Download PDF
Thromb Haemost 2002; 88(05): 716-722
DOI: 10.1055/s-0037-1613291
Review Article
Schattauer GmbH

Acquired Activated Protein C Resistance Associated with Anti-Protein S Antibody as a Strong Risk Factor for DVT in Non-SLE Patients

Junzo Nojima
1   Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan
2   Department of Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, Japan
,
Hirohiko Kuratsune
3   Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
,
Etsuji Suehisa
1   Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan
,
Tomio Kawasaki
4   Division of Vascular Surgery, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
,
Takashi Machii
3   Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
,
Teruo Kitani
3   Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
,
Yoshinori Iwatani
2   Department of Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, Japan
,
Yuzuru Kanakura
1   Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan
3   Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
› Author Affiliations
Further Information

Publication History

Received 12 March 2002

Accepted after revision 22 July 2002

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

Anti-phospholipid (aPL) antibodies (Abs) are well known to be associated with thromboembolic events in patients with systemic lupus erythematosus (SLE). However, the clinical relevance of aPL Abs in patients without SLE (non-SLE) who have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients with a first episode of clinically suspected deep vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs. The prevalence of acquired APC-R, in which case there was no factor V Leiden mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p <0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence intervals [CI], 2.45-32.7; p <0.001). Multivariate logistic analysis revealed that the presence of LA, aCL, anti- β2-glycoprotein I, anti-prothrombin and anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients, and that the presence of anti-protein S Abs was the most significant risk factor for DVT (OR, 5.88; 95% CI, 1.96-17.7; p <0.002). Furthermore, the presence of anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI, 8.53-391; p <0.0001). These results suggest that acquired APC-R may reflect functional interference by anti-protein S Abs of the protein C pathway, which action may represent an important mechanism for the development DVT in non-SLE patients.

Keywords

Acquired activated protein C resistance - anti-phospholipid antibodies - anti-protein C antibodies - anti-protein S antibodies - deep vein thrombosis
 

