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Mechanisms of antiphospholipid-induced thrombosis: Effects on the protein C system

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Abstract

An acquired resistance to activated protein C (APC) has been demonstrated in patients with antiphospholipid antibodies (aPL). Recent studies report interactions between β2 glycoprotein I (β2GPI) and prothrombin-binding antibodies and the protein C system. Some aPL in patients recognize one or more conformational epitopes shared by β2GPI and catalytic domains of APC. Both β2GPI and antiprothrombin antibodies are associated with APC resistance. Several clinical studies have focused on an association between aPL and APC resistance, determined by classic activated partial thromboplastin time-based tests. It has been shown in most studies that APC resistance was associated with lupus anticoagulants. APC resistance is also associated with thrombosis, especially venous thromboembolism. Several recent studies have reported a novel integrated approach of coagulation using calibrated automated thrombography. This technique allows an approach of APC sensitivity without interference with lupus anticoagulants. Clinical associations between APC resistance and thromboembolic events have been demonstrated.

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References and Recommended Reading

  1. Miyakis S, Lockshin MD, Atsumi T, et al.: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006, 4:295–306.

    Article  PubMed  CAS  Google Scholar 

  2. Galli M, Reber G, de Moerloose P, de Groot PG: Invitation to a debate on the serological criteria that define the antiphospholipid syndrome. J Thromb Haemost 2008, 6:399–401.

    Article  PubMed  CAS  Google Scholar 

  3. Wahl D, Thiebaugeorges O, Regnault V, et al.: Pursuing the debate on the serological criteria that define the antiphospholipid syndrome. J Thromb Haemost 2008, 6:1433–1435.

    Article  PubMed  CAS  Google Scholar 

  4. De Laat B, Mertens K, de Groot PG: Mechanisms of disease: antiphospholipid antibodies—from clinical association to pathological mechanism. Nat Clin Pract Rheumatol 2008, 4:192–199.

    Article  PubMed  Google Scholar 

  5. Esmon NL, Safa O, Smirnov MD, Esmon CT: Antiphospholipid antibodies and the protein C pathway. J Autoimmun 2000, 15:221–225.

    Article  PubMed  CAS  Google Scholar 

  6. Oosting JD, Derksen RH, Bobbink IW, et al.: Antiphospholipid antibodies directed against 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 

  7. Smirnov MD, Triplett DT, Comp PC, et al.: On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. J Clin Invest 1995, 95:309–316.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Borrell M, Sala N, de Castellarnau C, et al.: 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 

  10. Matsuda J, Gohchi K, Kawasugi K, et al.: Inhibitory activity of anti- β2-GP I antibody on factor Va degradation by activatedprotein C and its cofactor protein S. Am J Hematol 1995, 49:89–91.

    Article  PubMed  CAS  Google Scholar 

  11. Hwang KK, Grossman JM, Visvanathan S, et al.: Identification of anti-thrombin antibodies in the antiphospholipid syndrome that interfere with the inactivation of thrombin by antithrombin. J Immunol 2001, 167:7192–7198.

    PubMed  CAS  Google Scholar 

  12. Simmelink MJ, Horbach DA, Derksen RH, et al.: Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulant activity by competing with the binding of clotting factors for catalytic phospholipid surfaces. Br J Haematol 2001, 113:621–629.

    Article  PubMed  CAS  Google Scholar 

  13. Lecompte T, Wahl D, Perret-Guillaume C, et al.: Hypercoagulability resulting from opposite effects of lupus anticoagulants is predictive of thrombotic risk. Haematologica 2007, 92:714–715.

    Article  PubMed  Google Scholar 

  14. Hemker HC, Giesen P, Al Dieri R, et al.: Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003, 33:4–15.

    Article  PubMed  CAS  Google Scholar 

  15. Hemker HC, Al Dieri R, Béguin S: Thrombin generation assays: accruing clinical relevance. Curr Opin Hematol 2004, 11:170–175.

