Background:In 2009, the International Society for Thrombosis and Hemostasis (ISTH) issued interpretative guidelines for the performance and interpretation of lupus anticoagulant testing, including the dilute Russell Viper venom test (RVVT). At UCSF, we noted that the manufacturer guidelines approved by the FDA were not equivalent to these ISTH guidelines. As a result, we report RVVT results as positive if both sets of criteria are met, equivocal if only one set of criteria is met, and negative if neither the manufacturer nor the ISTH criteria are met.
Study design:We performed a retrospective review of all RVVT testing at UCSF performed between 6/4/2011 and 7/3/2013. Patients who had a RVVT test performed within that time period were included in the study. For patients with a prolonged RVVT screening time, we gathered records of their previous and subsequent antiphospholipid syndrome (APS) testing at UCSF as well as any history of prolonged aPTT. These laboratory data were correlated with any clinical history of clotting, embolism, bleeding, pregnancy morbidity, systemic lupus erythematosus (SLE) and/or death. Clinical history was obtained through review of the UCSF electronic medical record. This study was approved by the UCSF institutional review board (Human Research Protection Program, Committee on Human Research). UCSF uses Precision Biologic (Halifax, Nova Scotia, Canada) LA Check and LA Sure reagents for the RVVT.
Findings:21.6% of RVVT tests showed a prolonged clotting time. Of these, 12% met only the ISTH criteria for the diagnosis of LA, 11% met only the manufacturer criteria, 37% were positive by both sets of criteria, and 40% were not positive by either set of criteria. When comparing the manufacturer and ISTH criteria for RVVT positivity, the latter were more predictive of a concomitant positive Staclot LA (Diagnotica Stago, Parsippany, NJ) result (Risk ratio 1.806 (95th CI 1.133-2.877)). When comparing the manufacturer and ISTH criteria for RVVT positivity, the latter was non-significantly associated with a positive aPL immunoassay result (Risk ratio 6.682 (95th CI 0.8965-49.8)). Patients with a positive RVVT result by only ISTH criteria, only manufacturer criteria, or both did not differ in their relative risk for thrombosis, pregnancy morbidity, systemic lupus erythematosus, or death.
If prolonged activated partial thromboplastin time was the only reason for testing, none of these patients subsequently were diagnosed with APS.
Patients with an initial positive RVVT who were retested according to ISTH recommendations had a significantly increased risk of being diagnosed with APS during our study period (RR 7.827, 95th CI 1.89-32.41) as compared to those patients without an initial positive RVVT. This indicates an RVVT sensitivity of 0.846 and specificity of 0.7 for a diagnosis of APS.
Of 26 patients who had a positive RVVT (regardless of Staclot LA result) and had repeat testing, 11 (42%) went on to meet APS criteria. Of 35 patients who had a positive Staclot LA (regardless of RVVT result) and had repeat testing, 13 (37%) went on to meet APS criteria. In contrast, very few patients with only a positive RVVT or only a positive Staclot-LA were diagnosed with APS (2 patients out of 47). Those patients who tested positive on both RVVT and Staclot LA were significantly more likely to have an APS diagnosis than those positive with Staclot LA alone (RR 6.531, 95th CI 1.69-25.25).
Conclusion: This observational study should help laboratorians and physicians better interpret the clinical significance of RVVT results. The ISTH guidelines for RVVT interpretation appear to better correlate with Staclot LA positivity. ISTH and manufacturer criteria do not differ in prediction of subsequent thrombosis, pregnancy morbidity, SLE, or death. Whereas the frequently used term "triple-positivity" in antiphospholipid testing implies significant clinical APS risk and is defined by a single positive lupus anticoagulant in the presence of both anticardiolipin and anti-β2-glycoprotein antibodies, we show that those patients with combined positivity for two lupus anticoagulant assays (both RVVT and Staclot LA) have a 6.5-fold higher risk of subsequent APS diagnosis than those with single lupus anticoagulant positivity.
Wool:Inova Diagnostics: Honoraria.
Asterisk with author names denotes non-ASH members.