CAS  Google Scholar 

  32. Oosting JD, Preissner KT, Derksen RHWM, de Groot PhG. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro. Br J Haematol 1993;85:761–768.

    PubMed  CAS  Google Scholar 

  33. Canfield WM, Kisiel W. Evidence of normal functional levels of activated protein C inhibitor in combined Factor V/VIII deficiency disease. J Clin Invest 1982;70:1260–1272.

    PubMed  CAS  Google Scholar 

  34. De Groot PG, Horbach DA, Derksen RHWM. Protein C and other cofactors involved in the binding of antiphospholipid antibodies. Relation to the pathogenesis of thrombosis. Lupus 1996;5:488–493.

    PubMed  Google Scholar 

  35. Hanson SR, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest 1993;92:2003–2012.

    PubMed  CAS  Google Scholar 

  36. Griffin JH. Blood coagulation. The thrombin paradox. Nature 1995;378:337–338.

    CrossRef  PubMed  CAS  Google Scholar 

  37. Simmelink MJA, Fernandez JA, Derksen RHWM, Griffin JH, de Groot PhG. Low levels of activated protein C in patients with systemic lupus erythematosus do not relate to lupus anticoagulants but to low levels of factor II. Br J Haematology 2002;117:676–684.

    CrossRef  CAS  Google Scholar 

  38. Comp PC, deBault LE, Esmon NL, Esmon CT. Human thrombomodulin is inhibited by IgG from two patients with non-specific anticoagulants [abstract]. Blood 1983;62:299.

    Google Scholar 

  39. Freyssinet JM, Wiesel ML, Gauchy J, Boneu B, Cazenave JP. An IgM lupus anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity — a mechanism for thrombosis. Thromb Haemost 1986;55:309–313.

    PubMed  CAS  Google Scholar 

  40. Cariou R, Tobelem G, Bellucci S, et al. Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells — inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost 1988;60:54–58.

    PubMed  CAS  Google Scholar 

  41. Oosting JD, Preissner KT, Derksen RHWM, de Groot PhG. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro. Br J Haematol 1993;85:761–768.

    PubMed  CAS  Google Scholar 

  42. Schorer AE, Wickham NW, Watson KV. Lupus anticoagulant induces a selective defect in thrombinmediated endothelial prostacyclin release and platelet aggregation. Br J Haematol 1989;71:399–407.

    CrossRef  PubMed  CAS  Google Scholar 

  43. Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ. Role of beta 2-glycoprotein I and antiphospholipid antibodies in activation of protein C in vitro. J Clin Pathol 1993;46:908–911.

    PubMed  CAS  Google Scholar 

  44. Potzsch B, Kawamura H, Preissner KT, Schmidt M, Seelig C, Muller-Berghaus G. Acquired protein C dysfunction but not decreased activity of thrombomodulin is a possible marker of thrombophilia in patients with lupus anticoagulant. J Lab Clin Med 1995;25:56–65.

    Google Scholar 

  45. Kawakami M, Kitani A, Hara M, et al. Plasma thrombomodulin and alpha 2-plasmin inhibitorplasmin complex are elevated in active systemic lupus erythematosus. J Rheumatol 1992;19:1704–1709.

    PubMed  CAS  Google Scholar 

  46. Hurtado V, Montes R, Gris JC, et al. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for foetal death. Blood 2004;104:1369–1374.

    CrossRef  PubMed  CAS  Google Scholar 

  47. Franchi F, Biguzzi E, Cetin I, et al. Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Br J Haematol 2001;114:641–646.

    CrossRef  PubMed  CAS  Google Scholar 

  48. Gu JM, Crawley JT, Ferrell G, et al. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem 2002;277:43335–43343.

    CrossRef  PubMed  CAS  Google Scholar 

  49. Fijnheer R, Horbach DA, Donders RCJM, et al. Factor V Leiden, antiphospholipid antibodies and thrombosis in systemic lupus erythematosus. Thromb Haemost 1996;76:514–517.

    PubMed  CAS  Google Scholar 

  50. Malia RG, Kitchen S, Greaves M, Preston FE. Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies. Br J Haematol 1990;76:101–107.

    PubMed  CAS  Google Scholar 

  51. Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989;74:2426–2432.

    PubMed  CAS  Google Scholar 

  52. Borrell M, Sala N, de Castellarnau C, Lopez S, Gari M, Fontcuberta J. Immunoglobulin fractions isolated from patients with antiphospholipid antibodies prevent the inactivation of factor Va by activated protein C on human endothelial cells. Thromb Haemost 1992;68:268–272.

    PubMed  CAS  Google Scholar 

  53. Amer L, Kisiel W, Searles RP, Williams RC Jr. Impairment of the protein C anticoagulant pathway in a patient with systemic lupus erythematosus, anticardiolipin antibodies and thrombosis. Thromb Res 1990;57:247–258.

    CrossRef  PubMed  CAS  Google Scholar 

  54. Munoz-Rodriguez FJ, Reverter JC, Font J, et al. Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus. Lupus 2002;11:730–735.

    CrossRef  PubMed  CAS  Google Scholar 

  55. Nojima J, Kuratsune H, Suehisa E, et al. Acquired activated protein C resistance associated with antiprotein S antibody as a strong risk factor for DVT in non-SLE patients. Thromb Haemost 2002;8:716–722.

