Predicting Thrombosis in Systemic Lupus Erythematosus

Hans-Joachim Anders

Disclosures

Nat Clin Pract Nephrol. 2009;5(2):68-69. 

In This Article

Summary and Commentary

Summary

Biomarkers that reliably identify or even predict disease manifestations in systemic lupus erythematosus (SLE) are needed. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues reported on the predictive value of routine D-dimer measurements for future thromboembolic events in patients enrolled in the Ohio SLE study, a unique prospective, longitudinal evaluation of individuals with recurrently active SLE. As in other disease settings, low D-dimer levels (<0.5 µg/ml) excluded clotting at a given time point and identified a zero risk of future clotting events. Conversely, 42% of patients with a high D-dimer level (>2.0 µg/ml) subsequently experienced a clinically relevant clotting event, in some cases in the absence of antiphospholipid antibodies or lupus anticoagulant. This Practice Point commentary considers whether the D-dimer assay will remain simply a tool to rule out thrombosis in symptomatic patients with SLE or whether it could eventually be used to initiate preventive anticoagulation in asymptomatic patients.

Commentary

Clotting is a serious complication of systemic lupus erythematosus (SLE) for several reasons. First, clotting can cause persistent disability and death or fetal loss in pregnant women. Second, the clinical manifestations of clotting are often misleading in patients with SLE, leading to inappropriate drug use and delayed administration of anticoagulation. Third, although positive test results for antiphospholipid antibodies and lupus anticoagulant can predict lupus-associated disability,[1] routine tests that reliably predict clotting events in these individuals have not been established. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues sought to address this problem by evaluating the use of routinely measured D-dimer levels to predict clotting events in 100 consecutive patients enrolled in the Ohio SLE study.[2] The Ohio SLE study is a unique prospective, longitudinal evaluation of multiple biomarkers in patients with recurrently active SLE. Wu and colleagues hypothesized that elevated levels of D-dimer would predate and, therefore, predict clinical manifestations of thrombosis.

During follow-up, 15 of 100 patients assessed by Wu et al. exhibited signs or symptoms of incident thromboembolic events including pulmonary embolism, arterial thrombosis, unexplained hypoxic lung injury, microangiopathic antiphospholipid syndrome, Libman-Sacks endocarditis-related embolism, and thrombotic microangiopathic hemolytic anemia. The major conclusion of the authors was that all patients with SLE who experienced clotting had elevated D-dimer levels long before or shortly before the clinical diagnosis of the clotting event. Of the 15 patients who had evidence of thrombosis, 14 had D-dimer levels greater than 2.0 µg/ml (<0.5 µg/ml being considered a normal or negative result). By contrast, the presence of antiphospholipid antibodies or lupus anticoagulant could not reliably predict the time of clotting, as these markers were usually not abnormal within 6 months before the clinical diagnosis of the clotting event. However, combining the D-dimer assay results with measurements of these other two markers increased the sensitivity and specificity for prediction of a clotting event to 100% and 78%, respectively, with a positive predictive value of 0.5 and a negative predictive value of 1.0.

The negative predictive value of D-dimer levels reported by Wu et al. is in line with the results of previous studies that demonstrated the capacity of the D-dimer assay to exclude clotting at a given time point and to predict recurrent clotting events in other disease settings.[3] Hence, the D-dimer assay is potentially useful in the management of patients with SLE who present with symptoms such as shortness of breath, headache, atypical skin lesions, acrocyanosis, hemolysis, new-onset hypertension or decline of renal function, as the differential diagnosis of these conditions always includes clotting events. In such cases, a negative D-dimer assay result can rule out thrombosis as the cause of symptoms.

Furthermore, Wu et al. suggest that a positive D-dimer assay result predicts future clotting events in patients with SLE who lack symptoms of thrombosis. These authors report that a D-dimer level greater than 2.0 µg/ml was associated with a 42% risk of a future clotting event. However, their conclusion that elevated D-dimer levels discovered on routine measurements should lead to a careful evaluation for subclinical thrombosis is not fully supported by their data. Most patients with D-dimer levels greater than 2.0 µg/ml did not experience clotting during the observation period, or they had a positive test result years before clotting became evident. Furthermore, the clinical benefits of a predictive biomarker are most evident when the prevention of negative outcomes (e.g. clotting-related damage) by biomarker-based intervention (e.g. anticoagulation) outweighs the potential increase in complications caused by intervention (e.g. anticoagulation-associated bleeding). This issue was not addressed by Wu and colleagues. Finally, a more detailed analysis of the predictive value of D-dimer testing in the subgroups of patients with membranous lupus nephritis (n = 21) or nephrotic syndrome (n not reported) would have been interesting. Patients with nephrotic syndrome are at increased risk of thrombosis, and previous risk-benefit assessments support the use of oral anticoagulation in patients with nephrotic syndrome who have membranous glomerulonephritis and a serum albumin level of less than 20 g/l.[4] D-dimer assay results might, therefore, be of particular value in refining risk estimates of thrombosis in patients with nephrotic syndrome and membranous lupus nephritis.

The data presented by Wu et al. clearly support the use of the D-dimer assay to rule out clotting or to identify future clotting risk in patients with SLE. Whether positive D-dimer results can be cost-effectively and safely used as an indication for extended diagnostic tests or for preventive anticoagulation in patients with SLE who do not present with signs and symptoms of clotting events remains to be evaluated.

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