Semin Thromb Hemost 2022; 48(08): 971-977
DOI: 10.1055/s-0041-1742083
Review Article

Interaction between Antiphospholipid Antibodies and Protein C Anticoagulant Pathway: A Narrative Review

Vittorio Pengo
1   Thrombosis Research Laboratory, University of Padova, Padova, Italy
2   Arianna Foundation on Anticoagulation, Bologna, Italy
› Author Affiliations

Abstract

Thrombotic antiphospholipid syndrome (APS) is a condition in which thrombosis in venous, arterial, and/or small vessels is ascribed to the presence of antiphospholipid antibodies (aPL). Among the various proposed pathogenic theories to explain thrombotic APS, those involving the interaction between aPL and the protein C system have gained much consensus. Indeed, robust data show an acquired activated protein C resistance (APC-R) in these patients. The role of aPL in this impairment is clear, but the mechanism of action is uncertain, as the type of aPL and to what extent aPL are involved remains a gray area. Lupus anticoagulant (LA) is often associated with APC-R, but antibodies generating LA comprise those directed to β2-glycoprotein I and antiphosphatidylserine/prothrombin. Moreover, the induction of APC-R by aPL requires the presence of phospholipids and is suppressed by the presence of an excess of phospholipids. How phospholipids exposed on the cell membranes work in the system in vivo is unknown. Interestingly, acquired APC-R due to aPL might explain the clinical phenotypes of thrombotic APS. Indeed, the literature reports cases of both venous and arterial thromboembolism as well as skin necrosis, the latter observed in the severe form of protein C deficiency and in catastrophic APS.



