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The antiphospholipid syndrome and infection

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Abstract

Infectious agents have been implicated in the induction of antiphospholipid (aPL) antibodies and the development of the antiphospholipid syndrome (APS). This review focuses on the types of aPL antibodies detected in infections and addresses whether these antibodies are of clinical importance in patients with infections. Hepatitis C virus (HCV) infection is given special attention because this virus has the propensity to induce various autoimmune phenomena. Several aspects are emphasized that should be considered carefully when interpreting results. Most of the published data agree that thrombophilia is not observed in patients with infections (including HCV) because aPL antibodies are mostly the natural or nonpathogenic type. Thus, we do not recommend routinely testing for HCV in patients with APS. However, not all infection-associated aPL antibodies are cofactor independent. For instance, infections are increasingly recognized as a major precipitating condition of the catastrophic variant of APS, perhaps via mechanisms of molecular mimicry. Therefore, it may be possible to prevent this devastating evolution if the infectious process is promptly recognized and exhaustively treated.

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References and Recommended Reading

  1. Khamashta MA, Hughes GRV: Antiphospholipid antibodies and antiphospholipid syndrome. Curr Opin Rheumatol 1995, 7:389–394.

    Article  PubMed  CAS  Google Scholar 

  2. Asherson RA, Cervera R, Piette JC, et al.: The catastrophic antiphospholipid syndrome: clinical and laboratory features of 50 patients. Medicine 1998, 77:195–207. This paper summarizes the clinical and laboratory characteristics of 50 patients with catastrophic APS. Infections were recorded as the precipitating factor contributed to the development of catastrophic APS in three of 11 patients (27.2%) with identified factors.

    Article  PubMed  CAS  Google Scholar 

  3. Wilson WA, Gharavi AE, Koike T, et al.: International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999, 42:1309–1311.

    Article  PubMed  CAS  Google Scholar 

  4. Asherson R, Shoenfeld Y: The role of infection in the pathogenesis of catastrophic antiphospholipid syndrome: molecular mimicry? J Rheumatol 2000, 27:12–14.

    PubMed  CAS  Google Scholar 

  5. Rojas-Rodriguez J, Carrasco MG, Casals MR, et al.: Catastrophic antiphospholipid syndrome: clinical description and triggering factors in 8 patients. J Rheumatol 2000, 27:238–240. The authors described eight patients with catastrophic APS, focusing on the possible extrinsic factors that may trigger this condition. Infections of the skin and the respiratory, urinary, and gastrointestinal tract were recorded in 75% of patients, suggesting that prevention of this devastating form of APS may be possible if the infectious process is promptly recognized.

    PubMed  CAS  Google Scholar 

  6. McNeil HP, Krilis SA: Antiphospholipid antibodies. Aust NZ J Med 1991, 21:463–475.

    CAS  Google Scholar 

  7. Manoussakis MN, Tzioufas AG, Silis MP, et al.: High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol 1987, 69:557–565.

    PubMed  CAS  Google Scholar 

  8. Yannitsi SG, Manoussakis MN, Mavridis AK, et al.: Factors related to the presence of anticardiolipin and other autoantibodies in patients with chronic mental disorders. Biol Psychiatr 1990, 27:747–756.

    Article  CAS  Google Scholar 

  9. Petrovas C, Vlachoyiannopoulos PG, Kordossis T, et al.:Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with b2-GPI. J Autoimmun 1999, 13:347–355. This study demonstrates that HIV infection is associated with a high prevalence of antibodies against various phospholipids but not b2-GPI, irrespective of the disease stage, a history of Pneumocystis carinii infection, or co-infection with HCV. The aPL antibodies had low resistance to dissociating agents, a finding that probably reflects low antibody avidity. These results suggest that HIV infection-related aPL antibodies are nonthrombogenic.

    Article  PubMed  CAS  Google Scholar 

  10. Dalekos GN, Manoussakis MN, Goussia AC, et al.: Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies, and other autoantibodies in patients with ulcerative colitis. Gut 1993, 34:658–664.

    PubMed  CAS  Google Scholar 

  11. Dalekos GN, Manoussakis MN, Zervou E, et al.: Immunologic and viral markers in the circulation of anti-HIV negative addicts. Eur J Clin Invest 1993, 23:219–225.

