Antiphospholipid antibodies (APA) bind to cardiolipin or to phospholipid-associated plasma proteins such as β2-glycoprotein I, prothrombin, or annexin V and can occur in a variety of medical conditions (including autoimmune diseases and syphilis) as well as in individuals without medical illness. APA are usually detected as antibodies against cardiolipin (ACA), β2-glycoprotein I (anti-β2GPI), or as a lupus anticoagulant (LA). Antiphospholipid Syndrome, by definition, meets at least one clinical criterion (thrombosis or pregnancy morbidity and lacking an alternative diagnosis to explain these findings) and one laboratory criterion present on two or more occasions at least 12 weeks apart from the initial presentation.1 This definition is recognized to have some diagnostic limitations, and controversy remains on the optimal laboratory testing and reporting of positive results. APA are thought to be a risk factor for recurrent venous thromboembolism (VTE),2 and if persistent, they are often considered an indication for indefinite anticoagulant therapy. However, the magnitude of this risk, whether the risk varies across different subtypes of APA, or whether the antibody testing was transiently or persistently positive, remains unclear.
Dr. Clive Kearon and colleagues addressed these uncertainties in a substudy3 of the recent prospective, blinded D-dimer Optimal Duration Study (DODS).4 DODS enrolled patients 18 to 75 years of age with a first unprovoked proximal deep vein thrombosis or pulmonary embolism who had received anticoagulant therapy for three to seven months and who had neither a strong contraindication to nor a need for ongoing anticoagulant therapy. At enrollment, all patients were taking anticoagulant therapy, and D-dimer was measured. Patients with a positive D-dimer test remained on anticoagulant therapy indefinitely. Patients with a negative D-dimer test stopped anticoagulation, and D-dimer testing was repeated one month later. If the second D-dimer test was positive, anticoagulant therapy was restarted. If the second D-dimer was negative, patients remained off anticoagulants indefinitely. The authors observed all patients to detect recurrent VTE in a standardized fashion.4
In the substudy conducted by Dr. Kearon and colleagues, APA were tested in 307 patients on the DODS. They determined whether APA were associated with recurrent thrombosis in the 290 patients who, according to protocol, stopped anticoagulant therapy following a negative D-dimer test. Analyses for APA and D-dimer were performed at enrollment, at one month, and at seven months . The observation period for recurrent VTE in individual patients could be as short as one month (negative D-dimer at enrollment and positive D-dimer at one month) or for the whole duration of the study (negative D-dimer both at enrollment and at one month). APA were assessed as anticardiolipin antibodies, anti-β2GP1 antibodies, and/or a lupus anticoagulant (lupus anticoagulants were measured only at time points when patients were off anticoagulation) and measured centrally. Criteria for a positive APA test were predefined . About 25 percent of patients were APA-positive on one or more occasion. The prevalence of an APA did not differ according to whether the index VTE occurred in a man, a woman who was not taking estrogen, or a woman who was taking estrogen.
Overall , the rate of recurrent VTE was 5.4 percent per person-year (ppy) while patients were not anticoagulated. The rate of recurrent VTE did not differ significantly between patients with any APA or with no APA (8.2% ppy in patients with any APA and 4.5% ppy in patients with no APA; HR, 1.8; 95%CI, 0.9-3.7; p=0.09). This observation held when the analysis excluded women with estrogen-associated VTE (10.5% ppy in patients with any APA and 5.4% ppy in patients with no APA; HR, 1.9; 95% CI, 0.9-3.7; p=0.08). The association between APA and recurrent VTE did not appear to be strongly influenced by the cutoff that was used to classify an APA result as positive.
Notably, among patients meeting the Sapporo-Sydney criteria for diagnosis of antiphospholipid syndrome (persistent APA),1 the rate of recurrent VTE was higher than among patients with transient APA (13.0% ppy in patients with one or more of the same type of APA on the two occasions tested and 6.4% ppy in patients with APA on one occasion; HR, 1.8; 95% CI, 0.6-5.5; p=0.28). These patients (with persistent APA) faced a hazard ratio of recurrent VTE of 2.7 compared to patients who had no APA (95% CI, 1.1-6.7; p=0.03). Patients whose APA testing results were characterized by the presence of two or three types of APA on the same or different occasions faced the highest risk of recurrent VTE (21.1% ppy vs. 6.6% ppy in patients with only one type of APA on one or more occasions; HR, 3.1; 95% CI, 0.9-10.0, p=0.06). These observations held when the analyses excluded women with estrogen-associated VTE.
In Brief
The current American College of Chest Physicians guidelines suggest indefinite anticoagulation for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism who are not at high risk for bleeding.5 This decision to anticoagulate indefinitely has to be individualized based on an assessment of the patient’s bleeding risk. The work reviewed here informs this complex and individualized risk-versus-benefit analysis by providing evidence supporting indefinite anticoagulant therapy in patients with unprovoked VTE with persistent APA or more than one type of APA who have stopped anticoagulant therapy in response to a negative D-dimer result.
References
Competing Interests
Dr. Keel indicated no relevant conflicts of interest.