Publication History

Article published online:
12 January 2022

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  • References

  • 1 Esmon CT. The protein C pathway. Chest 2003; 124 (3, Suppl): 26S-32S
  • 2 Padda IS, Patel P, Citla Sridhar D. Protein S and C. [Updated 2021 May 7]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. . Available at: https://www.ncbi.nlm.nih.gov/books/NBK557814/
  • 3 Mosnier LO, Meijers JC, Bouma BN. Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 2001; 85 (01) 5-11
  • 4 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2445-2453
  • 5 Amiral J, Seghatchian J. Revisiting the activated protein C-protein S-thrombomodulin ternary pathway: impact of new understanding on its laboratory investigation. Transfus Apheresis Sci 2019; 58 (04) 538-544
  • 6 ten Kate MK, van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia 2008; 14 (06) 1222-1228
  • 7 Esmon CT. Protein C anticoagulant system–anti-inflammatory effects. Semin Immunopathol 2012; 34 (01) 127-132
  • 8 Cariou R, Tobelem G, Caen J. Circulating lupus-type anticoagulant, a risk factor for thrombosis by inhibition of protein C activation [in French]. C R Acad Sci III 1986; 303 (04) 113-118
  • 9 Cariou R, Tobelem G, Soria C, Caen J. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314 (18) 1193-1194
  • 10 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 (03) 309-313
  • 11 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 (01) 54-58
  • 12 Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989; 74 (07) 2426-2432
  • 13 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 (01) 101-107
  • 14 Pötzsch B, Kawamura H, Preissner KT, Schmidt M, Seelig C, Müller-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; 125 (01) 56-65
  • 15 Lo SC, Salem HH, Howard MA, Oldmeadow MJ, Firkin BG. Studies of natural anticoagulant proteins and anticardiolipin antibodies in patients with the lupus anticoagulant. Br J Haematol 1990; 76 (03) 380-386
  • 16 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 (03) 268-272
  • 17 Bokarewa MI, Blombäck M, Egberg N, Rosén S. A new variant of interaction between phospholipid antibodies and the protein C system. Blood Coagul Fibrinolysis 1994; 5 (01) 37-41
  • 18 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 (04) 844-849
  • 19 Martinuzzo M, Forastiero R, Adamczuk Y, Cerrato G, Carreras LO. Activated protein C resistance in patients with anti-beta 2 glycoprotein I antibodies. Blood Coagul Fibrinolysis 1996; 7 (07) 702-704
  • 20 Ruiz-Argüelles GJ, Garcés-Eisele J, Alarcón-Segovia D, Ruiz-Argüelles A. Activated protein C resistance phenotype and genotype in patients with primary antiphospholipid syndrome. Blood Coagul Fibrinolysis 1996; 7 (03) 344-348
  • 21 Field SL, Chesterman CN, Hogg PJ. Dependence on prothrombin for inhibition of activated protein C activity by lupus antibodies. Thromb Haemost 2000; 84 (06) 1132-1133
  • 22 Regnault V, Béguin S, Wahl D, de Maistre E, Coenraad Hemker H, Lecompte T. Thrombinography shows acquired resistance to activated protein C in patients with lupus anticoagulants. Thromb Haemost 2003; 89 (02) 208-212
  • 23 Zuily S, Ait Aissa K, Membre A, Regnault V, Lecompte T, Wahl D. Thrombin generation in antiphospholipid syndrome. Lupus 2012; 21 (07) 758-760
  • 24 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 (5–6) 539-545
  • 25 Lecompte T, Wahl D, Perret-Guillaume C, Hemker HC, Lacolley P, Regnault V. Hypercoagulability resulting from opposite effects of lupus anticoagulants is associated strongly with thrombotic risk. Haematologica 2007; 92 (05) 714-715
  • 26 Velasco-Rodríguez D, Laso RV, García-Raso A. et al. Thrombin generation in subjects with lupus anticoagulant without prior thrombosis or gestational morbidities. Thromb Res 2020; 196: 425-431
  • 27 Arachchillage DR, Efthymiou M, Mackie IJ, Lawrie AS, Machin SJ, Cohen H. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome. J Thromb Haemost 2014; 12 (11) 1801-1809
  • 28 Efthymiou M, Arachchillage DRJ, Lane PJ. et al. Antibodies against TFPI and protein C are associated with a severe thrombotic phenotype in patients with and without antiphospholipid syndrome. Thromb Res 2018; 170: 60-68
  • 29 Plasín-Rodríguez MA, Rodríguez-Pintó I, Patricio P. et al. The H1 haplotype of the endothelial protein C receptor protects against arterial thrombosis in patients with antiphospholipid syndrome. Thromb Res 2018; 169: 128-134
  • 30 Devreese K, Peerlinck K, Arnout J, Hoylaerts MF. Laboratory detection of the antiphospholipid syndrome via calibrated automated thrombography. Thromb Haemost 2009; 101 (01) 185-196
  • 31 Khamashta MA, Asherson RA, Hughes GR. Possible mechanisms of action of the antiphospholipid binding antibodies. Clin Exp Rheumatol 1989; 7 (Suppl. 03) S85-S89
  • 32 Oosting JD, Derksen RH, Hackeng TM. et al. In vitro studies of antiphospholipid antibodies and its cofactor, beta 2-glycoprotein I, show negligible effects on endothelial cell mediated protein C activation. Thromb Haemost 1991; 66 (06) 666-671
  • 33 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1993; 81 (10) 2618-2625
  • 34 Oosting JD, Preissner KT, Derksen RH, de Groot PG. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation in vitro. Br J Haematol 1993; 85 (04) 761-768
  • 35 Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ. Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro. J Clin Pathol 1993; 46 (10) 908-911
  • 36 Tsakiris DA, Yasikoff ML, Wolf F, Marbet GA. Anticardiolipin antibodies do not seem to be associated with APC resistance in vivo or in vitro. Ann Hematol 1995; 71 (04) 195-198