    Google Scholar 

  56. Galli M, Duca F, Ruggeri L, Finazzi G, Negri B, Moia M. Congenital resistance to activated protein C in patients with lupus anticoagulants: evaluation of two functional assays. Thromb Haemost 1998;80:246–249.

    PubMed  CAS  Google Scholar 

  57. Male C, Mitchell L, Julian J, Vegh P, et al. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2001;97:844–849.

    CrossRef  PubMed  CAS  Google Scholar 

  58. Gennari LC, Blanco AN, Alberto MF, Grosso SH, Peirano AA, Lazzari MA. Antiphospholipid antibodies impact the protein C (PC) pathway behavior. Am J Hematol 2002;71:128–130.

    CrossRef  PubMed  CAS  Google Scholar 

  59. Galli M, Ruggeri L, Barbui T. Differential effects of anti-beta2-glycoprotein I and antiprothrombin antibodies on the anticoagulant activity of activated protein C. Blood 1998;91:1999–2004.

    PubMed  CAS  Google Scholar 

  60. Izumi T, Pound ML, Su Z, Iverson GM, Ortel TL. Anti-beta(2)-glycoprotein I antibody-mediated inhibition of activated protein C requires binding of beta(2)-glycoprotein I to phospholipids. Thromb Haemost 2002;88:620–626.

    PubMed  CAS  Google Scholar 

  61. Nojima J, Kuratsune H, Suehisa E, et al. Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. Br J Haematol 2002;118:577–583.

    CrossRef  PubMed  CAS  Google Scholar 

  62. Horbach DA, van Oort E, Derksen RHWM, de Groot PG. Anti-prothrombin antibodies with LAC activity inhibits tenase, prothrombinase and protein C activity by increasing the affinity of prothrombin for phospholipids. Lupus 1998;7:S209.

    Google Scholar 

  63. Smirnov MD, Triplett DT, Comp PC, Esmon NL, Esmon CT. On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. J Clin Invest 1995;95:309–316.

    CrossRef  PubMed  CAS  Google Scholar 

  64. Esmon NL, Smirnov MD, Esmon CT. Thrombogenic mechanisms of antiphospholipid antibodies. Thromb Haemost 1997;78:79–82.

    PubMed  CAS  Google Scholar 

  65. Safa O, Hensley K, Smirnov MD, Esmon CT, Esmon NL. Lipid oxidation enhances the function of activated protein C. J Biol Chem 2001;276:1829–1836.

    CrossRef  PubMed  CAS  Google Scholar 

  66. Pratico D, Ferro D, Iuliano L, et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999;93:3401–3407.

    PubMed  CAS  Google Scholar 

  67. Mori T, Takeya H, Nishioka, Gabazza EC, Suzuki K. b2-glycoprotein I modulates the anticoagulant activity of protein C on the phospholipid surface. Thromb Haemost 1996;75:49–55.

    PubMed  CAS  Google Scholar 

  68. Atsuma T, Khamashta MA, Amengual O, et al. Binding of anti-cardiolipin antibodies to protein C via β2-glycoprotein I: a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system. Clin Exp Immunol 1998;112:325–333.

    CrossRef  Google Scholar 

  69. Kalafatis M, Simioni P, Tormene D, Beck DO, Luni S, Girolami A. Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations. Blood 2002;99:3985–3992.

    CrossRef  PubMed  CAS  Google Scholar 

  70. Harrison RL, Alperin JB. Concurrent protein C deficiency and lupus anticoagulant. Am J Hematol 1992;40:33–37.

    PubMed  CAS  Google Scholar 

  71. Parke AL, Weinstein RE, Bona R, et al. The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med 1992;93:49–56.

    CrossRef  PubMed  CAS  Google Scholar 

  72. Hasselaar P, Derksen RHWM, Blokzijl L, et al. Risk factors for thrombosis in lupus patients. Ann Rheum Dis 1989;48:933–940.

    CrossRef  PubMed  CAS  Google Scholar 

  73. Atsumi T, Khamashta MA, Ames PRJ, Ichikawa K, Koike T, Hughes GRV. Effect of 2 β-glycoprotein I and human monoclonal anticardiolipin antibody on the protein S/C4b-binding protein system. Lupus 1997;6:358–364.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology and Rheumatology & Clinical Immunology, University Medical Centre, Utrecht, Netherlands

    Philip G. de Groot PhD

  2. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands

    Ronald H. W. M. Derksen MD, PhD

Authors
  1. Philip G. de Groot PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald H. W. M. Derksen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Lupus Research Unit, St Thomas’ Hospital, London, UK

    M. A. Khamashta MD, FRCP, PhD (Deputy Head) (Deputy Head)

Rights and permissions

Reprints and Permissions

Copyright information

© 2006 Springer-Verlag London Limited

About this chapter

Cite this chapter

de Groot, P.G., Derksen, R.H.W.M. (2006). The Influence of Antiphospholipid Antibodies on the Protein C Pathway. In: Khamashta, M.A. (eds) Hughes Syndrome. Springer, London. https://doi.org/10.1007/1-84628-009-5_34

Download citation

  • DOI: https://doi.org/10.1007/1-84628-009-5_34

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-85233-873-2

  • Online ISBN: 978-1-84628-009-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

search

Navigation