Prevalence of antibodies to prothrombin in solid phase (aPT) and to phosphatidylserine-prothrombin complex (aPS/PT) in patients with and without lupus anticoagulant

Summary

Antibodies to prothrombin in solid phase (aPT) and those to phosphatidiyserine- prothrombin complex (aPS/PT) have been suggested to strongly correlate with the presence of lupus anticoagulant (LA). As their clinical diagnostic value and true relationship with the LA remains elusive, we designed this study to evaluate the prevalence and significance of aPT and aPS/PT in a large cohort of patients with and without LA. Samples from 257 patients were included. aPT and aPS/PT were tested by ELISA. LA was tested as per the current criteria from the ISTH Subcommittee on LA-Phospholipid-dependent antibodies. aPS/PT and aPT were found in 51% and 32% of LA-positive (LA+ve) patients and in 22% and 28% of LA-negative (LA-ve) patients, respectively. Thrombosis, particularly venous thrombosis was associated with IgG aPT in the LA+ve group (p=0.0006) and in the LA-ve group (p=0.017). Antibodies to phosphatidylserine-prothrombin, either IgG and IgM were associated with thrombosis in general (p=0.0003) in particularly with venous thrombosis in the LA+ve group (p<0.0001 for IgG and p=0.025 for IgM; respectively) and the LA-ve group (p=0.028, 0.02 and 0.001, respectively). Further multivariate logistic regression analysis showed that LA and of IgG and/or IgM aPS/PT were independent risk factors for thrombosis and pregnancy loss. In conclusion, aPS/PT, but not aPT, are more frequently found in patients with LA. Their association with thrombosis seems to be independent of the presence of LA.

Keywords

Prothrombin - phosphatidylserine-prothrombin complex - lupus anticoagulant - antiphospholipid syndrome

• References

• 1 Galli M, Comfurius P, Maasen C. et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 336: 1544-1547.
• 2 McNeil HP, Simpson RJ, Chesterman CN. et al. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-bound inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124.
• 3 Arvieux J, Darnige L, Caron C. et al. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 1120-1125.
• 4 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-2157.
• 5 Galli M, Beretta G, Daldossi M. et al. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77: 486-491.
• 6 Atsumi T, Ieko M, Bertolaccini ML. et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43: 1982-1993.
• 7 Atsumi T, Amengual O, Yasuda S. et al. Antiprothrombin antibodies--are they worth assaying?. Thromb Res 2004; 114: 533-538.
• 8 Pengo V, Denas G, Bison E. et al. Prevalence and significance of anti-prothrombin (aPT) antibodies in patients with Lupus Anticoagulant (LA). Thromb Res 2010; 126: 150-153.
• 9 Brandt JT, Triplett DA, Alving B. et al. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74: 1185-1190.
• 10 Pengo V, Tripodi A, Reber G. et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 07: 1737-1740.
• 11 Thiagarajan P, Pengo V, Shapiro S. The use of dilute Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-874.
• 12 Bertolaccini ML, Atsumi T, Khamashta MA. et al. Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus. J Rheumatol 1998; 25: 1104-1108.
• 13 Bertolaccini ML, Atsumi T, Koike T. et al. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost 2005; 93: 289-297.
• 14 Lakos G, Favaloro EJ, Harris EN. et al. International consensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64: 1-10.
• 15 Pierangeli SS, de Groot PG, Dlott J. et al. ‘Criteria’ aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011; 20: 182-190.
• 16 Amengual O, Atsumi T, Khamashta MA. et al. Specificity of ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol 1996; 35: 1239-1243.
• 17 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; 04: 295-306.
• 18 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512-519.
• 19 Bevers EM, Galli M, Barbui T. et al. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 066: 629-632.
• 20 Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83: 2878-2892.
• 21 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.
• 22 Galli M, Luciani D, Bertolini G. et al. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003; 102: 2717-2723.
• 23 Forastiero R, Martinuzzo M, Pombo G. et al. A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost 2005; 03: 1231-1238.
• 24 Bizzaro N, Ghirardello A, Zampieri S. et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study. J Thromb Haemost 2007; 05: 1158-1164.
• 25 Funke A, Bertolaccini ML, Atsumi T. et al. Autoantibodies to prothrombin-phosphatidylserine complex: clinical significance in systemic lupus erythematosus. Arthritis Rheum 1998; 41: S240 (abstract)
• 26 Atsumi T, Koike T. Antiprothrombin antibody: why do we need more assays?. Lupus 2010; 19: 436-439.