    Article  PubMed  CAS  Google Scholar 

  12. Dalekos GN, Wedemeyer H, Obermayer-Straub P, et al.: Epitope mapping of cytochrome P450 2D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment. J Hepatol 1999, 30:366–375.

    Article  PubMed  CAS  Google Scholar 

  13. Dalekos GN, Kistis K, Boumba D, et al.: Increased incidence of anticardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to antiphospholipid syndrome. Eur J Gastroenterol Hepatol 2000, 12:67–74. The authors prospectively investigated the possible etiopathogenetic link between APS and HCV infection in a two-directional model, which means investigation of aCL antibodies and aCL-related manifestations in HCV-infected patients and vice versa, the presence of HCV markers by ELISA, and polymerase chain reaction in patients with well-defined APS. They did not reveal a trend for such an etiopathogenetic association.

    PubMed  CAS  Google Scholar 

  14. Harris EN, Pierangeli SS, Gharavi AE: Diagnosis of the antiphospholipid syndrome: a proposal for use of laboratory tests. Lupus 1998, 7:144–148.

    Article  Google Scholar 

  15. Gharavi AE, Pierangeli SS, Harris EN: New developments in viral peptides and APL induction. J Autoimmun 2000, 15:227–230. This study shows the pathogenic effects of aPL antibodies induced by immunization with a human CMV-derived aPL-binding synthetic peptide, suggesting that aPL antibodies in patients with APS may be induced by b2-GPI-like Pl-binding products of common human bacteria or viruses.

    Article  PubMed  CAS  Google Scholar 

  16. Gharavi AE, Pierangeli SS: Origin of antiphospholipid antibodies: induction of aPL by viral peptides. Lupus 1998, 7:S52-S54.

    Article  PubMed  CAS  Google Scholar 

  17. Gharavi AE, Pierangeli SS, Colden-Stanfield M, et al.: GDKVinduced antiphospholipid antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. J Immunol 1999, 163:2922–2927.

    PubMed  CAS  Google Scholar 

  18. Brandt JT, Triplett DA, Alving B, et al.: Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemostat 1995, 74:1185–1190.

    CAS  Google Scholar 

  19. Silvestris F, Frassanito MA, Cafforio P, et al.: Antiphosphatidylserine antibodies in human immunodeficiency virus-1 patients with evidence of T-cell apoptosis and mediate antibody-dependent cellular cytotoxicity. Blood 1996, 87:5185–5195.

    PubMed  CAS  Google Scholar 

  20. Cacoub P, Renou C, Rosenthal E, et al.: Extrahepatic manifestations associated with hepatitis C virus infection. Medicine 2000, 79:47–56. The prevalence of aCL antibodies in HCV-positive/HIV-positive patients was significantly higher than that found in HCV-positive/ HIV-negative patients, suggesting a synergistic effect of dual virus infection in the induction of aCL antibodies. After multivariate logistic regression analysis, the authors found that only aCL positivity, thrombocytopenia, and arthralgia were significantly associated with HIV positivity in patients infected with HCV.

    Article  PubMed  CAS  Google Scholar 

  21. de Larranaga GF, Forastiero RR, Carreras LO, et al.: Different types of antiphospholipid antibodies in AIDS: comparison with syphilis and the antiphospholipid syndrome. Thromb Res 1999, 96:19–25.

    Article  PubMed  Google Scholar 

  22. Gonzalez C, Leston A, Garcia-Berrocal B, et al.: Antiphosphatidylserine antibodies in patients with autoimmune disease and HIV-infected patients: effects of Tween 20 and relationship with antibodies to beta2-glycoprotein I. J Clin Lab Anal 1999, 13:59–64.

    Article  PubMed  CAS  Google Scholar 

  23. Abuaf N, Laperche S, Rajoely B, et al.: Autoantibodies to phospholipids and to the coagulation protein in AIDS. Thromb Haemostat 1997, 77:856–861.

    CAS  Google Scholar 

  24. Brew BJ, Miller J: Human immunodeficiency virus type 1-related transient neurological deficits. Am J Med 1996, 101:257–261.

