Prothrombin Antibodies, IgG

The antiphospholipid antibody syndrome (APS) is the most common acquired risk factor for thrombosis.^1-4 Individuals with APS have an increased risk for venous thrombosis, stroke, myocardial infarction, thromboembolism, thrombocytopenia, and/or recurrent miscarriages. Both clinical and laboratory features must be present for the diagnosis of APS to be made. Diagnostic tests for APS are based on the detection of autoantibodies directed against phospholipid-binding proteins. These autoantibodies can be measured directly by enzyme-linked immunoassays or indirectly, through their effect on clot-based coagulation assays. Lupus anticoagulants (LA) are a group of antiphospholipid autoantibodies that extend the clotting time of phospholipid-dependent clotting assays.^1,2 Unlike specific factor inhibitor antibodies that are associated with bleeding, LA are usually associated with increased risk of thrombosis. LA do not specifically inhibit individual coagulation factors; rather they neutralize anionic phospholipid-protein complexes that are involved in the coagulation process.

The most commonly detected antigenic protein targets associated with LA are β₂-glycoprotein 1 and prothrombin. Antibodies to prothrombin can be detected in as many as 66% of patients with LA.¹ Many patients will be positive for LA and one or both of the more common associated proteins (β₂-glycoprotein 1 and prothrombin). However, some patients with clinical symptoms of APS can be positive for prothrombin antibodies and negative for LA.^3,4 Several studies have revealed the presence of prothrombin antibodies, especially the IgG isotype, correlates with a history of venous thrombosis.^4,5 The IgG isotype of prothrombin antibody has also been shown to be associated with pregnancy loss.⁶

The majority of prothrombin antibodies are of low affinity.¹ However, some patients develop high affinity antibodies that complex with prothrombin and cause its rapid clearance from the bloodstream.³ The resulting reduction in prothrombin levels can lead to extended prothrombin times and abnormal bleeding in severe cases.³ Hypoprothrombinemia associated with prothrombin antibodies has been reported most frequently in children but has occasionally been seen in adults.²

Prolongation of clot-based assays by LA is highly dependent on the sensitivity of the reagent employed. Reagents with reduced amounts of phospholipid, such as the aPTT-LA and dilute Russell viper venom time (dRVVT), have enhanced sensitivity for LA. Studies have indicated that prothrombin antibodies exert their effect on in vitro clotting assays by inhibiting the activation of factor X and prothrombin.³

This effect is revealed most often by an extension of clotting tests that evaluate the entire intrinsic pathway, such as the aPTT-LA.³ Antibodies to β₂-glycoprotein 1 tend to have a stronger effect on the dRVVT assay than on other overall clotting assays.³ It should be noted that some prothrombin antibodies have no effect on in vitro clotting assays and can only be detected by the ELISA method.³

1. Triplett DA. Antiphospholipid antibodies. Arch Pathol Lab Med. 2002 Nov; 126(11):1424-1429. PubMed 12421152

2. Alving BM. Diagnosis and management of patients with the antiphospholipid syndrome. J Thromb Thrombolysis. 2001 Sep; 12(1):89-93. PubMed 11711694

3. Galli M. Anti-prothrombin antibodies. In Asherson RA, Cervera R, Piette JC, Shoenfeld Y, eds. The Antiphospholipid Syndrome II: Autoimmune Thrombosis. Elsevier. 2002:59-69.

4. de Groot PG, Horbach DA, Simmelink MJ, van oort E, Derksen RH. Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant. Lupus. 1998; 7(Suppl 2):S32-36. PubMed 9814669

5. Ishikura K, Wada H, Kamikura Y, et al. High prevalence of antiprothrombin antibody in patients with deep vein thrombosis. Am J Hematol. 2004 Aug; 76(4):338-342. PubMed 15282665

6. von Landenberg P, Matthias T, Zaech J, et al. Antiprothrombin antibodies are associated with pregnancy loss in patients with the antiphospholipid syndrome. Am J Reprod Immunol. 2003 Jan; 49(1):51-56. PubMed 12733594