  • 37 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 (01) 309-316
  • 38 Esmon NL, Smirnov MD, Safa O, Esmon CT. Lupus anticoagulants, thrombosis and the protein C system. Haematologica 1999; 84 (05) 446-451
  • 39 Safa O, Hensley K, Smirnov MD, Esmon CT, Esmon NL. Lipid oxidation enhances the function of activated protein C. J Biol Chem 2001; 276 (03) 1829-1836
  • 40 Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M. Inhibitory activity of anti-beta 2-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S. Am J Hematol 1995; 49 (01) 89-91
  • 41 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 (06) 1999-2004
  • 42 Galli M, Willems GM, Rosing J. et al. Anti-prothrombin IgG from patients with anti-phospholipid antibodies inhibits the inactivation of factor Va by activated protein C. Br J Haematol 2005; 129 (02) 240-247
  • 43 Atsumi T, Khamashta MA, Amengual O. et al. Binding of anticardiolipin antibodies to protein C via beta2-glycoprotein I (beta2-GPI): a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system. Clin Exp Immunol 1998; 112 (02) 325-333
  • 44 Carson CW, Comp PC, Rezaie AR, Esmon NL, Esmon CT. Antibodies to thrombomodulin are found in patients with lupus anticoagulant and unexplained thrombosis. J Rheumatol 2000; 27 (02) 384-390
  • 45 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 (04) 620-626
  • 46 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 (02) 577-583
  • 47 Ieko M, Nakabayashi T, Takeda M, Naitoh S, Atsumi T, Koike T. The inhibition of protein C anticoagulant activity by anti-β2-glycoprotein I (β2GPI) antibodies isolated from patients with antiphospholipid syndrome by chromatography methods. Mod Rheumatol 2002; 12 (01) 44-49
  • 48 Hwang KK, Yang CD, Yan W, Grossman JM, Hahn BH, Chen PP. A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C. Arthritis Rheum 2003; 48 (06) 1622-1630
  • 49 Safa O, Esmon CT, Esmon NL. Inhibition of APC anticoagulant activity on oxidized phospholipid by anti-beta2-glycoprotein I monoclonal antibodies. Blood 2005; 106 (05) 1629-1635
  • 50 Nojima J, Kuratsune H, Suehisa E, Iwatani Y, Kanakura Y. Acquired activated protein C resistance associated with IgG antibodies against beta2-glycoprotein I and prothrombin as a strong risk factor for venous thromboembolism. Clin Chem 2005; 51 (03) 545-552
  • 51 Liestøl S, Sandset PM, Mowinckel MC, Wisløff 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 (11) 2204-2210
  • 52 van Hylckama Vlieg A, Montes R, Rosendaal FR, Hermida J. Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis. J Thromb Haemost 2007; 5 (07) 1449-1454
  • 53 de Laat B, Eckmann CM, van Schagen M, Meijer AB, Mertens K, van Mourik JA. 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 (08) 757-764
  • 54 Nojima J, Iwatani Y, Ichihara K. et al. Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus. Thromb Res 2009; 124 (01) 127-131
  • 55 Kaneshige R, Nojima J, Motoki Y, Tsuneoka H. aCL/β2GPI and aPS/PT show synergic thrombogenic effects in suppressing anticoagulant activity of APC and stimulating tissue factor expression and TNF-α secretion by mononuclear cells. Thromb Res 2019; 181: 52-58
  • 56 Zuily S, de Laat B, Guillemin F. et al. Anti-domain I β2-glycoprotein I antibodies and activated protein C resistance predict thrombosis in antiphospholipid syndrome: TAC(I)T Study. J Appl Lab Med 2020; 5 (06) 1242-1252
  • 57 Ramirez GA, Mackie I, Nallamilli S. et al. Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?. Rheumatology (Oxford) 2021; 60 (03) 1376-1386
  • 58 Pontara E, Cattini MG, Cheng C, Bison E, Denas G, Pengo V. Insight into the hypercoagulable state of high-risk thrombotic APS patients: contribution of aβ2GPI and aPS/PT antibodies. J Thromb Haemost 2021; 19 (03) 805-813
  • 59 Cattini MG, Bison E, Pontara E, Cheng C, Denas G, Pengo V. Tetra positive thrombotic antiphospholipid syndrome: Major contribution of anti-phosphatidyl-serine/prothrombin antibodies to lupus anticoagulant activity. J Thromb Haemost 2020; 18 (05) 1124-1132
  • 60 Cheng C, Pontara E, Tonello M. et al. Antibody profiles comprising anti phosphatidylserine/prothrombin differently affect thrombin generation and protein C resistance in antiphospholipid antibody carriers. Clin Chim Acta 2020; 510: 796-801
  • 61 Ruiz-Arguelles GJ, Ruiz-Arguelles A, Deleze M, Alarcón-Segovia D. Acquired protein C deficiency in a patient with primary antiphospholipid syndrome. Relationship to reactivity of anticardiolipin antibody with thrombomodulin. J Rheumatol 1989; 16 (03) 381-383
  • 62 Halbmayer WM, Haushofer A, Schön R, Fischer M. Influence of lupus anticoagulant on a commercially available kit for APC-resistance. Thromb Haemost 1994; 72 (04) 645-646
  • 63 Martorell JR, Muñoz-Castillo A, Gil JL. False positive activated protein C resistance test due to anti-phospholipid antibodies is corrected by platelet extract. Thromb Haemost 1995; 74 (02) 796-797
  • 64 Amer L, Kisiel W, Searles RP, Williams Jr RC. Impairment of the protein C anticoagulant pathway in a patient with systemic lupus erythematosus, anticardiolipin antibodies and thrombosis. Thromb Res 1990; 57 (02) 247-258
  • 65 Zivelin A, Gitel S, Griffin JH. et al. Extensive venous and arterial thrombosis associated with an inhibitor to activated protein C. Blood 1999; 94 (03) 895-901
  • 66 Mahmoodi BK, Brouwer JL, Veeger NJ, van der Meer J. Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study. Circulation 2008; 118 (16) 1659-1667
  • 67 Francès C, Tribout B, Boisnic S. et al. Cutaneous necrosis associated with the lupus anticoagulant. Dermatologica 1989; 178 (04) 194-201