    Article  PubMed  CAS  Google Scholar 

  25. Vlachoyiannopoulos P, Petrovas C, Tektonidou M, et al.: Antibodies to b2-glycoprotein-I: urea resistance, binding specificity, and association with thrombosis. J Clin Immunol 1998, 18:380–391. This study evaluated whether the urea resistance of anti-b2-GPI antibodies is an additional parameter associated with APS. Their results support the notion that resistance to dissociating agents such as urea can be used as a serum characteristic in addition to antibody titer to identify patients with APS.

    Article  PubMed  CAS  Google Scholar 

  26. Dalekos GN, Obermayer-Straub P, Maeda T, et al.: Antibodies against cytochrome P4502A6 (CYP2A6) in patients with chronic viral hepatitis (CVH) are mainly linked to hepatitis C virus (HCV) infection. Digestion 1998, 59:36–37.

    Article  Google Scholar 

  27. Leroy V, Arvieux J, Jacob MC, et al.: Prevalence and significance of anticardiolipin, anti-b2-glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol 1998, 101:468–474.

    Article  PubMed  CAS  Google Scholar 

  28. Prieto J, Yuste JR, Beloqui O, et al.: Anticardiolipin antibodies in chronic hepatitis C: implication of hepatitis C virus as the cause of the antiphospholipid syndrome. Hepatology 1996, 23:199–204.

    Article  PubMed  CAS  Google Scholar 

  29. Biron C, Andreani H, Blanc P, et al.: Prevalence of antiphospholipid antibodies in patients with chronic liver disease related to alcohol or hepatitis C virus: correlation with liver injury. J Lab Clin Med 1998, 131:243–250.

    Article  PubMed  CAS  Google Scholar 

  30. Sthoeger ZM, Fogel M, Smirov A, et al.: Anticardiolipin autoantibodies in serum samples and cryoglobulins of patients with chronic hepatitis C infection. Ann Rheum Dis 2000, 59:483–486. This study showed a high prevalence of IgG aCL antibodies in HCV patients but with no b2-GPI dependence. Furthermore, it demonstrated the localization of aCL antibodies in some cryoprecipitates, suggesting reactivity of these antibodies with HCV epitopes, which can be found in the cryoprecipitates.

    Article  PubMed  CAS  Google Scholar 

  31. Matsuda J, Saitoh N, Gotoh M, et al.: High prevalence of antiphospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-a. Am J Gastroenterol 1995, 90:1138–1141.

    PubMed  CAS  Google Scholar 

  32. Ordi-Ros J, Villarreal J, Monegal F, et al.: Anticardiolipin antibodies in patients with chronic hepatitis C virus infection: characterization in relation to antiphospholipid syndrome. Clin Diagn Lab Immunol 2000, 7:241–244. This study reported a low prevalence of aCL antibodies in 243 patients with HCV (3.3%). In addition, no cross-reactivity between aCL antibodies and HCV antigens was found, suggesting that aCL antibodies in HCV infection are an epiphenomenon without any clinical significance.

    Article  PubMed  CAS  Google Scholar 

  33. Baid S, Pascual M, Williams WW, et al.: Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients. J Am Soc Nephrol 1999, 10:146–153.

    PubMed  CAS  Google Scholar 

  34. Harada M, Fujisawa Y, Sakisaka S, et al.: High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications. J Gastroenterol 2000, 35:272–277.

    Article  PubMed  CAS  Google Scholar 

  35. Mangia A, Margaglione M, Cascavilla I, et al.: Anticardiolipin antibodies in patients with liver disease. Am J Gastroenterol 1999, 94:2983–2987.

    Article  PubMed  CAS  Google Scholar 

  36. Giordano P, Galli M, Del Vecchio GC, et al.: Lupus anticoagulant, anticardiolipin antibodies and hepatitis C virus infection in thalassaemia. Br J Haematol 1998, 102:903–906.

    Article  PubMed  CAS  Google Scholar 

  37. Al-Saeed A, Makris M, Malia RG, et al.: The development of antiphospholipid antibodies in haemophilia is linked to infection with hepatitis C. Br J Haematol 1994, 88:845–848.

    PubMed  CAS  Google Scholar 

  38. Cacoub P, Musset L, Amoura Z, et al.: Anticardiolipin, anti-b2-glycoprotein I, and antinucleosome antibodies in hepatitis C virus infection and mixed cryoglobulinemia. J Rheumatol 1997, 24:139–144.

