Taipan snake venom time for antiphospholipid syndrome solves a 20‐year diagnostic challenge

Abstract

An 8-year-old boy presented with multiple episodes of erythematous painful necrotic eruptions since the age of 18 months. The lesions had initially developed on the patient's heels and toes (Fig. 1), and over time had also started to involve his ears, inner thighs and hips. During each episode, the lesions began as small purple macules, which increased in size during a few hours. The lesions were extremely painful and could persist for several months. They occurred more frequently and were more severe during the winter months. The child was otherwise healthy, and no relevant family history was reported.Extensive laboratory investigations (Table S1) for vasculitis and vasculopathy were performed. Vasculitis screens were negative. Fibrinogen, plasma viscosity, antithrombin, Protein S and Protein C levels were normal.Genetic testing found no evidence of prothrombin G20201A mutation. A heterozygous Factor V Leiden mutation was detected; however, as this confers only a slightly increased risk of thrombosis, it was felt that this mutation was insufficient to explain the full clinical presentation. 1 Cryoglobulinaemia, cryofibrinogenaemia and congenital thrombotic thrombocytopenic purpura were excluded. Screening tests for anticardiolipin and anti-b2-glycoprotein I antibodies were negative. Lupus anticoagulant (LA) was negative by three independent methods [dilute Russell viper venom time (dRVVT), kaolin clotting time and

International multicenter, multiplatform study to validate Taipan snake venom time as a lupus anticoagulant screening test with ecarin time as the confirmatory test: Communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies

“…There is no gold standard against which LA results can be verified as no single assay can detect every LA, so performance of TSVT/ET in detecting known LA necessarily employed the dRVVT and APTT pairing as a pseudo‐gold standard comparator. A large body of evidence attests to the diagnostic efficacy of the dRVVT and APTT pairing, yet it is not infallible because of between‐manufacturer variability of same‐type reagents, 6,25,38,41,54,55 and that some LA preferentially manifest in other assays 6,18,19,27,36,56–59 …”

“…Only 1.8% of LA‐negative nonanticoagulated patients were TSVT/ET positive, whereas 7.0% of non‐APS anticoagulated patients were TSVT/ET positive. Given that some of the anticoagulated patients were being treated for thromboses without previous testing for aPL, and that TSVT/ET has been shown to detect LA unreactive in dRVVT and APTT, at least some of the apparent false‐positives may have be genuine LA 19,27,56 …”

“…A large body of evidence attests to the diagnostic efficacy of the dRVVT and APTT pairing, yet it is not infallible because of between-manufacturer variability of same-type reagents, 6,25,38,41,54,55 and that some LA preferentially manifest in other assays. 6,18,19,27,36,[56][57][58][59] This introduces a selection bias potentially disadvantaging assays evaluated against dRVVT and APTT because they may, in part, be sensitive to different antibody subpopulations. Taking that into account, the 72.1% sensitivity of TSVT/ET to all the LA was good and comparable to, or better, than that reported for some dRVVT reagents in comparison studies.…”

“…Only 1.8% of LA-negative nonanticoagulated patients were TSVT/ET positive, whereas 7.0% of non-APS anticoagulated patients were TSVT/ET positive. Given that some of the anticoagulated patients were being treated for thromboses without previous testing for aPL, and that TSVT/ET has been shown to detect LA unreactive in dRVVT and APTT, at least some of the apparent falsepositives may have be genuine LA 19,27,56. Nonetheless, specificity was calculated by treating them as false-positives when they were, strictly speaking, merely dRVVT and APTT negative.Argatroban was not included in spiking experiments but the patient data indicate potential for false-negatives as argatroban concentration increases.…”

Direct oral anticoagulants‐Remove versus Taipan snake venom time for detection of a lupus anticoagulant in patients taking oral direct factor Xa inhibitors

“…The TSVT has been previously investigated as a method to detect an LA in patients on DFXaIs. 10 , 13 , 18 , 19 , 20 , 21 The advantage of a TSVT/ET assay is that no preanalytical inactivation step is necessary for LA detection on DFXaI because prothrombin activation bypasses the effects of factor Xa inhibitors. 13 The ISTH has previously issued guidance within this area and concluded that there was “no conclusive independent evidence reported on their diagnostic efficacy” and that studies had small numbers of patients mostly on rivaroxaban with challenges in kit standardization and availability likely to limit widespread utility and generalizability.…”