Lupus anticoagulants (LA) are antibodies directed against phospholipid-binding proteins that prolong phospholipid-dependent coagulation assays.1-3 Lupus anticoagulants derive their name from the fact that they were first observed in patients with systemic lupus erythematosus (SLE); however, the vast majority of individuals with lupus anticoagulants do not have SLE. These antibodies were referred to as anticoagulants because they delay clotting in in vitro clotting assays. It has subsequently been shown that lupus anticoagulants are associated with an increased clinical tendency toward thrombosis, not anticoagulation in vivo, making the name lupus anticoagulant a misnomer.1 While lupus anticoagulants are occasionally found in patients with arterial thrombosis, they are much more frequently observed in patients with venous thrombosis and/or resultant pulmonary embolism.4
In clot-based assays, lupus anticoagulants neutralize anionic phospholipids that are involved in the coagulation cascade. Coagulation screening assays, such as the activated partial thromboplastin time (aPTT), Russell viper venom time (RVVT), and prothrombin time (PT), can be affected by lupus anticoagulants. The extent of clotting time prolongation is highly dependent on the sensitivity of the reagent employed. Reagents with reduced amounts of phospholipid, such as the hexagonal phospholipid neutralization assay (Staclot LA®) and dilute Russell viper venom time (dRVVT), have enhanced sensitivity for lupus anticoagulants.2 The standard prothrombin time (PT) is rarely affected by lupus anticoagulants because of the high concentration of phospholipid in the reagent thromboplastin.3 Many lupus anticoagulants are discovered as the result of routine screening with the standard aPTT test−despite the fact that standard aPTT reagents are not as sensitive for lupus anticoagulants as other assays specifically designed for lupus anticoagulant detection.1,6
Due to the heterogeneity of lupus anticoagulant antibodies, no single assay identifies all cases. 2 The International Society on Thrombosis and Haemostasis (ISTH) has established criteria for the diagnosis of lupus anticoagulants, originally proposed in 1995 and revised in 2009. The ISTH has defined the minimum diagnostic criteria for lupus anticoagulants to include2,3,7:
- A prolonged clotting time in a screening assay, such as aPTT-LA or dRVVT
- Mixing studies indicating the presence of an inhibitor
- Positive confirmatory studies demonstrating phospholipid dependence of the inhibitor
- No evidence of other coagulopathies through the use of specific factor assays if the confirmatory step is negative or there is evidence of a specific factor inhibitor
The 2009 ISTH criteria also specify that integrated tests, which include screening and confirmation steps in a single test, do not require the performance of the mixing test and may be interpreted according to their defined cutoff values. Integrated tests include tests such as the dRVVT (paired screening and confirmation steps) and hexagonal phospholipid neutralization (Staclot LA®)2 Often the evaluation for lupus anticoagulants is confounded by an acute-phase response or anticoagulant therapy. This is particularly the case when a patient is hospitalized and started on anticoagulant therapy before samples for coagulation testing can be drawn. If the patient has acute thrombosis, many acute-phase proteins, such as fibrinogen, factor VIII, and C4B-binding protein, will be elevated and can affect coagulation assays.
The serendipitous detection of an extended aPTT during a preoperative screen should trigger a thorough review of the patient's history. Testing for antiphospholipid antibodies may not be indicated if the patient's clinical history is not suggestive of APS.1,3,6 Alternatively, an extended aPTT may be detected in an individual who presents with the clinical features consistent with APS. In this case, solid-phase ELISA tests for antiphospholipid antibodies should also be performed in order to establish or exclude the diagnosis. If the lupus anticoagulants or antiphospholipid antibody testing is positive, testing should be repeated in 12 or more weeks to confirm the persistence of the antibody.
Very rarely, individuals with lupus anticoagulants will present with an extended prothrombin time and significant clinical bleeding due to a decreased concentration of prothrombin.1-3,6 It is thought that the lupus anticoagulants in these individuals bind to prothrombin and cause it to be removed from the circulation. In these cases, lupus anticoagulants are not acting as inhibitors of prothrombin but are rather nonneutralizing antibodies. Unlike most patients with lupus anticoagulants, these patients will have an extended prothrombin time due to the prothrombin deficiency. Since these antiprothrombin antibodies are nonneutralizing, they cannot be detected with a normal plasma mixing study. When the prothrombin time is extended in a patient with evidence of lupus anticoagulants, antibodies to prothrombin should be considered in the differential diagnosis.
1. Triplett DA. Coagulation abnormalities. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Baltimore, Md: Lippincott Williams and Wilkins; 2002:1033-1049.
2. 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 Standardization Committee of the ISTH. Thromb Haemost. 1995; 74(4):1185-1190. PubMed 8560433
3. Alving BM. The antiphospholipid syndrome: Clinical presentation, diagnosis, and patient management. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis.Philadelphia, Pa: WB Saunders; 2002: 181-196.
4. Bick RL. Antiphospholipid thrombosis syndromes. Clin Appl Thromb Hemost. 2001 Oct; 7(4):241-258. PubMed 11697705
5. Liestol S, Jacobsen EM, Wisloff F. Dilute prothrombin tIme-based lupus ratio test. Integrated LA testing with recombinant tissue thromboplastin. Thromb Res. 2002; 105(2):177-182. PubMed 11958810
6. Hirsh J, Anand SS, Halperin JL, et al. Guide to anticoagulant therapy. Heparin: A statement for health care professionals from the American Heart Association. Circulation. 2001; 103(24):2994-3018.PubMed 11413093
7. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002; 346(10):752-763. PubMed 11882732