Lupus anticoagulant, anticardiolipin antibodies, fetal loss, and systemic lupus erythematosus.

UPUS ANTICOAGULANTS (LA) and anticardioL lipin (ACL) antibodies (ACLA) belong to a heterogenous group of antibodies directed against negatively charged pho~pholipids.l-~ However, more recent studies would suggest that these antibodies are directed to epitopes of other proteins that are complexed with negatively charged phospholipid~>-~ Although antiphospholipid antibodies are frequently found in otherwise healthy persons, the presence of these antibodies is closely associated with the occurrence of arterial and venous thromboembolism, thrombocytopenia, fetal loss, and a variety of other conditions in patients with and without systemic lupus erythematosus (SLE).1-5 However, the nature of the association between antiphospholipid antibodies and these clinical events, and whether they are directly causative or rather represent a consequence of the clinical condition with no direct pathophysiologic role, is unknown. ACLA are usually detected by solid-phase immunoassays, whereas the LA is measured as an activity that prolongs lipid-dependent clotting reactions assayed by coagulation Because both antibodies react with phospholipids and are frequently found in the plasma of the same patients, it has been suggested that they are identical.1° However, in a number of studies, ACLA can be separated from LA activity, and in many patients the activities are discordant.11-17 Therefore, performing assays for both types of antiphospholipid antibodies in a given patient maximizes the likelihood of detecting these activities. Although testing for ACLA is now well standardized: tests for LA have not been well standardized, and there is no established reliable method for their quantitation. Many tests for the detection of LA activity have been but there is little agreement among workers in the field regarding the optimum test for detecting LA activity.l8 However, it is generally agreed that coagulation assays with either dilute or no phospholipid are the most sensitive,l8-*l whereas correction of the prolonged clotting time by added phospholipid increases specificity.2,22 Moreover, all plasma used in testing should be centrifuged at 5 to 15,OOOg for 10 to 15 minutes or filtered to render them platelet free and avoid activity that can neutralize the LA.21,22 Although it has been recognized that LA and ACLA activity can fluctuate in a given patient over time, similar to other au t~ant ibodies ,~~ correlation of clinical events with the presence of these antibodies in patients with or without SLE is very meager. Recently, in an attempt to answer this question, Long et aIz3 performed a cross-sectional study of 69 unselected consecutive patients with SLE using five coagulation assays for the LA and an enzyme-linked immunosorbent assay (ELISA) for ACLA. These tests were measured on two separate occasions and then correlated with specific objective criteria for the diagnosis of venous and/or arterial thromboembolic disorders. The patients were considered to be persistently psotive for the LA if one or more of the coagulation tests was positive on both occasions, transiently positive if one or more was positive on one occasion and all tests were negative on the other, and negative if all five tests were normal on both occasions. Patients were considered to be persistently positive for ACLA if the IgG and/or IgM assays were positive on both occasions, whereas they were considered to be transiently positive if the test was positive on one occasion and negative on the other. Twenty-four of the 69 patients (34.8%) were persistently LA positive, 7 (10%) were transiently positive, and 38 (55.1%) were persistently negative. Fourteen of the 24 patients who had persistently positive LA tests had different profiles of positivity with respect to the five clotting assays used at different times. Fifteen of the 69 patients (21.7%) were ACLA positive, 14 (24.3%) were transiently positive, and 40 (58%) were persistently negative. Statistically significant associations were shown between prior thromboembolic events and positive ACLA alone and both LA and ACL positivity, whereas there was an insignificant trend between thromboembolism and LA positivity alone. Interestingly, the strength of the association between LAIACLA positivity was much reduced when transiently positive patients were included as positive. In this study, there was no coagulation test that best correlated with thromboembolic events, and the results of the same LA clotting test and the ELISA for ACLA changed frequently in individual patients. In this issue of Blood,24 the same group who performed the above study applied a similar investigative design in an attempt to determine whether an association exists between fetal loss and the presence of antiphospholipid antibodies in patients with SLE. Although several studies have suggested such a relationship in patients with SLE, a recent review of the published studies could not unequivocally establish a definite association.B Moreover, in a recent well-controlled prospective cohort study in patients without SLE presenting with an initial episode of fetal loss, no relationship could be established between the presence of antiphospholipid antibodies and fetal loss.26 In the study published in this issue, 42 consecutive patients with SLE with 122 pregnancies and with a history of at least one pregnancy loss were studied; 11 had a history of one pregnancy loss and 7 had two or more pregnancy losses. A history of pregnancy loss occurred in 24 of the 55 pregnancies in patients with persistent LA positivity compared with