  • References

  • 1 Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies. Blood 1994; 84: 2854-67.
    PubMedGoogle Scholar
  • 2 Cabiedes J, Cabral AR, Alarcon-Segovia D. Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-beta 2-glycoprotein-I than with antiphospholipid antibodies. J Rheumatol 1995; 22: 1899-906.
    PubMedGoogle Scholar
  • 3 D’Angelo A, Safa O, Crippa L, Garlando A, Sabbadini MG, Vigan’D’Angelo S. Relationship of lupus anticoagulant, anticardiolipin, anti-beta2-GPI and anti-prothrombin autoantibodies with history of thrombosis in patients with the clinical suspicion of APA-syndrome. Thromb Haemost 1997; 78: 967-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Greaves M. Antiphospholipid antibodies and thrombosis. Lancet 1999; 353: 1348-53.
    CrossrefPubMedGoogle Scholar
  • 5 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332-8.
    CrossrefPubMedGoogle Scholar
  • 6 Galli M, Finazzi G, Barbui T. Antiphospholipid antibodies: predictive value of laboratory tests. Thromb Haemost 1997; 78: 75-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Horbach DA, van Oort E, Donders RC, Derksen RH, de Groot PG. 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: 916-24.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311: 1525-8.
    CrossrefPubMedGoogle Scholar
  • 9 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 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: 2618-25.
    PubMedGoogle Scholar
  • 11 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: 844-9.
    CrossrefPubMedGoogle Scholar
  • 12 Ginsberg JS, Wells PS, Brill-Edwards P. et al. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
    PubMedGoogle Scholar
  • 13 Simioni P, Prandoni P, Zanon E. et al. Deep venous thrombosis and lupus anticoagulant. A case-control study. Thromb Haemost 1996; 76: 187-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Nojima J, Kuratsune H, Suehisa E. et al. Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essential risk factor for venous thromboembolism in patients with systemic lupus erythematosus. Br J Haematol 2001; 114: 647-54.
    CrossrefPubMedGoogle Scholar
  • 15 Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffatti A. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75: 721-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-57.
    PubMedGoogle Scholar
  • 17 Nojima J, Kuratsune H, Suehisa E. et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem 2001; 47: 100815.
    PubMedGoogle Scholar
  • 18 Nojima J, Suehisa E, Akita N. et al. Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant. Br J Haematol 1997; 96: 447-50.
    CrossrefPubMedGoogle Scholar
  • 19 Nojima J, Suehisa E, Kuratsune H. et al. High prevalence of thrombocytopenia in SLE patients with a high level of anticardiolipin antibodies combined with lupus anticoagulant. Am J Hematol 1998; 58: 55-60.
    CrossrefPubMedGoogle Scholar
  • 20 Matsuura E, Igarashi Y, Fujimoto M. et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 885-91.
    PubMedGoogle Scholar
  • 21 Igarashi M, Matsuura E, Igarashi Y. et al. Human beta2-glycoprotein I as an anticardiolipin cofactor determined using mutants expressed by a baculovirus system. Blood 1996; 87: 3262-70.
    PubMedGoogle Scholar
  • 22 Fujimura H, Kambayash J, Monden M, Kato H, Miyata T. Coagulation factor V Leiden mutation may have a racial background. Thromb Haemost 1995; 74: 1381-2.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis 2001; 12: 95-9.
    CrossrefPubMedGoogle Scholar
  • 24 Shimamoto M, Yoshimura T, Kimura N. et al. Protein C in human plasma determined by homogeneous enzyme immunoassay with use of a centrifugal analyzer. Clin Chem 1988; 34: 1834-8.
    PubMedGoogle Scholar
  • 25 Nomura T, Suehisa E, Kawasaki T, Okada A. Frequency of protein S deficiency in general Japanese population. Thromb Res 2000; 100: 367-71.
    CrossrefPubMedGoogle Scholar
  • 26 Palosuo T, Virtamo J, Haukka J. et al. High antibody levels to prothrombin imply a risk of deep venous thrombosis and pulmonary embolism in middle-aged men – nested case-control study. Thromb Haemost 1997; 78: 1178-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 De Stefano V, Martinelli I, Mannucci PM. et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341: 801-6.
    CrossrefPubMedGoogle Scholar
  • 28 Martinelli I, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Mannucci PM. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol 2000; 111: 1223-9.
    CrossrefPubMedGoogle Scholar
  • 29 Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C-resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 797-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Picillo U, De Lucia D, Palatiello E. et al. Association of primary antiphospholipid syndrome with inherited activated protein C resistance. J Rheumatol 1998; 25: 1232-4.
    PubMedGoogle Scholar
  • 31 Zivelin A, Gitel S, Griffin JH. et al. Extensive venous and arterial thrombosis associated with an inhibitor to activated protein C. Blood 1999; 94: 895-901.
    PubMedGoogle Scholar
  • 32 Haim N, Lanir N, Hoffman R, Haim A, Tsalik M, Brenner B. Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism. Am J Med 2001; 110: 91-6.
    CrossrefPubMedGoogle Scholar
  • 33 Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-7.
    CrossrefPubMedGoogle Scholar
  • 34 Henkens CM, Bom VJ, Seinen AJ, van der Meer J. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Rosing J, Tans G, Nicolaes GA. et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second-and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-8.
    CrossrefPubMedGoogle Scholar
  • 36 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; 07: 702-4.
    CrossrefPubMedGoogle Scholar
  • 37 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: 101-7.
    CrossrefPubMedGoogle Scholar
  • 38 de Groot PG, Horbach DA, Derksen RH. Protein C and other cofactors involved in the binding of antiphospholipid antibodies: relation to the pathogenesis of thrombosis. Lupus 1996; 05: 488-93.
    CrossrefPubMedGoogle Scholar
  • 39 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-93.
    PubMedGoogle Scholar
  • 40 Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem 1993; 268: 2872-7.
    PubMedGoogle Scholar
  • 41 Koppelman SJ, Hackeng TM, Sixma JJ, Bouma BN. Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII. Blood 1995; 86: 1062-71.
    PubMedGoogle Scholar