    Google Scholar 

  39. Gotoh M, Matsuda J: Human immunodeficiency virus rather than hepatitis C virus infection is relevant to the development of an anti-cardiolipin antibody. Am J Hematol 1995, 50:220–222.

    Article  PubMed  CAS  Google Scholar 

  40. Reber G, Arvieux J, Comby E, et al.: Multicenter evaluation of nine commercial kits for quantification of anticardiolipin antibodies. The Working Group on Methodologies in Haemostasis from the GEHT (Group d’Etudes sur l’Hemostase et la Thrombose). Thromb Haemost 1995, 73:444–452.

    PubMed  CAS  Google Scholar 

  41. Munoz-Rodriguez F, Tassies D, Font J, et al.: Prevalence of hepatitis C virus infection in patients with antiphospholipid syndrome. J Hepatol 1999, 30:770–773. In this study, the prevalence of HCV infection markers in 88 patients with APS was low and similar to that of healthy individuals, suggesting that HCV does not seem to be involved in the pathogenesis of this syndrome.

    Article  PubMed  CAS  Google Scholar 

  42. Shah NM, Khamashta MA, Atsumi T, et al.: Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998, 7:3–6.

    Article  PubMed  CAS  Google Scholar 

  43. McNally T, Purdy G, Mackie IJ, et al.: The use of an anti-b2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995, 91:471–473.

    PubMed  CAS  Google Scholar 

  44. Hunt JE, McNeil HP, Morgan GJ, et al.: A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992, 1:75–81.

    PubMed  CAS  Google Scholar 

  45. Forastiero RR, Martinuzzo ME, Kordich LC, et al.: Reactivity to beta 2 glycoprotein I clearly differentiates anticardiolipin antibodies from antiphospholipid syndrome and syphilis. Thromb Haemost 1996, 75:717–720.

    PubMed  CAS  Google Scholar 

  46. Sorice M, Pittoni V, Griggi T, et al.: Specificity of anti-phospholipid antibodies in infectious mononucleosis: a role for anti-cofactor protein antibodies. Clin Exp Immunol 2000, 120:301–306.

    Article  PubMed  CAS  Google Scholar 

  47. Mengarelli A, Minotti C, Palumbo G, et al.: High levels of antiphospholipid antibodies are associated with cytomegalovirus infection in unrelated bone marrow and cord blood allogeneic stem cell transplantation. Br J Haematol 2000, 108:126–131.

    Article  PubMed  CAS  Google Scholar 

  48. Louizou S, Cazabon JK, Walport MJ, et al.: Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus. Arthritis Rheum 1997, 40:103–108.

    Article  Google Scholar 

  49. Uthman I, Tabbarah Z, Gharavi AE: Hughes syndrome associated with cytomegalovirus infection. Lupus 1999, 8:775–777.

    Article  PubMed  CAS  Google Scholar 

  50. Labarca JA, Rabaggliati M, Radrigan FJ, et al.: Antiphospholipid syndrome associated with cytomegalovirus infection: case report and review. Clin Infect Dis 1997, 24:197–200.

    PubMed  CAS  Google Scholar 

  51. Yapez A, Cedillo L, Neyrolles O, et al.: Mycoplasma penetrans bacteremia and primary antiphospholipid syndrome. Emerg Infect Dis 1999, 5:164–167.

    Article  Google Scholar 

  52. Hayem G, Kassis N, Nicaise P, et al.: Systemic lupus erythematosus-associated catastrophic antiphospholipid syndrome occurring after typhoid fever: a possible role of Salmonella lipopolysaccharide in the occurrence of diffuse vasculopathycoagulopathy. Arthritis Rheum 1999, 42:1056–1061.

    Article  PubMed  CAS  Google Scholar 

  53. Blank M, George J, Fishman P, et al.: Ciprofloxacin immunomodulation of experimental antiphospholipid syndrome associated with elevation of interleukin-3 and granulocytemacrophage colony-stimulating factor expression. Arthritis Rheum 1998, 41:224–232.

    Article  PubMed  CAS  Google Scholar 

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Dalekos, G.N., Zachou, K. & Liaskos, C. The antiphospholipid syndrome and infection. Curr Rheumatol Rep 3, 277–285 (2001). https://doi.org/10.1007/s11926-001-0031-4

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