    Article  PubMed  CAS  Google Scholar 

  16. Regnault V, Hemker HC, Wahl D, Lecompte T: Phenotyping the haemostatic system by thrombography—potential for the estimation of thrombotic risk. Thromb Res 2004, 114:539–545.

    Article  PubMed  CAS  Google Scholar 

  17. Lin WS, Chen PC, Yang CD, et al.: Some antiphospholipid antibodies recognize conformational epitopes shared by b2-glycoprotein I and the homologous catalytic domains of several serine proteases. Arthritis Rheum 2007, 56:1638–1647.

    Article  PubMed  CAS  Google Scholar 

  18. de Laat B, Eckmann CM, van Schagen M, et al.: Correlation between the potency of a beta2-glycoprotein I-dependent lupus anticoagulant and the level of resistance to activated protein C. Blood Coagul Fibrinolysis 2008, 19:757–764.

    Article  PubMed  Google Scholar 

  19. Membre A, Wahl D, Latger-Cannard V, et al.: The effect of platelet activation on the hypercoagulability induced by murine monoclonal antiphospholipid antibodies. Haematologica 2008, 93:566–573.

    Article  PubMed  CAS  Google Scholar 

  20. Male C, Mitchell L, Julian J, 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Brouwer JL, Bijl M, Veeger NJ, et al.: The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004, 104:143–148.

    Article  PubMed  CAS  Google Scholar 

  23. Kassis J, Neville C, Rauch J, et al.: Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis. Thromb Haemost 2004, 92:1312–1319.

    PubMed  CAS  Google Scholar 

  24. Halbmayer WM, Haushofer A, Schon R, Fischer M: Influence of lupus anticoagulant on a commercially available kit for APC resistance. Thromb Haemost 1994, 72:645–646.

    PubMed  CAS  Google Scholar 

  25. Aznar J, Villa P, Espana F, et al.: Activated protein C resistance phenotype in patients with antiphospholipid antibodies. J Lab Clin Med 1997, 130:202–208.

    Article  PubMed  CAS  Google Scholar 

  26. Gardiner C, Cohen H, Jenkins A, et al.: Detection of acquired resistance to activated protein C associated with antiphospholipid antibodies using a novel clotting assay. Blood Coagul Fibrinolysis 2006, 17:477–483.

    Article  PubMed  CAS  Google Scholar 

  27. Liestol S, Sandset PM, Mowinckel MC, Wisloff F: Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost 2007, 5:2204–2210.

    Article  PubMed  CAS  Google Scholar 

  28. Wahl DG, Guillemin F, De Maistre E, et al.: Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus. A meta-analysis. Lupus 1997, 6:467–473.

    Article  PubMed  CAS  Google Scholar 

  29. Horbach DA, van Oort E, Donders RC, et al.: Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996, 76:916–924.

    PubMed  CAS  Google Scholar 

  30. Wahl D, de Maistre E, Guillemin F, et al.: The risk of recurrent venous thromboembolism associated with phospholipid and patients without systemic lupus erythematosus. Q J Med 1998, 91:125–130.

    CAS  Google Scholar 

  31. Regnault V, Béguin S, Wahl D, et al.: Thrombinography shows acquired resistance to activated protein C in patients with lupus anticoagulants. Thromb Haemost 2003, 89:208–212.

    PubMed  CAS  Google Scholar 

  32. Dargaud Y, Luddington R, Gray E, et al.: Effect of standardization and normalization on imprecision of calibrated automated thrombography: an international multicentre study. Br J Haematol 2007, 39:303–309.

    Article  Google Scholar 

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Correspondence to Denis Wahl.

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Wahl, D., Membre, A., Perret-Guillaume, C. et al. Mechanisms of antiphospholipid-induced thrombosis: Effects on the protein C system. Curr Rheumatol Rep 11, 77–81 (2009). https://doi.org/10.1007/s11926-009-0011-7

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